a literature review on impact of covid 19

• Research article
• Open access
• Published: 04 June 2021

Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews

• Israel Júnior Borges do Nascimento 1 , 2 ,
• Dónal P. O’Mathúna 3 , 4 ,
• Thilo Caspar von Groote 5 ,
• Hebatullah Mohamed Abdulazeem 6 ,
• Ishanka Weerasekara 7 , 8 ,
• Ana Marusic 9 ,
• Livia Puljak   ORCID: orcid.org/0000-0002-8467-6061 10 ,
• Vinicius Tassoni Civile 11 ,
• Irena Zakarija-Grkovic 9 ,
• Tina Poklepovic Pericic 9 ,
• Alvaro Nagib Atallah 11 ,
• Santino Filoso 12 ,
• Nicola Luigi Bragazzi 13 &
• Milena Soriano Marcolino 1

On behalf of the International Network of Coronavirus Disease 2019 (InterNetCOVID-19)

BMC Infectious Diseases volume  21 , Article number:  525 ( 2021 ) Cite this article

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Navigating the rapidly growing body of scientific literature on the SARS-CoV-2 pandemic is challenging, and ongoing critical appraisal of this output is essential. We aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Nine databases (Medline, EMBASE, Cochrane Library, CINAHL, Web of Sciences, PDQ-Evidence, WHO’s Global Research, LILACS, and Epistemonikos) were searched from December 1, 2019, to March 24, 2020. Systematic reviews analyzing primary studies of COVID-19 were included. Two authors independently undertook screening, selection, extraction (data on clinical symptoms, prevalence, pharmacological and non-pharmacological interventions, diagnostic test assessment, laboratory, and radiological findings), and quality assessment (AMSTAR 2). A meta-analysis was performed of the prevalence of clinical outcomes.

Eighteen systematic reviews were included; one was empty (did not identify any relevant study). Using AMSTAR 2, confidence in the results of all 18 reviews was rated as “critically low”. Identified symptoms of COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%) and gastrointestinal complaints (5–9%). Severe symptoms were more common in men. Elevated C-reactive protein and lactate dehydrogenase, and slightly elevated aspartate and alanine aminotransferase, were commonly described. Thrombocytopenia and elevated levels of procalcitonin and cardiac troponin I were associated with severe disease. A frequent finding on chest imaging was uni- or bilateral multilobar ground-glass opacity. A single review investigated the impact of medication (chloroquine) but found no verifiable clinical data. All-cause mortality ranged from 0.3 to 13.9%.

Conclusions

In this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic were of questionable usefulness. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards.

Peer Review reports

The spread of the “Severe Acute Respiratory Coronavirus 2” (SARS-CoV-2), the causal agent of COVID-19, was characterized as a pandemic by the World Health Organization (WHO) in March 2020 and has triggered an international public health emergency [ 1 ]. The numbers of confirmed cases and deaths due to COVID-19 are rapidly escalating, counting in millions [ 2 ], causing massive economic strain, and escalating healthcare and public health expenses [ 3 , 4 ].

The research community has responded by publishing an impressive number of scientific reports related to COVID-19. The world was alerted to the new disease at the beginning of 2020 [ 1 ], and by mid-March 2020, more than 2000 articles had been published on COVID-19 in scholarly journals, with 25% of them containing original data [ 5 ]. The living map of COVID-19 evidence, curated by the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre), contained more than 40,000 records by February 2021 [ 6 ]. More than 100,000 records on PubMed were labeled as “SARS-CoV-2 literature, sequence, and clinical content” by February 2021 [ 7 ].

Due to publication speed, the research community has voiced concerns regarding the quality and reproducibility of evidence produced during the COVID-19 pandemic, warning of the potential damaging approach of “publish first, retract later” [ 8 ]. It appears that these concerns are not unfounded, as it has been reported that COVID-19 articles were overrepresented in the pool of retracted articles in 2020 [ 9 ]. These concerns about inadequate evidence are of major importance because they can lead to poor clinical practice and inappropriate policies [ 10 ].

Systematic reviews are a cornerstone of today’s evidence-informed decision-making. By synthesizing all relevant evidence regarding a particular topic, systematic reviews reflect the current scientific knowledge. Systematic reviews are considered to be at the highest level in the hierarchy of evidence and should be used to make informed decisions. However, with high numbers of systematic reviews of different scope and methodological quality being published, overviews of multiple systematic reviews that assess their methodological quality are essential [ 11 , 12 , 13 ]. An overview of systematic reviews helps identify and organize the literature and highlights areas of priority in decision-making.

In this overview of systematic reviews, we aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Methodology

Research question.

This overview’s primary objective was to summarize and critically appraise systematic reviews that assessed any type of primary clinical data from patients infected with SARS-CoV-2. Our research question was purposefully broad because we wanted to analyze as many systematic reviews as possible that were available early following the COVID-19 outbreak.

Study design

We conducted an overview of systematic reviews. The idea for this overview originated in a protocol for a systematic review submitted to PROSPERO (CRD42020170623), which indicated a plan to conduct an overview.

Overviews of systematic reviews use explicit and systematic methods for searching and identifying multiple systematic reviews addressing related research questions in the same field to extract and analyze evidence across important outcomes. Overviews of systematic reviews are in principle similar to systematic reviews of interventions, but the unit of analysis is a systematic review [ 14 , 15 , 16 ].

We used the overview methodology instead of other evidence synthesis methods to allow us to collate and appraise multiple systematic reviews on this topic, and to extract and analyze their results across relevant topics [ 17 ]. The overview and meta-analysis of systematic reviews allowed us to investigate the methodological quality of included studies, summarize results, and identify specific areas of available or limited evidence, thereby strengthening the current understanding of this novel disease and guiding future research [ 13 ].

A reporting guideline for overviews of reviews is currently under development, i.e., Preferred Reporting Items for Overviews of Reviews (PRIOR) [ 18 ]. As the PRIOR checklist is still not published, this study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 statement [ 19 ]. The methodology used in this review was adapted from the Cochrane Handbook for Systematic Reviews of Interventions and also followed established methodological considerations for analyzing existing systematic reviews [ 14 ].

Approval of a research ethics committee was not necessary as the study analyzed only publicly available articles.

Eligibility criteria

Systematic reviews were included if they analyzed primary data from patients infected with SARS-CoV-2 as confirmed by RT-PCR or another pre-specified diagnostic technique. Eligible reviews covered all topics related to COVID-19 including, but not limited to, those that reported clinical symptoms, diagnostic methods, therapeutic interventions, laboratory findings, or radiological results. Both full manuscripts and abbreviated versions, such as letters, were eligible.

No restrictions were imposed on the design of the primary studies included within the systematic reviews, the last search date, whether the review included meta-analyses or language. Reviews related to SARS-CoV-2 and other coronaviruses were eligible, but from those reviews, we analyzed only data related to SARS-CoV-2.

No consensus definition exists for a systematic review [ 20 ], and debates continue about the defining characteristics of a systematic review [ 21 ]. Cochrane’s guidance for overviews of reviews recommends setting pre-established criteria for making decisions around inclusion [ 14 ]. That is supported by a recent scoping review about guidance for overviews of systematic reviews [ 22 ].

Thus, for this study, we defined a systematic review as a research report which searched for primary research studies on a specific topic using an explicit search strategy, had a detailed description of the methods with explicit inclusion criteria provided, and provided a summary of the included studies either in narrative or quantitative format (such as a meta-analysis). Cochrane and non-Cochrane systematic reviews were considered eligible for inclusion, with or without meta-analysis, and regardless of the study design, language restriction and methodology of the included primary studies. To be eligible for inclusion, reviews had to be clearly analyzing data related to SARS-CoV-2 (associated or not with other viruses). We excluded narrative reviews without those characteristics as these are less likely to be replicable and are more prone to bias.

Scoping reviews and rapid reviews were eligible for inclusion in this overview if they met our pre-defined inclusion criteria noted above. We included reviews that addressed SARS-CoV-2 and other coronaviruses if they reported separate data regarding SARS-CoV-2.

Information sources

Nine databases were searched for eligible records published between December 1, 2019, and March 24, 2020: Cochrane Database of Systematic Reviews via Cochrane Library, PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Sciences, LILACS (Latin American and Caribbean Health Sciences Literature), PDQ-Evidence, WHO’s Global Research on Coronavirus Disease (COVID-19), and Epistemonikos.

The comprehensive search strategy for each database is provided in Additional file 1 and was designed and conducted in collaboration with an information specialist. All retrieved records were primarily processed in EndNote, where duplicates were removed, and records were then imported into the Covidence platform [ 23 ]. In addition to database searches, we screened reference lists of reviews included after screening records retrieved via databases.

Study selection

All searches, screening of titles and abstracts, and record selection, were performed independently by two investigators using the Covidence platform [ 23 ]. Articles deemed potentially eligible were retrieved for full-text screening carried out independently by two investigators. Discrepancies at all stages were resolved by consensus. During the screening, records published in languages other than English were translated by a native/fluent speaker.

Data collection process

We custom designed a data extraction table for this study, which was piloted by two authors independently. Data extraction was performed independently by two authors. Conflicts were resolved by consensus or by consulting a third researcher.

We extracted the following data: article identification data (authors’ name and journal of publication), search period, number of databases searched, population or settings considered, main results and outcomes observed, and number of participants. From Web of Science (Clarivate Analytics, Philadelphia, PA, USA), we extracted journal rank (quartile) and Journal Impact Factor (JIF).

We categorized the following as primary outcomes: all-cause mortality, need for and length of mechanical ventilation, length of hospitalization (in days), admission to intensive care unit (yes/no), and length of stay in the intensive care unit.

The following outcomes were categorized as exploratory: diagnostic methods used for detection of the virus, male to female ratio, clinical symptoms, pharmacological and non-pharmacological interventions, laboratory findings (full blood count, liver enzymes, C-reactive protein, d-dimer, albumin, lipid profile, serum electrolytes, blood vitamin levels, glucose levels, and any other important biomarkers), and radiological findings (using radiography, computed tomography, magnetic resonance imaging or ultrasound).

We also collected data on reporting guidelines and requirements for the publication of systematic reviews and meta-analyses from journal websites where included reviews were published.

Quality assessment in individual reviews

Two researchers independently assessed the reviews’ quality using the “A MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2)”. We acknowledge that the AMSTAR 2 was created as “a critical appraisal tool for systematic reviews that include randomized or non-randomized studies of healthcare interventions, or both” [ 24 ]. However, since AMSTAR 2 was designed for systematic reviews of intervention trials, and we included additional types of systematic reviews, we adjusted some AMSTAR 2 ratings and reported these in Additional file 2 .

Adherence to each item was rated as follows: yes, partial yes, no, or not applicable (such as when a meta-analysis was not conducted). The overall confidence in the results of the review is rated as “critically low”, “low”, “moderate” or “high”, according to the AMSTAR 2 guidance based on seven critical domains, which are items 2, 4, 7, 9, 11, 13, 15 as defined by AMSTAR 2 authors [ 24 ]. We reported our adherence ratings for transparency of our decision with accompanying explanations, for each item, in each included review.

One of the included systematic reviews was conducted by some members of this author team [ 25 ]. This review was initially assessed independently by two authors who were not co-authors of that review to prevent the risk of bias in assessing this study.

Synthesis of results

For data synthesis, we prepared a table summarizing each systematic review. Graphs illustrating the mortality rate and clinical symptoms were created. We then prepared a narrative summary of the methods, findings, study strengths, and limitations.

For analysis of the prevalence of clinical outcomes, we extracted data on the number of events and the total number of patients to perform proportional meta-analysis using RStudio© software, with the “meta” package (version 4.9–6), using the “metaprop” function for reviews that did not perform a meta-analysis, excluding case studies because of the absence of variance. For reviews that did not perform a meta-analysis, we presented pooled results of proportions with their respective confidence intervals (95%) by the inverse variance method with a random-effects model, using the DerSimonian-Laird estimator for τ 2 . We adjusted data using Freeman-Tukey double arcosen transformation. Confidence intervals were calculated using the Clopper-Pearson method for individual studies. We created forest plots using the RStudio© software, with the “metafor” package (version 2.1–0) and “forest” function.

Managing overlapping systematic reviews

Some of the included systematic reviews that address the same or similar research questions may include the same primary studies in overviews. Including such overlapping reviews may introduce bias when outcome data from the same primary study are included in the analyses of an overview multiple times. Thus, in summaries of evidence, multiple-counting of the same outcome data will give data from some primary studies too much influence [ 14 ]. In this overview, we did not exclude overlapping systematic reviews because, according to Cochrane’s guidance, it may be appropriate to include all relevant reviews’ results if the purpose of the overview is to present and describe the current body of evidence on a topic [ 14 ]. To avoid any bias in summary estimates associated with overlapping reviews, we generated forest plots showing data from individual systematic reviews, but the results were not pooled because some primary studies were included in multiple reviews.

Our search retrieved 1063 publications, of which 175 were duplicates. Most publications were excluded after the title and abstract analysis ( n = 860). Among the 28 studies selected for full-text screening, 10 were excluded for the reasons described in Additional file 3 , and 18 were included in the final analysis (Fig. 1 ) [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Reference list screening did not retrieve any additional systematic reviews.

PRISMA flow diagram

Characteristics of included reviews

Summary features of 18 systematic reviews are presented in Table 1 . They were published in 14 different journals. Only four of these journals had specific requirements for systematic reviews (with or without meta-analysis): European Journal of Internal Medicine, Journal of Clinical Medicine, Ultrasound in Obstetrics and Gynecology, and Clinical Research in Cardiology . Two journals reported that they published only invited reviews ( Journal of Medical Virology and Clinica Chimica Acta ). Three systematic reviews in our study were published as letters; one was labeled as a scoping review and another as a rapid review (Table 2 ).

All reviews were published in English, in first quartile (Q1) journals, with JIF ranging from 1.692 to 6.062. One review was empty, meaning that its search did not identify any relevant studies; i.e., no primary studies were included [ 36 ]. The remaining 17 reviews included 269 unique studies; the majority ( N = 211; 78%) were included in only a single review included in our study (range: 1 to 12). Primary studies included in the reviews were published between December 2019 and March 18, 2020, and comprised case reports, case series, cohorts, and other observational studies. We found only one review that included randomized clinical trials [ 38 ]. In the included reviews, systematic literature searches were performed from 2019 (entire year) up to March 9, 2020. Ten systematic reviews included meta-analyses. The list of primary studies found in the included systematic reviews is shown in Additional file 4 , as well as the number of reviews in which each primary study was included.

Population and study designs

Most of the reviews analyzed data from patients with COVID-19 who developed pneumonia, acute respiratory distress syndrome (ARDS), or any other correlated complication. One review aimed to evaluate the effectiveness of using surgical masks on preventing transmission of the virus [ 36 ], one review was focused on pediatric patients [ 34 ], and one review investigated COVID-19 in pregnant women [ 37 ]. Most reviews assessed clinical symptoms, laboratory findings, or radiological results.

Systematic review findings

The summary of findings from individual reviews is shown in Table 2 . Overall, all-cause mortality ranged from 0.3 to 13.9% (Fig. 2 ).

A meta-analysis of the prevalence of mortality

Clinical symptoms

Seven reviews described the main clinical manifestations of COVID-19 [ 26 , 28 , 29 , 34 , 35 , 39 , 41 ]. Three of them provided only a narrative discussion of symptoms [ 26 , 34 , 35 ]. In the reviews that performed a statistical analysis of the incidence of different clinical symptoms, symptoms in patients with COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%), gastrointestinal disorders, such as diarrhea, nausea or vomiting (5.0–9.0%), and others (including, in one study only: dizziness 12.1%) (Figs. 3 , 4 , 5 , 6 , 7 , 8 and 9 ). Three reviews assessed cough with and without sputum together; only one review assessed sputum production itself (28.5%).

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

Three reviews described methodologies, protocols, and tools used for establishing the diagnosis of COVID-19 [ 26 , 34 , 38 ]. The use of respiratory swabs (nasal or pharyngeal) or blood specimens to assess the presence of SARS-CoV-2 nucleic acid using RT-PCR assays was the most commonly used diagnostic method mentioned in the included studies. These diagnostic tests have been widely used, but their precise sensitivity and specificity remain unknown. One review included a Chinese study with clinical diagnosis with no confirmation of SARS-CoV-2 infection (patients were diagnosed with COVID-19 if they presented with at least two symptoms suggestive of COVID-19, together with laboratory and chest radiography abnormalities) [ 34 ].

Therapeutic possibilities

Pharmacological and non-pharmacological interventions (supportive therapies) used in treating patients with COVID-19 were reported in five reviews [ 25 , 27 , 34 , 35 , 38 ]. Antivirals used empirically for COVID-19 treatment were reported in seven reviews [ 25 , 27 , 34 , 35 , 37 , 38 , 41 ]; most commonly used were protease inhibitors (lopinavir, ritonavir, darunavir), nucleoside reverse transcriptase inhibitor (tenofovir), nucleotide analogs (remdesivir, galidesivir, ganciclovir), and neuraminidase inhibitors (oseltamivir). Umifenovir, a membrane fusion inhibitor, was investigated in two studies [ 25 , 35 ]. Possible supportive interventions analyzed were different types of oxygen supplementation and breathing support (invasive or non-invasive ventilation) [ 25 ]. The use of antibiotics, both empirically and to treat secondary pneumonia, was reported in six studies [ 25 , 26 , 27 , 34 , 35 , 38 ]. One review specifically assessed evidence on the efficacy and safety of the anti-malaria drug chloroquine [ 27 ]. It identified 23 ongoing trials investigating the potential of chloroquine as a therapeutic option for COVID-19, but no verifiable clinical outcomes data. The use of mesenchymal stem cells, antifungals, and glucocorticoids were described in four reviews [ 25 , 34 , 35 , 38 ].

Laboratory and radiological findings

Of the 18 reviews included in this overview, eight analyzed laboratory parameters in patients with COVID-19 [ 25 , 29 , 30 , 32 , 33 , 34 , 35 , 39 ]; elevated C-reactive protein levels, associated with lymphocytopenia, elevated lactate dehydrogenase, as well as slightly elevated aspartate and alanine aminotransferase (AST, ALT) were commonly described in those eight reviews. Lippi et al. assessed cardiac troponin I (cTnI) [ 25 ], procalcitonin [ 32 ], and platelet count [ 33 ] in COVID-19 patients. Elevated levels of procalcitonin [ 32 ] and cTnI [ 30 ] were more likely to be associated with a severe disease course (requiring intensive care unit admission and intubation). Furthermore, thrombocytopenia was frequently observed in patients with complicated COVID-19 infections [ 33 ].

Chest imaging (chest radiography and/or computed tomography) features were assessed in six reviews, all of which described a frequent pattern of local or bilateral multilobar ground-glass opacity [ 25 , 34 , 35 , 39 , 40 , 41 ]. Those six reviews showed that septal thickening, bronchiectasis, pleural and cardiac effusions, halo signs, and pneumothorax were observed in patients suffering from COVID-19.

Quality of evidence in individual systematic reviews

Table 3 shows the detailed results of the quality assessment of 18 systematic reviews, including the assessment of individual items and summary assessment. A detailed explanation for each decision in each review is available in Additional file 5 .

Using AMSTAR 2 criteria, confidence in the results of all 18 reviews was rated as “critically low” (Table 3 ). Common methodological drawbacks were: omission of prospective protocol submission or publication; use of inappropriate search strategy: lack of independent and dual literature screening and data-extraction (or methodology unclear); absence of an explanation for heterogeneity among the studies included; lack of reasons for study exclusion (or rationale unclear).

Risk of bias assessment, based on a reported methodological tool, and quality of evidence appraisal, in line with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method, were reported only in one review [ 25 ]. Five reviews presented a table summarizing bias, using various risk of bias tools [ 25 , 29 , 39 , 40 , 41 ]. One review analyzed “study quality” [ 37 ]. One review mentioned the risk of bias assessment in the methodology but did not provide any related analysis [ 28 ].

This overview of systematic reviews analyzed the first 18 systematic reviews published after the onset of the COVID-19 pandemic, up to March 24, 2020, with primary studies involving more than 60,000 patients. Using AMSTAR-2, we judged that our confidence in all those reviews was “critically low”. Ten reviews included meta-analyses. The reviews presented data on clinical manifestations, laboratory and radiological findings, and interventions. We found no systematic reviews on the utility of diagnostic tests.

Symptoms were reported in seven reviews; most of the patients had a fever, cough, dyspnea, myalgia or muscle fatigue, and gastrointestinal disorders such as diarrhea, nausea, or vomiting. Olfactory dysfunction (anosmia or dysosmia) has been described in patients infected with COVID-19 [ 43 ]; however, this was not reported in any of the reviews included in this overview. During the SARS outbreak in 2002, there were reports of impairment of the sense of smell associated with the disease [ 44 , 45 ].

The reported mortality rates ranged from 0.3 to 14% in the included reviews. Mortality estimates are influenced by the transmissibility rate (basic reproduction number), availability of diagnostic tools, notification policies, asymptomatic presentations of the disease, resources for disease prevention and control, and treatment facilities; variability in the mortality rate fits the pattern of emerging infectious diseases [ 46 ]. Furthermore, the reported cases did not consider asymptomatic cases, mild cases where individuals have not sought medical treatment, and the fact that many countries had limited access to diagnostic tests or have implemented testing policies later than the others. Considering the lack of reviews assessing diagnostic testing (sensitivity, specificity, and predictive values of RT-PCT or immunoglobulin tests), and the preponderance of studies that assessed only symptomatic individuals, considerable imprecision around the calculated mortality rates existed in the early stage of the COVID-19 pandemic.

Few reviews included treatment data. Those reviews described studies considered to be at a very low level of evidence: usually small, retrospective studies with very heterogeneous populations. Seven reviews analyzed laboratory parameters; those reviews could have been useful for clinicians who attend patients suspected of COVID-19 in emergency services worldwide, such as assessing which patients need to be reassessed more frequently.

All systematic reviews scored poorly on the AMSTAR 2 critical appraisal tool for systematic reviews. Most of the original studies included in the reviews were case series and case reports, impacting the quality of evidence. Such evidence has major implications for clinical practice and the use of these reviews in evidence-based practice and policy. Clinicians, patients, and policymakers can only have the highest confidence in systematic review findings if high-quality systematic review methodologies are employed. The urgent need for information during a pandemic does not justify poor quality reporting.

We acknowledge that there are numerous challenges associated with analyzing COVID-19 data during a pandemic [ 47 ]. High-quality evidence syntheses are needed for decision-making, but each type of evidence syntheses is associated with its inherent challenges.

The creation of classic systematic reviews requires considerable time and effort; with massive research output, they quickly become outdated, and preparing updated versions also requires considerable time. A recent study showed that updates of non-Cochrane systematic reviews are published a median of 5 years after the publication of the previous version [ 48 ].

Authors may register a review and then abandon it [ 49 ], but the existence of a public record that is not updated may lead other authors to believe that the review is still ongoing. A quarter of Cochrane review protocols remains unpublished as completed systematic reviews 8 years after protocol publication [ 50 ].

Rapid reviews can be used to summarize the evidence, but they involve methodological sacrifices and simplifications to produce information promptly, with inconsistent methodological approaches [ 51 ]. However, rapid reviews are justified in times of public health emergencies, and even Cochrane has resorted to publishing rapid reviews in response to the COVID-19 crisis [ 52 ]. Rapid reviews were eligible for inclusion in this overview, but only one of the 18 reviews included in this study was labeled as a rapid review.

Ideally, COVID-19 evidence would be continually summarized in a series of high-quality living systematic reviews, types of evidence synthesis defined as “ a systematic review which is continually updated, incorporating relevant new evidence as it becomes available ” [ 53 ]. However, conducting living systematic reviews requires considerable resources, calling into question the sustainability of such evidence synthesis over long periods [ 54 ].

Research reports about COVID-19 will contribute to research waste if they are poorly designed, poorly reported, or simply not necessary. In principle, systematic reviews should help reduce research waste as they usually provide recommendations for further research that is needed or may advise that sufficient evidence exists on a particular topic [ 55 ]. However, systematic reviews can also contribute to growing research waste when they are not needed, or poorly conducted and reported. Our present study clearly shows that most of the systematic reviews that were published early on in the COVID-19 pandemic could be categorized as research waste, as our confidence in their results is critically low.

Our study has some limitations. One is that for AMSTAR 2 assessment we relied on information available in publications; we did not attempt to contact study authors for clarifications or additional data. In three reviews, the methodological quality appraisal was challenging because they were published as letters, or labeled as rapid communications. As a result, various details about their review process were not included, leading to AMSTAR 2 questions being answered as “not reported”, resulting in low confidence scores. Full manuscripts might have provided additional information that could have led to higher confidence in the results. In other words, low scores could reflect incomplete reporting, not necessarily low-quality review methods. To make their review available more rapidly and more concisely, the authors may have omitted methodological details. A general issue during a crisis is that speed and completeness must be balanced. However, maintaining high standards requires proper resourcing and commitment to ensure that the users of systematic reviews can have high confidence in the results.

Furthermore, we used adjusted AMSTAR 2 scoring, as the tool was designed for critical appraisal of reviews of interventions. Some reviews may have received lower scores than actually warranted in spite of these adjustments.

Another limitation of our study may be the inclusion of multiple overlapping reviews, as some included reviews included the same primary studies. According to the Cochrane Handbook, including overlapping reviews may be appropriate when the review’s aim is “ to present and describe the current body of systematic review evidence on a topic ” [ 12 ], which was our aim. To avoid bias with summarizing evidence from overlapping reviews, we presented the forest plots without summary estimates. The forest plots serve to inform readers about the effect sizes for outcomes that were reported in each review.

Several authors from this study have contributed to one of the reviews identified [ 25 ]. To reduce the risk of any bias, two authors who did not co-author the review in question initially assessed its quality and limitations.

Finally, we note that the systematic reviews included in our overview may have had issues that our analysis did not identify because we did not analyze their primary studies to verify the accuracy of the data and information they presented. We give two examples to substantiate this possibility. Lovato et al. wrote a commentary on the review of Sun et al. [ 41 ], in which they criticized the authors’ conclusion that sore throat is rare in COVID-19 patients [ 56 ]. Lovato et al. highlighted that multiple studies included in Sun et al. did not accurately describe participants’ clinical presentations, warning that only three studies clearly reported data on sore throat [ 56 ].

In another example, Leung [ 57 ] warned about the review of Li, L.Q. et al. [ 29 ]: “ it is possible that this statistic was computed using overlapped samples, therefore some patients were double counted ”. Li et al. responded to Leung that it is uncertain whether the data overlapped, as they used data from published articles and did not have access to the original data; they also reported that they requested original data and that they plan to re-do their analyses once they receive them; they also urged readers to treat the data with caution [ 58 ]. This points to the evolving nature of evidence during a crisis.

Our study’s strength is that this overview adds to the current knowledge by providing a comprehensive summary of all the evidence synthesis about COVID-19 available early after the onset of the pandemic. This overview followed strict methodological criteria, including a comprehensive and sensitive search strategy and a standard tool for methodological appraisal of systematic reviews.

In conclusion, in this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all the reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic could be categorized as research waste. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards to provide patients, clinicians, and decision-makers trustworthy evidence.

Availability of data and materials

All data collected and analyzed within this study are available from the corresponding author on reasonable request.

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Acknowledgments

We thank Catherine Henderson DPhil from Swanscoe Communications for pro bono medical writing and editing support. We acknowledge support from the Covidence Team, specifically Anneliese Arno. We thank the whole International Network of Coronavirus Disease 2019 (InterNetCOVID-19) for their commitment and involvement. Members of the InterNetCOVID-19 are listed in Additional file 6 . We thank Pavel Cerny and Roger Crosthwaite for guiding the team supervisor (IJBN) on human resources management.

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

Helene Fuld Health Trust National Institute for Evidence-based Practice in Nursing and Healthcare, College of Nursing, The Ohio State University, Columbus, OH, USA

Dónal P. O’Mathúna

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IJBN conceived the research idea and worked as a project coordinator. DPOM, TCVG, HMA, IW, AM, LP, VTC, IZG, TPP, ANA, SF, NLB and MSM were involved in data curation, formal analysis, investigation, methodology, and initial draft writing. All authors revised the manuscript critically for the content. The author(s) read and approved the final manuscript.

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

Adjusted scoring of AMSTAR 2 used in this study for systematic reviews of studies that did not analyze interventions.

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

Table of overlapping studies, containing the list of primary studies included, their visual overlap in individual systematic reviews, and the number in how many reviews each primary study was included.

Additional file 5: Appendix 5.

A detailed explanation of AMSTAR scoring for each item in each review.

Additional file 6: Appendix 6.

List of members and affiliates of International Network of Coronavirus Disease 2019 (InterNetCOVID-19).

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Borges do Nascimento, I.J., O’Mathúna, D.P., von Groote, T.C. et al. Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews. BMC Infect Dis 21 , 525 (2021). https://doi.org/10.1186/s12879-021-06214-4

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A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection

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• Viral infection

COVID-19, the disease caused by SARS-CoV-2, has claimed approximately 5 million lives and 257 million cases reported globally. This virus and disease have significantly affected people worldwide, whether directly and/or indirectly, with a virulent pathogen that continues to evolve as we race to learn how to prevent, control, or cure COVID-19. The focus of this review is on the SARS-CoV-2 virus’ mechanism of infection and its proclivity at adapting and restructuring the intracellular environment to support viral replication. We highlight current knowledge and how scientific communities with expertize in viral, cellular, and clinical biology have contributed to increase our understanding of SARS-CoV-2, and how these findings may help explain the widely varied clinical observations of COVID-19 patients.

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A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection

Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants

Small molecules in the treatment of COVID-19

Introduction.

As of November 21st, 2021, over 257 million cases of coronavirus disease 2019 (COVID-19) have been reported, and more than 5 million lives claimed globally [ 1 ]. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Development of vaccines against SARS-CoV-2 provide a major step forward in reducing COVID-19’s impact. However, the pandemic is ongoing, and the continued viral transmission allows for accumulation of mutations in the viral genome, which can provide advantages in replication, immune escape, increased transmissibility, or diagnostic detection failure [ 2 ]. With the quickly evolving SARS-CoV-2 variants and the slow rate of vaccination globally, it is critical to fully understand this novel virus and disease.

Coronaviruses are named as such because the S proteins resemble a halo or corona on scanning electron microscope imagery [ 3 ]. SARS-CoV-2 belongs to the genus Betacoronavirus. Of the human Betacoronavirus, including OC43, HKU1, SARS-CoV-1, and Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) [ 4 ]. SARS-CoV-2 bears the highest genetic sequence similarity to SARS-CoV-1 [ 5 ]. Accordingly, COVID-19, caused by SARS-CoV-2, resembles SARS, caused by SARS-CoV-1, in many ways, but with some important differences [ 6 ]. Key characteristics of SARS-CoV-1 and 2 include: 1) a positive-sense RNA virus with a large genome of ~30 kilobases; 2) a large, enveloped virus containing a helical nucleocapsid with the virus’s genetic code, with an exterior studded in several spike proteins that facilitate the infection of host cells), and 3) similar genomic structures. The first 2/3 of both genomes encodes for two macro polypeptides pp1a/pp1b (see Fig.  1 ). Pp1a/pp1b are auto-proteolytically processed to generate 16 non-structural proteins (NSP).

Structural elements of the virus, including the spike protein, envelope, membrane, and internal components such as the viral single-stranded RNA and nucleocapsid proteins (above). SARS-CoV-2 genome components (below).

The main virus-specific functions of the SARS-CoV-2 NSPs are: NSP1 - cellular mRNA degradation, global translation inhibition; NSP2 - cell cycle progression disruption; NSP3 - formation of double-membrane vesicles (DMVs; SARS-CoV-2 protease); NSP4 - formation of DMVs; NSP5 - main SARS-CoV-2 protease; NSP6 - formation of DMVs, NSP7 - replication complex; NSP8 – primase; NSP9 - RNA binding protein; NSP10 - cofactor of NSP14 & NSP16; NSP11 - unknown, NSP12 - RNA-dependent RNA polymerase; NSP13 - RNA helicase, 5ʹ phosphatase, NSP14 - N7-MTase, 3ʹ-5ʹ exonuclease; NSP15 – endonuclease; and NSP16–2ʹ-O-MTase, mRNA capping.

The remaining 1/3 of the SARS-CoV-2 genome encodes for the structural proteins S (spike), E (envelope), M (membrane), and N (nucleocapsid), and several open reading frames (ORFs; (3a, 6, 7a, 7b, 8, 9b, and 10) [ 7 ]. The S protein binds the host cell receptor, which for SARS-CoV-1/2 is the human angiotensin-converting enzyme 2 (hACE2) (see Fig.  2 and Supplementary Table  1 ). These proteins share homology and function with SARS-CoV-1.

Structural interactions between the virus and target cell, including the viral spike protein, ACE2-receptor, TMPRSS2 reaction to cleave and begin the viral intracellular internalization (above, A ), and consequent signal transduction pathways stimulated by the virus as it hijacks pathways to turn the infected cell into a SARS-CoV-2 producing factory (below, B ).

There are two notable differences between SARS-CoV-1 and SARS-CoV-2. First is the presence of the ORF8 polypeptide found in SARS-CoV-2 but not in SARS-CoV-1. SARS-CoV-1 has a 29 nucleotide (nt) deletion (del) which splits it into ORF8a and ORF8b. Second, SARS-CoV-2 contains a gene encoding a novel orphan protein, ORF10, which is not present in SARS-CoV-1 [ 7 ].

SARS-CoV-2’s evolutionary rate has been estimated to be around 9’×’10 −4 substitutions per site per year [ 8 ], while also having a high transmissibility, large portion of asymptomatic cases [ 9 ], large pool of susceptible hosts to replicate in [ 10 , 11 ], and on-going environmental pressures (e.g., low vaccination rates and changes in policies allowing human carriers to continue to transmit the virus), which have allowed SARS-CoV-2 to accumulate mutation in its genome.

Mutations have been detected in all parts of the viral genome, including in the leader 5ʹ untranslated region (UTR), orf1ab (NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, and NSP14), spike, ORF3a, ORF8, nucleocapsid, and ORF10 [ 8 ]. These genomic changes have been shown to influence viral immune evasion, inflammasome interaction, helicase, exonuclease proofreading mechanism, the activity of the RNA-dependent RNA polymerase (RdRp) and thereby viral replication, infectivity, and cell release [ 12 ].

Mutations associated with the spike are of particular interest, as they influence human-to-human transmission, as well as human-to-animal passage. Within the spike, mutations tend to fall into four general classes, those that affect the receptor-binding domain (RBD), which are of importance because some may provide both immune escape or a fitness advantage, as well as facilitate reverse zoonotic events. There are some mutations that occur in the N-terminal domain (NTD), which is the portion most exposed on the virus surface. There is evidence for immune selection in this region, and preliminary evidence that at least one of these changes (delH69/delV70) could improve fitness [ 13 ]. Mutations in or near the furin cleavage site, and several groupings close to the D614G mutation, possibly affect infection efficiency and can also be important for neutralizing antibodies.

This large SARS-CoV-2 genome diversity has been categorized by different nomenclature systems, describing variants of varied public health interest or concern. Pango lineages B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) have been classified as “variants of concern” (VOC) because they present mutations that have been shown to impact diagnostics, treatments, or vaccines, conferring increased transmissibility and increased disease severity. The impact of these mutations highlights the need for further research not only on the mechanisms of SARS-CoV-2 intracellular processes, but also how the extracellular environment may lead to further spread of the virus and subsequent public health burden.

The SARS-CoV-2 virus can exert physiological effects by directly infecting cells and via intercellular signaling by the infected cells. In this review, we provide insight into SARS-CoV-2 infection and intracellular host responses (targets, pathways, networks, biological processes, and functional adaptations) to viral invasion. We emphasize a canonical set of reactions induced by SARS-CoV-2, which we have organized for the reader’s consideration. However, there is tremendous variation in cellular responses to SARS-CoV-2, depending on factors including the cell type, organ type, metabolic and physiological context, patient genetics, individual clinical characteristics (e.g., age, sex, comorbidities), and stage/severity in the COVID-19 disease.

This is the first of a three-part comprehensive series of linked reviews on SARS-CoV-2 covering: intracellular effects (present study); extracellular consequences (review 2); and current and potential therapeutics (review 3). This review and the two that will follow aim to provide a foundational understanding of the current knowledge on SARS-CoV-2, from basic biology to clinical outcome and therapy avenues, that highlight future areas of research and could help inform public health interventions across the world.

Infected tissue and cell types

SARS-CoV-2 targets the nasal cavity and lungs; however, the detailed cellular tropism remains unclear, and likely varies among individuals. Furthermore, there is increased variability of viral cellular tropism with the emergent SARS-CoV-2 variants, which include Alpha, Beta, Gamma, Epsilon, Eta, Iota, Kappa, 1.617.3, Mu, Zeta, and in particular, Delta and Omicron, as well as the various lineages of each variant [ 14 ]. This is related with SARS-CoV-2’s mutation ability affecting its antigenic phenotype to circumvent immunity. The spike protein mediates attachment of the virus to host cell-surface receptors and fusion between virus and cell membranes; it is also the principal target for neutralizing antibodies generated following infection, and is the component for both mRNA and adenovirus-based vaccines [ 15 ]. Several studies have contributed to the current understanding of how mutations in the SARS-CoV-2 spike protein affect neutralization and emergence of new strains, which include studies of traditional escape mutation, targeted characterization of particular mutations, and wider investigations of large numbers of circulating variants [ 16 ]. These are active areas of research, in particular given the continued emergence of new lineages of new variants. A study of human, bat, non-human primate, and mouse cell lines showed various cell types were susceptible to the virus. These included pulmonary, intestinal, hepatic, renal, and neuronal, with cell lines expressing the hACE-2 receptor (hACE-2) having a generally greater viral load [ 17 ]. Although cell lines do not reflect physiological conditions, this research indicates that SARS-CoV-2 can infect many cell types, and that hACE-2 provides a critical entry mechanism [ 18 ]. Epithelial, vascular endothelial, pancreas, and mucosal cell types can all be infected by the virus [ 19 , 20 , 21 ].

Several investigations have employed 3D organoid cultures to simulate more physiological conditions than cell cultures [ 22 ]. In one such study, lung and colonic organoid models showed SARS-CoV-2 infection was reduced when various SARS-CoV-2 entry inhibitors were applied [ 22 ]. Another study illustrated the flexibility of different organoid models, such as pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons from human pluripotent stem cells, and adult primary cells (human islets, hepatocyte, and cholangiocytes) to test viral effects such as cytokine production, gene expression, and other physiological responses. The resultant data correlated well with some patient autopsy samples [ 22 ] indicating organoids provide a valuable disease modeling tool [ 18 ].

In one study of post-mortem patients, immunohistochemistry and immunofluorescence revealed viral antigen (spike protein) in pneumocytes and hyperplastic cells around the bronchioles, mucosal epithelia, submucosal glands, gland ducts of the trachea, glands of the small intestine, distal tubules and collecting ducts of the kidneys, islets of Langerhans, glands and intra-islet ducts of the pancreas, and vascular tissues of the brain and heart [ 23 ]. Few viral antigens were present in the large intestine and renal proximal tubules, and none in the liver. A follow-up colocalization analysis showed ACE2 and viral antigen in the lung, trachea, small intestine, kidney, pancreas, and heart. In the brain, ACE2-expressing cells were detected, but they were negative for the viral antigen [ 23 ]. Endothelial cells of multiple organs were infected, supporting the clinical observations of endotheliitis in some COVID-19 patients.

Single-cell RNA sequencing (scRNA-seq) demonstrated ACE2 receptor expression was primarily restricted to lung pneumocytes, gut absorptive enterocytes, and nasal mucosa goblet secretory cells [ 24 ]. In general, the distribution of ACE2 receptors may in part explain the systemic diversity and range of SARS-CoV-2’s effects. Further research into infection of these cell types versus others in mucosal barrier organs will be important to determine cell-types that serve as initial entry ways for the virus into the body.

Human autopsy studies [ 21 ] have shown that SARS-CoV-2 infects multiple organs including lungs, pharynx, liver, nasal mucosa, trachea, intestines, skin, pancreas, kidney, brain, and heart. A study of 27 patients showed multi-organ tropisms (lung, pharynx, heart, liver, brain, and kidneys), with the highest levels of SARS-CoV-2 copies per cell, as detected by in situ hybridization and indirect immunofluorescence, in the respiratory tract, and lower levels in the kidneys, liver, heart, and brain [ 21 ]. Transcriptional profiling of nasopharyngeal swabs, patient autopsy, and body-wide tissues (e.g. heart, liver, lung, kidney, and lymph nodes), provided further evidence of the physiologically systemic effects of SARS-CoV-2 [ 24 ].

These studies suggest that the virus has a varying range of expression within each organ, which may be influenced by levels of the ACE2-receptor and related entry factors (Transmembrane protease, serine-2 [TMPRSS2], transferrin receptor protein 1 [TRFC1], cluster of differentiation 4 [CD4], and neuropilin-1 [NRP1]) within each organ-type [ 24 ]. This further highlights the varied organ and tissues that are capable of being infected by the virus, and the resultant wide-range of patient symptoms.

The physiological status of the individual significantly affects COVID-19 morbidity and mortality [ 25 , 26 ]. Notably, patients with pre-existing conditions of obesity, hypertension, and diabetes have a less favorable disease outcome, likely in part due to the elevated levels of inflammation and metabolic disturbances associated with those conditions [ 25 ]. Conversely, SARS-CoV-2 infection may exacerbate pre-existing conditions, leading to more severe COVID-19 outcome [ 27 ].

SARS-CoV-2 Receptors – Angiotensin Converting Enzyme-2 (ACE2)

The cellular surface receptor ACE2, a key regulator of the Renin-Angiotensin Aldosterone System (RAAS). It is speculated to be the primary SARS-CoV-2 viral target for entry. SARS-CoV-2 is thought to infect multiple organs in part due to the widespread distribution, expression, and polymorphisms of ACE2 [ 28 , 29 ].

ACE2’s molecular function in the human RAAS pathway is to cleave Angiotensin I to produce Angiotensin 1–9, and break down Angiotensin II into Angiotensin 1–7. RAAS moderates blood pressure and osmolarity by means of hormonal feedback control. In response to binding of ACE2 to the ACE2 receptor (ACE2R), blood vessels vasoconstrict. This process is mediated by G-protein-signaling, activating phospholipase C and increasing cytosolic Ca 2+ concentrations. ACE2 also plays an important role in inactivating Des-Arg9-Bradykinin (DABK), a bradykinin involved in inflammation. This inactivation promotes C-X-C motif chemokine 5 (CXCL5), macrophage inflammatory protein-2 (MIPS2), keratinocytes-derived chemokine (KC), and tumor necrosis factor-〈 (TNF-α) activity, drawing leukocytes into the affected tissues [ 30 ].

Decreased ACE2 receptor expression can have detrimental effects. Computational models of COVID-19 suggest the role of a bradykinin storm in the pathophysiology of the disease. In this model, the Kallikrein-Kinin and Renin-Angiotensin-Aldosterone Systems are integrated, with cross-talk mediated by the degradation of bradykinin by ACE and prolylcarboxypeptidase [ 31 ]. This behavior makes the SARS-CoV-2 spike protein behave akin to an ACE-inhibiting drug [ 32 ]. Thus, disruption of ACE2 expression from SARS-CoV-2 binding can lead to altered tissue function and exacerbate disease.

The ~600-kDa trimeric S proteins can bind to ACE2 through the RBD required for membrane fusion (see Fig.  2 ). The binding initiates viral internalization, with the cleavage of S1/S2 inducing a conformational change from prefusion into post-fusion. S1 consists of the NTD, the RBD, and subdomain 1 and 2 (SD1 and SD2). S2 contains the hydrophobic fusion peptide and is responsible for the viral and cell membrane fusion [ 33 ]. SARS-CoV-2 S-protein shows varying states of conformational shifts of the RBD site progressing towards proteolytic processing, making the viral RBD more accessible to ACE2, with the cleavage at the S1/S2 leading towards RBD open confirmation and viral internalization [ 33 , 34 ]. The S- and RBD-viral sites are notable for affecting transmission and disease severity, and variants have been shown to accumulate mutations at these sites leading to increased S- and RBD affinity with ACE2 [ 35 ]. Understanding the biology of the SARS-CoV-2 surface interactions will help elucidate how the virus can invade multiple organ systems and cell types.

Calcium Ion (Ca 2+ ) Signaling

The calcium ion (Ca 2+ ) is essential for many aspects of cellular physiology and viral replication. Experimental data on the relation between Ca 2+ signaling and SARS-CoV-2 infection and replication is sparse. However, studies of other coronaviruses (e.g., SARS-CoV-1, MERS-CoV) have reported that these viruses utilize Ca 2+ for host fusion [ 36 ]. The fusion protein (FP) of MERS-CoV binds to one Ca 2+ ion, while the SARS-CoV-2 spike (S) protein has two FP domains, FP1 and FP2, and binds to two Ca 2+ ions for host cell entry [ 37 ]. SARS-CoV-2 appears to affect cellular function by altering the host Ca 2+ homeostasis in ways that promote viral infection and reproduction (see Fig.  3 ). One mechanism is through disruption of calcium channels and pumps (e.g., voltage-gated calcium channels (VGCCs), receptor-operated calcium channels, store-operated calcium channels, transient receptor-potential ion channels, and Ca 2+ -ATPase) [ 28 , 37 ]. This leads to increased intracellular Ca 2+ concentrations, resulting in virus-induced cell lysis [ 28 , 37 ]. The interaction between the virus and VGCCs may also promote virus-host cell fusion for entry [ 28 ].

Structural elements of the virus, including the spike protein, envelope, membrane, and internal components such as the viral single-stranded RNA and nucleocapsid proteins (above).

Viroporins, transmembrane pore-forming proteins that alter membrane permeability to ions including Ca 2+ by forming membrane channels, are a characteristic of a diversity of virus. SARS-CoV-1/2 each encode viroporins. SARS-CoV-1 encodes for three viroporin proteins ORF3a, E and ORF8b, which alter ion homeostasis within the cell, and have important roles in pathogenesis and promoting viral fitness. SARS-CoV-2 encodes two of these viroporin proteins, E and ORF3a; however, the ORF8 protein of SARS-CoV-2 is highly divergent from SARS-CoV-1 ORF8b and lacks the viroporin sequence of SARS-CoV-1 ORF8b.

The E and ORF3a proteins of coronaviruses impact Ca 2+ homeostasis in the host, by acting as calcium ion channels, enhancing the virion’s entry and replication potential [ 38 ]. The SARS-CoV-2-E protein is a 76 amino acid (aa) integral membrane protein with one transmembrane domain (TMD) that allows the E protein to form protein-lipid channels in membranes that promote permeability to Ca 2+ ions. The SARS-CoV-2-ORF3a protein is 274 aa in length, harbors three helical TMD, and is a Na + or Ca 2+ ion channel protein. The alteration of Ca 2+ homeostasis by SARS-COV-1-E and SARS-COV-2-E proteins promotes SARS-CoV-1/2 fitness and elicits the production of chemokines and cytokines, contributing to pathogenesis. Ion channel activity modulation by the SARS-CoV-1-ORF3a protein also modulates viral release [ 39 ]. Therefore, when SARS-CoV-2 infects the human body, the resultant dysregulation of Ca 2+ homeostasis may contribute to morbidity and mortality. COVID-19 patients have been noted to have low serum calcium levels overall [ 40 ].

We speculate that Ca 2+ dysregulation could lead to increased cellular oxidative stress and shifts in metabolic activity. Low Ca 2+ may also be coupled with viral infection and internalization through the ACE2R, which synergizes with Ca 2+ signaling pathways. Understanding these reverberations will increase our insight into the basic biology of the effects of SARS-CoV-2 infection on the various organ systems.

Intracellular signaling

Viral infection and hijacking of cell-surface receptors begin to trigger activation of multiple intracellular pathways in addition to Ca 2+ signaling. As infection proceeds, SARS-CoV-2 manipulates, or totally reprograms, the normal metabolism and signaling of the host cell, optimizing the molecular environment to enable the viral replication cycle. This involves interfering with signaling pathways that regulate processes of DNA repair and replication, immune response, transcription, metabolism, cell cycle, and apoptosis [ 39 ].

SARS-CoV-2 infection alters phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), Type I and III interferon, transforming growth factor-β (TGF-β), Toll-like receptors (TLR), and nuclear factor kappa-light chain enhancer (NF-κB) pathways. These pathways are dysregulated in the setting of SARS-CoV-2 to antagonize host antiviral responses and are vital for viral replication, entry, propagation, and/or apoptosis/viral release. For instance, severe COVID-19 is characterized by an inflammatory profile dominated by NF-κB activity [ 41 ]. The SARS-CoV-2-encoded NSP13 and Open Reading Frame 9c (ORF9c) proteins can interact directly with elements of the transducin-like enhancer (TLE) family of proteins and thus regulate the NF-κB inflammatory response [ 42 ]. While broad activation of NF-κB is induced by a variety SARS-CoV-2-encoded products, Open Reading Frame 7a (ORF7a) specifically is a potent stimulator of NF-κB associated proinflammatory chemo- and cytokines, which are elevated in the presence of severe COVID-19. NF-κB plays a similar role in other coronavirus infections.

Host antiviral immunity requires an optimal and coordinated response to control viral infections; this immunity is mediated by several host sensors, notably pattern recognition receptors (PRR). PRRs identify damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively). SARS-CoV-2 infects the cell via the endosomal compartment, and may activate TLRs, such as TLR4, resulting in increased NF-κB activity and expression [ 42 , 43 ]. The MyD88-mediated TRIF activation of TLR downstream pathways triggers the nuclear translocation of NF-κB, IFN regulatory factor 3 (IRF-3), and IFN regulatory factor 7 (IRF-7), resulting in the expression of innate immunity proinflammatory cytokines (interleukin-1 [IL-1], interleukin-6 [IL- 6], TNF-α) and interferons (IFNs). Continuous activation of TLR can increase MyD88 and Interleukin-1β (IL-1β), which then can further activate NF-κB [ 43 ]. RNA viruses are detected by several sensors, such as TLRs 3, 7 and 8. TLR3 recognizes double stranded RNA, while TLR7 and TLR8 single stranded RNA. In addition to ssRNA and dsRNA, viral proteins can act as PAMPS and potentiate inflammatory signaling through the stimulation of surface TLRs. Interestingly, in SARS-CoV-2, TLR2 is a critical mediator of envelope protein detection and driver of pathogenesis through inflammatory process augmentation [ 44 ]. Some individuals with severe COVID-19 have mutations in genes associated with type I and III IFN pathways [ 45 ]. Ten percent of individuals that progress to severe COVID-19 pneumonia display elevated amounts of neutralizing antibodies against type I IFN-α2 and IFN-ω [ 46 ]; these antibodies are not present in healthy or asymptomatic individuals. Of note, albeit TLR3 activation is critical for viral clearance, TLR3 hyperactivation can lead to a cytokine storm and the subsequent severe COVID-19. Other receptors are also involved in SARS-CoV-2 recognition, such as the proteins of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5). Once inside the cell, double strand viral RNA can be recognized by RIG-I/MDA5, thus initiating an antiviral response through mitochondrial antiviral signaling (MAVS). MAVS activated the downstream pathways, IκB kinase α/β (IKK) and TBK1/IKKε, leading to translocation of NF-κB and/or IRF3 into the nucleus and induction of genes involved with innate antiviral immunity and the subsequent induction of IFN-stimulated genes (ISGs).

Inhibition of IFNs and ISGs is a tactic used by several viruses to evade host antiviral responses [ 47 ], and SARS-CoV-2-mediated IFNs and ISGs dysregulation appears to be an important strategy used by this virus to replicate and disrupt immune homeostasis. Furthermore, therapies with type I and III IFNs alone or combined with other drugs suppressed SARS-CoV-2, ameliorating COVID-19 disease [ 48 ].

The cytokine TGF-β triggers the Janus kinases (JAKs) / signal transducer and activator of transcription (STAT) proteins (JAK/STAT) pathway in certain contexts, while suppressing it in others [ 49 ]. It has been proposed that SARS-CoV-2 proteins, particularly NSP1 and ORF6, may dysregulate STAT1 and STAT3, leading to a positive feedback loop where coagulopathy triggers TLR4 via PAI-1 binding, circularly activating STAT; for this reason, therapeutic targeting of the Janus kinase pathway has been proposed [ 50 ].

The innate immune response is a first step to protecting against pathogens, which stimulate the interferon signaling pathway and expression of IFN-I, leading to an antiviral cellular response [ 51 ]. Coronaviruses have developed mechanisms to hinder IFN-expression and reduce the production of IFN. This suppression has been shown to correlate with disease severity and mortality [ 52 ]. This holds true for SARS-CoV-2, with recent studies showing that viral proteins ORF6, ORF8, and nucleocapsid being potent inhibitors of the IFN-I signaling pathway [ 53 ].

Metabolic adaptations

Viruses rely on host cell machinery to propagate, promoting anabolism for generation of macromolecules needed for virion replication and assembly (see Fig.  2 ). Consequently, viral proteins (see Supplementary Table  1 ) affect intracellular pathways, leading to subsequent adaptations by the cellular metabolism where the mitochondria plays a central role.

We reported recently through study of COVID-19 patient samples (i.e., nasopharyngeal swab samples, various organs from autopsy COVID-19 samples, murine lung tissues, and various organs from hamsters being infected with SARS-CoV-2) that heavy suppression occurs of mitochondrial functions in various organs [ 54 ]. Specifically, in the course of SARS-CoV-2 infection, the virus blocks the transcription of discrete groups of mitochondrial genes from major bioenergetic organs, while upregulation occurs in others as a compensatory mechanism to rescue the damage occurring in the major bioenergetic organs. This demonstrated a dynamic evolution of mitochondrial gene expression and cellular energetics as the virus progresses from one organ to the next. Transcriptomic changes in the nasopharyngeal infected samples revealed that during initial SARS-CoV-2 infection, nDNA coded mitochondrial genes are blocked and the co-inhibited genes were found to group together as components of preassembly modules of the mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II, III, IV and V. At the time of death for COVID-19 patients, we showed virtually all mitochondrial function were inhibited in the heart, suggesting cardiac mitochondrial dysfunction in longer term COVID-19 pathology. In addition, mTOR signaling and the integrated stress response were highly dysregulated throughout all organs. Lastly, mitochondrial inhibition was shown to activate HIF-1α and its target genes shifting cellular metabolism away from catabolism and towards viral synthesis. Our results indicate that manipulation of mitochondrial function may be an important approach for mitigating the severity of COIVID-19.

SARS-CoV-2 infection of human monocytes [ 55 ] and human pulmonary alveolar epithelial (HPAEpiC) cells [ 56 ] induced mitochondrial reactive oxygen species (mROS) production, increased HIF-1α protein levels and upregulated expression of HIF-1α target genes [ 57 ]. The stability of hypoxia inducible factor-1α (HIF-1α) during a SARS-CoV-2 infection was shown to increase the production of pro-inflammatory cytokines and SARS-CoV-2 replication [ 55 , 56 , 57 ]. The expression of ORF3a in human embryonic kidney 293 T-antigen cells (HEK293T) cells increased the stability of HIF-1α and induced mROS production, which is an activator of HIF-1α. Together these results suggest that ORF3a induces mROS production to activate HIF-1α, which in turn triggers a shift in cellular metabolism to favor glycolysis, resulting in increased viral replication and transcription of pro-inflammatory cytokines.

Following host cell infection, the SARS-CoV-2 replication/transcription complex synthesizes ~30 kb viral genomes as well as the subgenomic RNAs required to encode for viral structural and mechanistic proteins. Between 1–5 h post-infection, the percentage of coronavirus-encoded protein per total cellular protein translation may increase by as much as 20,000 times, with the fraction of viral to cellular RNA ultimately reaching as high as 90% intracellularly [ 58 ]. To accommodate this huge shift towards viral replication, there is certainly a requirement of a shift in cellular metabolism to accommodate for viral synthesis. An investigation of SARS-CoV-2 metabolism during the initial 48-hours post viral infection showed that amino acid availability and synthesis are altered, de novo purine synthesis intermediates are accumulated, intracellular glucose and folate are depleted, and lactate levels are elevated [ 59 ]. This suggests a viral strategy of upregulating purine metabolism at the post-translational level to coincide with the shutting off of the majority of host proteins at translation levels.

Virus-infected cells also commonly exhibit the Warburg effect - increased glycolytic metabolism in the presence of inadequate oxygen for oxidative phosphorylation - to supply reducing equivalents and precursors for macromolecule biosynthesis, and to support generation of ATP needed for also increasing nucleotide and lipid biosynthesis. Metabolic shifts include dysregulated Ca 2+ signaling and increased mitochondrial generation of ROS. How SARS-CoV-2 induces host cell nucleotide metabolism remains unanswered.

Mitochondrial metabolism and function are highly impacted in multiple ways. With the shift towards glycolysis, there is a reduction in oxidative phosphorylation affecting the mitochondria and its function. SARS-CoV-2 may interact with the mitochondria to destabilize its oxidative phosphorylation capacity. Coronavirus replication requires the formation of double-membrane vesicles (DMVs) derived from endoplasmic reticulum (ER). These DMVs serve as a site for viral replication and help conceal the virus from host cellular defenses. Interestingly, mitochondrial stress is known to induce mitochondria-derived vesicles (MDVs) that communicate with the ER. It is conceivable that SARS-CoV-2 disruption of mitochondrial function results in the induction of (double-membrane) MDVs. SARS-CoV-2 RNA present in the mitochondria induces mitochondrial dysfunction. Increased DMVs can provide opportunity for viruses to hide and replicate [ 60 ].

SARS-CoV-2 and all subgenomic RNAs are enriched in the host mitochondria, and viral genome’s 5ʹ - and 3ʹ -UTRs contain distinct mitochondrial localization signals [ 61 ], indicating that the viral RNA may hijack the mitochondria, an interesting hypothesis for experimental validation [ 61 ]. Other recent studies have mapped physical interactions of SARS-CoV-2 encoded proteins with mitochondrial localized proteins. These interactions include: NSP8 interaction with mitochondrial ribosomal protein s2 (MRPS2), mitochondrial ribosomal protein s5 (MRPS5), mitochondrial ribosomal protein s25 (MRPS25), and mitochondrial ribosomal protein s27 (MRPS27) ribosomal proteins; ORF9c interaction with mitochondrial NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 1 (NDUFAF1) and NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 9 (NDUFB9); ORF10 interaction with TIMM8; and NSP7 interaction with mitochondrial NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 2 (NDUFAF2). NDUFAF1, NDUFAF2, NDUFB9, and NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 10 (NDUFA10) are all key players in the assembly of complex I, and NDUFA10 is suggested as being one of the master regulators of the SARS-CoV-2 pathology [ 7 ]. Interactions were also observed between viral M protein and ATPase Na + /K + Transporting Subunit Beta 1 (ATP1B1), ATPase H + Transporting V1 Subunit A (ATP6V1A), acyl-coenzyme A dehydrogenase (ACADM), Alpha-aminoadipic semialdehyde synthase (AASS), Peptidase, Mitochondrial Processing Subunit Beta (PMPCB), Pitrilysin Metallopeptidase 1 (PITRM1), Coenzyme Q8B (COQ8B), and Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA); these proteins are each components of critical mitochondrial metabolic pathways. SARS-CoV-2-encoded ORF9b protein interacts and localizes with Translocase Of Outer Mitochondrial Membrane 70 (TOMM70) [ 7 ], a mitochondrial import receptor important for transporting proteins into mitochondria and, more importantly, in modulating anti-viral cellular defense pathways [ 62 ]. These mitochondrial interactions offer glimpses of the viral effect on glycolytic and oxidative phosphorylation pathways and the potential side effects.

Another example of COVID-19’s mitochondrial-related impacts is the over-production of cellular ROS [ 63 ]. ROS and reactive nitrogen species have diverse functions in biological systems; oxidatively attacking pathogens, regulating cell proliferation, and key signaling functions [ 64 ]. However, dysregulation of ROS is implicated in many diseases, including the hyper-inflammatory late phase of COVID-19 [ 65 ]. As a part of normal redox metabolism, superoxide radicals are converted into hydrogen peroxide by the action of superoxide dismutase. The hydrogen peroxide is subsequently broken down into water by glutathione peroxidase. During COVID-19, isoforms of enzymes, including glutathione peroxidase and thioredoxin reductase, may be directly targeted and proteolyzed by the SARS-CoV-2 protease, Mpro.

SARS-CoV-2 is thought to suppress the ROS-associated Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor that regulates the expression of antioxidant proteins that protect against oxidative damage. Dysregulation of the Nrf2 pathway will exacerbate the pro-oxidative stress caused by the virus [ 66 ]. SARS-CoV-2 may suppress the accumulation of the selenoprotein transcripts, which are crucial for the correct functioning of Phospholipid hydroperoxide glutathione peroxidase (GPX4) and mitochondria function [ 67 ]. This redox impairment would lead to a buildup of hydrogen peroxide, which could trigger inflammation by promoting the activity of the mitogen-activated protein kinase (MAPK), NF-κB, and the nuclear NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome [ 68 ].

Due to the multiple effects of SARS-CoV-2 that alter cellular metabolic and oxidative states, there are multiple directions to deplete NAD+, loss of cellular ATP and reduced Poly-ADP-ribose polymerase (PARP) activity, each of which have cytotoxic effects of their own [ 69 ]. In general, NADPH, synthesized from NAD+, is necessary for many key redox reactions; a reduced level of NADPH could play a mechanistic role in cellular metabolic changes from SARS-CoV-2 infection.

SARS-CoV-2 mediated reduction in ATP and nitric oxide signaling induces cell stress

Cellular metabolism adapts to the alterations induced by SARS-CoV-2 infection of the cell (see Fig.  4 ). These adaptations depend on the cell and tissue type. Here, we focus on ATP signaling, which is relevant to epithelial cells, and nitric oxide (NO) signaling, which tends to be perturbed in endothelial cells [ 70 ]. Activation of each pathway at low levels provides protection to the host.

Metabolic pathways and shifts that lead to cellular dysregulation and viral activation to lead towards viral replication (above).

ATP production from oxidative phosphorylation, glycolysis, and other pathways is critical to support cellular physiology, but this molecule also has signaling properties, which can be particularly beneficial in epithelial cells [ 70 ]. Perturbations in ATP generation induced by the virus in epithelial cells [ 71 ] can lead to ATP release from the apical or basolateral spaces, and subsequent extracellular ATP signaling [ 72 ]. It can stimulate P2 receptors on neighboring epithelial cells to activate signal transduction pathways and alter cellular function in adjacent cells even if they are not infected, thus priming naive host cells for confrontation with the virus [ 71 , 72 ].

In the endothelium, nitric oxide directly affects mitochondrial metabolism through interaction with cytochrome C, providing cytoprotection against free radicals. However, reduction of NO bioavailability, due to the increased oxidative stress state caused by SARS-CoV-2-elevated superoxides, results in the formation of peroxynitrites (ONOO-). The reduced NO diffusion to neighboring vascular smooth muscle may impair vascular function [ 73 ]. Peroxynitrite also causes injury to the mitochondria and reduces ATP synthesis, with all of the concomitant negative effects. Therefore, loss of NO bioavailability has major cellular consequences, inducing shifts in multiple enzymatic pathways, cell injury, and death.

Like ATP, NO acts as a biological signaling molecule. This dissolved gas rapidly diffuses across cell membranes and regulates various functions across the body [ 73 ]. The vascular endothelium is the predominant cellular source of NO production, and it plays a critical role in maintaining cardiovascular function. Factors that reduce endothelial NO production (increased oxidative stress, changes in NO synthase synthesis) negatively affect endothelial function [ 73 ]. The cascade of inflammation and oxidative stress triggered by COVID-19 leads to the formation of superoxide free radicals, impairing biological processes and increasing cytotoxicity in the host cells [ 74 ]. The instantaneous reaction of superoxide and NO yields ONOO-, a powerful, cytotoxic nitrating agent. This reaction effectively destroys the NO, rendering it unavailable for its normal regulatory purposes. Thus, the downregulation of NO bioavailability is thought to be a central factor in the severity of COVID-19-associated endotheliitis and the onset of endothelial dysfunction [ 75 ].

The causative agent of the COVID-19 the pandemic, SARS-CoV-2, has caused loss of incomes, economic crises, morbidities, and loss of life worldwide. Here, we describe the virus and review state-of-the-art information about the processes it utilizes to enter and reprogram the human host machinery. We detail research on early infection using evidence from patient samples, organoids and cells, and non-human animal studies. Each of these has limitations but taken together provide unique observational and mechanistic insight on SARS-CoV-2 infection.

COVID-19 is a pleiotropic condition. Viral insults and subsequent cellular metabolic adaptations differ in the context of cell-type, genotype and environmental influences. Thus, much of what we have presented applies to specific cell types and contexts, and we have attempted to cover these contexts.

Key avenues of future research on SARS-CoV-2 infection and propagation include: 1) defining the mechanisms of how the virus enters cells, and the protein and receptor molecules that are critical to this process; 2) elucidating the dynamics of how protein machinery is captured and retrofitted for viral purposes in a cell-specific manner; 3) understanding how the host genetics and environment can affect the ability of the virus to infect; 4) understanding the impact of SARS-CoV-2 on glycolysis and oxidative phosphorylation; and 5) revealing how the mitochondria adapts to ultimately shift its physiology from steady-state.

In the best-case scenario for the SARS-CoV-2 virus, infection leads to a cascade of intracellular adaptations in which multiple networks are remodeled, from transcription to metabolism to signal transduction, shifting the invaded host cell from its original physiology into a SARS-CoV-2 replication system, and causing the emission of new viral particles and signaling molecules. The subsequent disease events will reverberate across the body’s cells and organs. This will be the subject of our Part 2 review (in preparation).

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Acknowledgements

The opinions expressed in this article are those of the authors and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

This work was supported by supplemental funds for COVID-19 research from Translational Research Institute of Space Health through NASA Cooperative Agreement NNX16AO69A (T-0404) to AB, and by a NASA Space Biology Postdoctoral Fellowship (80NSSC19K0426) to SAN. MJT is a recipient of The Evelyn Grollman Glick Scholar Award and supported by research funding from The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Van Andel Research Institute through the Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by AACR, and Specialized Program of Research Excellence (SPORE) program, through the National Cancer Institute (NCI), grant P50CA254897.

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These authors contributed equally: David A. Jamison and S. Anand Narayanan.

This author jointly supervised this work: Afshin Beheshti.

Authors and Affiliations

COVID-19 International Research Team, Medford, MA, USA

David A. Jamison Jr., S. Anand Narayanan, Nídia S. Trovão, Joseph W. Guarnieri, Michael J. Topper, Pedro M. Moraes-Vieira, Viktorija Zaksas, Keshav K. Singh, Eve Syrkin Wurtele & Afshin Beheshti

Department of Nutrition & Integrative Physiology, Florida State University, Tallahassee, FL, USA

• S. Anand Narayanan

Fogarty International Center, National Institutes of Health, Bethesda, MD, USA

Nídia S. Trovão

Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Joseph W. Guarnieri

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Michael J. Topper

Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil

Pedro M. Moraes-Vieira

Obesity and Comorbidities research Center (OCRC), University of Campinas, Campinas, SP, Brazil

Experimental Medicine Research Cluster, University of Campinas, Campinas, Brazil

Center for Translational Data Science, University of Chicago, Chicago, IL, USA

Viktorija Zaksas

Department of Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Keshav K. Singh

Center for Metabolic Biology, Bioinformatics and Computational Biology, and Genetics Development, and Cell Biology, Iowa State University, Ames, IA, USA

Eve Syrkin Wurtele

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

• Afshin Beheshti

KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA

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Conceptualization: DAJ; Writing – Original Draft: DAJ, SN; Writing – Review and Editing: AB, ESW, KKS, JWG, MJT, VZ, PMMV, DAJ, SN, NST. Visualization: DAJ, SN, JWG; Supervision: AB; Funding Acquisition: AB.

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Jamison, D.A., Anand Narayanan, S., Trovão, N.S. et al. A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet 30 , 889–898 (2022). https://doi.org/10.1038/s41431-022-01108-8

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• Published: 05 June 2021

Covid-19 and non-communicable diseases: evidence from a systematic literature review

• Zlatko Nikoloski 1 ,
• Ada Mohammed Alqunaibet 2 ,
• Rasha Abdulrahman Alfawaz 2 ,
• Sami Saeed Almudarra 3 ,
• Christopher H. Herbst 4 ,
• Sameh El-Saharty 5 ,
• Reem Alsukait 4 &
• Abdullah Algwizani 2  

BMC Public Health volume  21 , Article number:  1068 ( 2021 ) Cite this article

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Since early 2020, the Covid-19 pandemic has engulfed the world. Amidst the growing number of infections and deaths, there has been an emphasis of patients with non-communicable diseases as they are particularly susceptible to the virus. The objective of this literature review is to systematize the available evidence on the link between non-communicable diseases and Covid-19.

We have conducted a systematic review of the literature on Covid-19 and non-communicable diseases from December, 2019 until 15th of November, 2020. The search was done in PubMed and in doing so we used a variety of searching terms in order to isolate the final set of papers. At the end of the selection process, 45 papers were selected for inclusion in the literature review.

The results from the review indicate that patients with certain chronic illnesses such as diabetes, hypertension (and other cardiovascular diseases), chronic respiratory illnesses, chronic kidney and liver conditions are more likely to be affected by Covid-19. More importantly, once they do get infected by the virus, patients with chronic illnesses have a much higher likelihood of having worse clinical outcomes (developing a more severe form of the disease or dying) than an average patient. There are two hypothesized channels that explain this strong link between the chronic illnesses enumerated above and Covid 19: (i) increased ACE2 (angiotensin-converting enzyme 2) receptor expressions, which facilitates the entry of the virus into the host body; and (ii) hyperinflammatory response, referred to as “cytokine storm”. Finally, the literature review does not find any evidence that diabetes or hypertension related medications exacerbate the overall Covid-19 condition in chronic illness patients.

Conclusions

Thus, the evidence points out to ‘business as usual’ disease management model, although with greater supervision. However, given the ongoing Covid-19 vulnerabilities among people with NCDs, prioritizing them for the vaccination process should also figure high on the agenda on health authorities.

Peer Review reports

Introduction

The novel Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) caused a cluster of pneumonia cases in China at the end of 2019. After a few months, it led to a pandemic that has spread throughout most countries of the world. SARS-CoV-2 disease (Covid-19) primarily manifests as a lung infection and its clinical course is characterized by respiratory symptoms ranging from a mild respiratory infection (including fever, cough and fatigue) to pneumonia, acute respiratory distress syndrome (ARDS), shock, and death. While Covid-19 had been initially considered as a respiratory infection, causing harm primarily through inflammatory and immunological processes in the respiratory tract, emerging evidence points out that patients with non-communicable diseases (NCDs) are at higher risk of contracting Covid-19 and suffering worse consequences; moreover, emerging evidence points to a strong feedback mechanism between Covid-19 and existing chronic illnesses (e.g. diabetes) thus further contributing to organ damage and fatal consequences.

The interplay between Covid-19 and NCD shows a set of different effects, both direct and indirect. Direct effects relate primarily to the fact that there is a significant number of preliminary reports connecting certain pre-existing conditions, such as cardiac failure, coronary heart disease, hypertension and diabetes, to a more severe course of Covid-19. Thus, comorbidities may play an important role both in increased susceptibility for infection with SARS-CoV-2 as well as increase the risk of a more severe course of the disease. For now, it seems that an important mechanism is inflammation in the small vessels, particularly in the heart and lungs, but potentially also in other organs, e.g. digestive tract.

Indirect effects are more difficult to measure as they may range from the avoidance of using health services due to the fear of infection. This may lead to: (a) delays in the diagnosis of more acute conditions, such as acute myocardial infarction (AMI) or stroke (CVI); (b) skipping screening appointments or their cancellation due to the running epidemic; (c) lengthening of the waiting lists for diagnostic and therapeutic procedures.

An important feature of the Covid-19 pandemic is also the fact that the knowledge about it is only being gained and it is still unfolding. We are faced with an interesting challenge, where it has become easy to publish quickly about the different findings. But this goes against the scientific rigor in some cases. It is essential to exert an above average level of caution when interpreting results.

Against this background, we conduct this literature review with the main purpose of shedding more light on: (i) the prevalence of Covid-19 (and hence susceptibility) among patients with chronic illnesses; (ii) the analytical link between NCDs, disease progression and disease outcome among patients with selected NCDs; (iii) the pathways through which Covid-19 impacts upon patients with various NCDs from a clinical perspective and (iv) to provide a more definitive answer on the link between medications used to manage various NCDs and Covid-19 progression and outcome.

Methodology

We conducted literature review on published papers from 31st of December, 2019 until the 15th of November, 2020. The search was done in PubMed and in doing so we used a variety of searching terms in order to isolate the final set of papers. The template below provides a snapshot of the search mechanisms that we used:

(“covid 19” or “COVID 19” or “sars Cov 2” or “coronavirus” or “corona virus”) and (“non communicable diseases” or “non communicable disease” or “NCD” or “NCDs” or “chronic illnesses” or “chronic diseases”)

(“covid 19” or “COVID 19” or “sars Cov 2” or “coronavirus” or “corona virus”) and (“diabetes” or “cardiovascular diseases” or “hypertension” or “cancer” or “kidney disease”).

The studies that were extracted were carefully examined. The inclusion criteria included, inter alia, prevalence of the NCDs in the search criteria. Moreover, we also included studies that reported clinical outcomes in form of disease severity as well as death. The studies were limited to adult humans and had to be written in English in order to be considered. Duplicate studies, letters, case reports, abstracts, studies written in languages other than English were excluded.

No ethical approval was needed, given that this was a literature review of published studies.

Figure  1 above provides a snapshot of the selection criteria for the papers in this literature review. Initially, 2732 records were identified and after screening for titles, abstracts and full papers, 45 records were retained which were used in this literature review and which we elaborate on throughout this paper.

Flow chart of the publication selection process. Source: Authors

Covid-19 and diabetes

Most of the studies included in this literature review study the link between Covid-19 and diabetes (Table  1 ). A strand of this literature has focused on studying the prevalence of diabetes in Covid-19 patients, albeit descriptively. According to the existing studies, the prevalence of diabetes in Covid-19 patients varies, but it is almost always in double digit levels. More specifically, the prevalence of diabetes among Covid-19 patients ranges from 14% [ 1 ], 17% [ 2 ], 22% [ 3 ] to 44% [ 4 ] (Additional file 1 : Table A1).

A special strand of the literature has also focused on a more analytical link between diabetes and Covid-19, focusing on a few specific outcomes, such as mortality or severity of the disease. The common thread in this strand of the literature is that patients with diabetes show a consistently lower likelihood of survival or recovery and are much more likely to have a severe disease progression, compared to the non-diabetic patients.

In a retrospective case series, Yan et al. [ 5 ] for example, report that the survival rate was lower among the diabetic patients compared to the non-diabetic ones. More specifically, in their study, the HR was 1.5 (95% CI 1.0–2.3) after adjustment for demographic factors. Similarly, Yan et [ 6 ] find the patients with diabetes had consistently and independently poorer outcomes with a relative risk of dying at 3.0 (95% CI 1.3–6.8). In the context of Mexico, a study also found that diabetes is associated with hospitalization and worse outcomes among patients with Covid-19. These findings are echoed in some existing literature reviews [ 7 ]. For example, in a study by Du et al. [ 8 ], the risk of severe cases was higher in Covid-19 patients with diabetes (RR = 2.1, 95%CI 1.8–2.6) and the risk of death was also higher in Covid-19 patients with diabetes (RR = 3.2, 95%CI 2.6–3.8). Furthermore, and going beyond mortality as an outcome, Praveen et al. [ 9 ] find that diabetes was lower in the survivors (OR: 0.6; 95%CI: 0.4–0.9) and non-severe patients (OR: 1.7; 95%CI 1.2–2.3). Finally, Noor et al. [ 10 ] found a significant association between Covid-19 and mortality among diabetes patients (RR 1.9, 95% CI 1.2–2.8).

A few of the literature reviews that we include have conducted meta-analyses in order to further unearth the link between diabetes and Covid-19 mortality. In most of the cases, the authors find statistically significant link between diabetes and dying from Covid-19 with odds ratios higher than one. In a meta-analysis by Wu et al. [ 11 ], the authors find a close link between diabetes and mortality with OR of 1.75. In another literature review conducted by Ssentonoga et al. [ 12 ], diabetes was associated with a significantly greater risk of mortality from Covid-19 (OR 1.5, 95% CI 1.0–2.2). In the rest of the studies, the odds ratios capturing the link between diabetes and Covid-19 mortality teeter around 2.5 [ 13 , 14 , 15 , 16 , 17 ]. In only one of the studies the odds ratios of death due to Covid-19 among diabetics were higher than 3. More specifically, Lu et al. [ 18 ] find that diabetes comorbidity was one of the key mortality risk factors (OR = 3.7, 95% CI 2.4–5.9). Furthermore, and taking a more comprehensive approach Awortwe et al. [ 19 ] suggest that cardio-metabolic syndrome (mainly characterized by insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension, and central adiposity) is associated with negative clinical outcomes including mortality (risk difference RD 0.1, 95%-CI 0.1–0.2), admission to ICU (RD 0.1, 95%-CI 0.04–0.2) and severe infection (RD 0.1, 95%-CI 0.01–0.09) in Covid-19 patients (Additional file  1 : Table A1).

Covid-19 and hypertension/cardiovascular diseases

The second most studied set of chronic illnesses are cardiovascular illnesses, including hypertension (Table 1 ). Similarly, to the case of diabetes, one strand of the literature has focused descriptively on the prevalence of hypertension and cardiovascular diseases among Covid-19 patients. In a literature review, Wolff et al. [ 20 ], establish that, along with diabetes, hypertension and other cardiovascular diseases are the most prevalent chronic illnesses among Covid-19 patients. The prevalence of hypertension in Covid-19 patients vary, from 15.6% [ 4 ], 16.4% [ 21 ], 22% [ 1 ], 27.4% [ 2 ] to 38.6% [ 3 ]. Similarly, the prevalence of other cardiovascular diseases is in double-digits varying form 4.7% [ 4 ], 8.9% [ 2 ], 12.1% [ 21 ], 13% [ 1 ] to 17.5% [ 3 ]. (Additional file 1 : Table A2).

In the second strand of the literature, the authors establish a more analytical link between hypertension (and the rest of the cardiovascular diseases) and negative clinical outcomes (e.g. death or severity of illness) among Covid-19 patients. In that respect, the link between hypertension and Covid-19 outcomes is particularly studied. A very comprehensive literature review by Pranata et al. [ 22 ] suggests that hypertension was associated with increased composite poor outcome (risk ratio (RR) 2.1 95% CI 1.9–2.4) and its sub-group, including mortality (RR 2.2 95% CI 1.7–2.8), severe Covid-19 (RR 2.0, CI 1.7–2.5), ARDS (RR 1.6, 95% CI: 1.1–2.4), ICU care (RR 2.1, 95% CI: 1.3–3.3), and disease progression (RR 3.0, 95% CI: 1.5–6.0). Similarly, in a literature review by Parveen et al. [ 9 ], hypertension was positively associated with death (OR: 0.5; 95% CI: 0.3–0.7), ICU care (OR: 0.4; 95%CI: 0.2–0.8) and severity (OR: 2.7; 95% CI 1.3–5.7) (Additional file 1 : Table A2).

While establishing a link between hypertension and Covid-19 mortality, most of the literature reviews also conduct meta-analyses, which find significantly higher odds of Covid-19 mortality among hypertensive patients, with odds ratios usually ranging from 2.5 to 3 [ 10 , 12 , 13 , 14 , 23 , 24 , 25 ]. Finally, only in one of the meta-analyses were the odds ratios of dying from Covid-19 among hypertensive patients was higher than 3. More specifically, a literature review by Liu et al. [ 17 ] confirms the finding that hypertension (OR 3.4, 95% CI 2.5–4.7) was one of the key mortality risk factors.

Similarly, to hypertension, a strand of this literature has focused exclusively on the clinical outcomes of Covid-19 patients with other cardio-vascular comorbidities. In a study by Gu et al. [ 26 ], the estimated mortality risk in patients with pre-existing coronary heart disease (CHD) was three times that of those without CHD. The estimated 30-day survival probability for a profile patient with pre-existing CHD (65-year-old woman with no other comorbidities) was 0.5 (95% CI 0.3–0.8). Furthermore, a study in Oman [ 27 ] found that patients with cardiac injury had higher mortality than those without cardiac injury (53.3% vs 7.1%). The literature review by de Almeida-Pittito [ 13 ] mentioned above also suggested that cardiovascular disease was strongly associated with both severity and mortality, respectively (OR 4.0 95% CI 2.8–5.9 and OR 6.3 95% CI 3.7–10.8) also reflecting the previous findings [ 10 ]. In addition, the literature review by Matshushita et al. [ 23 ] suggested that acute myocardial injury, determined by elevated high-sensitivity troponin levels, is commonly observed in severe cases, and is strongly associated with mortality. Moreover, a comprehensive review by Ssentonoga et al. [ 12 ] found that cardiovascular disease (risk ratio (RR) 2.3, 95% CI 1.6–3.2) and congestive heart failure (RR 2.03 95% CI 1.3–3.2) were associated with a significantly greater risk of mortality from Covid-19. A review by Khan et al. [ 16 ] found that higher likelihood of dying was found among Covid-19 patients who had pre-existing cardiovascular diseases (odds ratio 3.4 95% CI 2.9–4.1), reflecting the findings by Liu et al. [ 17 ]. Finally, a literature review by Hessami et al. [ 28 ] indicated that acute cardiac injury, (OR: 13.3, 95% CI 7.4–24.0), heart failure (OR: 6.7, 95% CI 3.3–13.5), arrhythmia (OR: 2.8, 95% CI 1.4–5.3), coronary artery disease (OR: 3.8, 95% CI 2.4–5.9), and cardiovascular disease (OR: 2.6, 95% CI 1.9–3.6) were significantly associated with Covid-19 mortality (Additional file 1 : Table A2).

Covid-19 and COPD

The third most prevalent chronic illness associated with negative outcomes due to Covid-19 is COPD (chronic obstructive pulmonary disease) as well as other underlying chronic illnesses. As in the rest of the literature, here as well, there are two strands that emerge: one of them is focused on the link between Covid-19 and chronic respiratory illnesses from a descriptive point of view, while the second strand is more analytical. In their literature review, Mahmud et al. [ 1 ] and Bajgain et al. [ 2 ] find that most prevalent chronic comorbid conditions were, inter alia, respiratory diseases (5%).

The second strand of the literature is more analytical and tries to establish a more robust link between pre-existing chronic lung illnesses and Covid-19 disease outcomes. Nachtigall et al. [ 29 ] for example argue that pre-existing lung disease was one of the main predictors of death (HR 1.6; 95%CI 1.2–2.2). Similarly, Lu et al. [ 18 ] in a literature review suggest that chronic lung disease (OR 3.4, 95% CI 1.8–6.5) was one of the key mortality risk factors, which is further echoed in the other studies included in this literature review [ 14 , 16 , 17 ] (Additional file 1 : Table A3).

Finally, a special strand of the literature has focused on COPD as the most dominant pulmonary chronic illness and its link with Covid-19. Graziani et al. [ 30 ] find that compared with COPD-free individuals, COPD patients with Covid-19 showed significantly poorer disease prognosis, as evaluated by hospitalizations (31.1% vs. 39.8%: OR 1.6; 95% CI 1.1–1.2) and mortality (3.4% vs. 9.3%: OR 2.9; 95% CI 2.3–3.8). In their literature review, Awortwe et al. [ 19 ], indicated that chronic obstructive pulmonary disease, inter alia, worsen the clinical outcomes including mortality (risk difference RD 0.1, 95%-CI 0.05–0.2), admission to ICU (RD 0.1, 95%-CI 0.04–0.2) and severe infection (RD 0.05, 95%-CI 0.01–0.09) in Covid-19 patients (Additional file 1 : Table A3).

Covid-19 and chronic kidney disease

The fourth most common chronic illnesses associated with negative outcomes related to Covid-19 are chronic kidney diseases. In a literature review by Bajgain et al. [ 2 ], around 2.6% of patients with chronic kidney disease also had Covid-19.

A literature review by Awowrtwe et al. [ 19 ] found a significantly higher likelihood of poor Covid-19 outcomes among patients with chronic kidney disease. Results suggested that chronic kidney disease, inter alia, was associated with worse clinical outcomes including mortality (risk difference RD 0.1, 95%-CI 0.1–0.12), admission to ICU (RD 0.1, 95%-CI 0.04–0.2) and severe infection (RD 0.05, 95%-CI 0.01–0.09) in Covid-19 patients. A literature review by Sepandi et al. [ 14 ] found that some chronic diseases such as kidney disorder (OR 2.6 95% CI 1.2–5.6) can increase the risk of Covid-19 mortality, which is similar to the rest of the studied included in this review [ 12 , 16 , 31 ] (Additional file 1 : Table A4).

Covid-19 and cancer

As in the rest of the chronic illnesses the literature on the link between Covid-19 and cancers could be divided into two strands. In the first one, authors are mainly concerned with finding the prevalence of cancer among Covid-19 patients. The literature reviews that we cover suggest prevalence of cancer among Covid-19 patients ranging from 1.2% [ 4 ] to 3.5% [ 2 ] and 8% [ 1 ] (Table A 5 ).

The second strand of the literature has analytically established a link between cancer and Covid-19 outcomes. In a literature review by Noor et al. [ 10 ] a significant association were found between mortality among Covid-19 infected patients and cancer (RR 2.3, 95% CI 1.8–3.0). Similarly, a literature review by Ssentonoga et al. [ 12 ] found that cancer (1.5 95% CI 1.01 to 2.2) was associated with a significantly greater risk of mortality from Covid-19. In their own review, Khan et al. [ 16 ] suggest higher likelihood of deaths was found among Covid-19 patients who had any types of cancers (OR 2.2, 95% CI 1.6–3.0). Finally, and specifically focusing on cancer patients, Zhang et al. [ 32 ] find a significantly higher mortality rate, particularly if the anti-tumour treatment was within the last 14 days. There is a nuance however. While existing evidence finds that the fatality rate in the lung cancer patients with Covid-19 was 32.9% (95% CI 27.9 to 38.0%) and the fatality rate in haematological cancer patients was 34.2% (95% CI 23.1 to 46.2%), in other types of solid cancer excluding lung, the overall case fatality and severe event rates were 17.2% (95% CI 12.3 to 22.7%) [ 33 ]. Similarly, another study finds that patients with solid versus hematologic cancers exhibit different clinical outcomes, with patients with hematologic cancers having a significantly higher mortality relative to patients with solid cancers after accounting for confounders [ 34 ].

Covid-19 and liver disease

The literature on the link between Covid-19 and chronic liver disease is less sanguine. In three of the four studies that we had identified, there is a clear link between existing liver chronic illness and higher likelihood of mortality. Oyelade et al. [ 35 ] found that in patients with Covid-19 and underlying liver diseases, 57.3% (43/75) of cases were severe, with 17.65% mortality. Khan et al. [ 16 ] found that there was a higher likelihood of deaths was found among Covid-19 patients who had pre-existing liver diseases (OR = 2.4, 95% CI 1.5–3.7), echoing previously established notion [ 10 ]. However, in another literature review, Wang et al. [ 31 ] found no relationship between Covid-19 mortality and pre-existing liver disease (Table A 6 ).

Covid-19 and asthma

As in the rest of the cases, a strand of the literature has focused on estimating the prevalence of asthma among Covid-19 patients. In a study in South Korea, the prevalence of asthma among Covid-19 patients was 2.9% [ 36 ], somewhat similar to another review which finds that asthma is a pre-morbid condition in about 1.6% of the Covid-19 patients [ 37 ]. Another systematic review of the link between asthma and Covid-19 finds a somewhat higher prevalence of asthma among Covid-19 patients (7.46%) [ 38 ] echoing the heterogeneity of prevalence across different countries and regions as reported in another systematic review [ 39 ].

The second strand of the literature has focused on studying the clinical outcomes of asthma patients with Covid-19. A systematic literature review finds that there was no significant difference in the combined risk of requiring admission to ICU and/or receiving mechanical ventilation for people with asthma (RR 0.87, 95% CI 0.94–1.37) and risk of death from Covid-19 (RR 0.87; 95% CI 0.68–1.10) [ 38 ].These findings are similar to the ones conducted in another meta-analysis [ 40 , 41 ]. Overall, the literature suggests that asthma is not an independent risk factors for the clinical outcomes of Covid-19 [ 36 ]. In a study by Chibba et al. [ 42 ], asthma was not associated with an increased risk of hospitalization (relative risk, 0.96; 95% CI, 0.8–1.2) after adjusting for age, sex, and comorbidities. Similarly, a literature review by Morais-Almeida et al. [ 43 ] found that there is no strong evidence supporting that patients with asthma have a higher risk of becoming seriously ill from coronavirus disease 2019 (Table A 7 ).

There are a few findings that stem from this review on the link between Covid-19 and non-communicable diseases. First, as evidenced by this review, studies have observed a high prevalence of certain chronic illnesses (diabetes, hypertension) among Covid-19 patients. Second, and going beyond descriptive observation, majority of the studies find that Covid-19 patients have higher likelihood of worse clinical outcomes (e.g. higher mortality) compared to patients without chronic illnesses. This is particularly the case for diabetes, hypertension, COPD and chronic kidney disease. Third, while our findings are similar for the rest of the chronic illnesses featured in this review, they are less sanguine in the case of chronic liver disease. Finally, the result of the literature review suggests no link between asthma and Covid-19.

While the research on the interplay between diabetes and Covid-19 is still ongoing, there are a few preliminary findings/research hypotheses that have been put forth as to why diabetic patients are associated with more pronounced Covid-19 complications.

First, the existing knowledge suggests that patients with chronic illnesses (diabetes, hypertension, other cardio-vascular diseases, chronic kidney disease) have increased ACE2 (angiotensin-converting enzyme 2) receptor expressions, which facilitates the entry of the virus into the host body [ 44 ]. Moreover, as the study by Erener et al. [ 45 ] suggests, ACE2 is expressed in various tissues including the lung, heart, kidney tubules, the luminal surface of the small intestine, blood vessels, endocrine and exocrine pancreas [ 45 ]. Similar explanations, specific to cardio-vascular diseases have been put forth by Pranata et al. [ 22 ]. In the case of asthma, it has been argued that respiratory epithelial cells in patients with asthma have decreased gene expression for ACE2 receptors and therefore may be protective against Covid-19 infection [ 46 ].

Another potential reason for the increased risk of severe Covid-19 disease in patients with chronic illnesses might be attributed to the hyperinflammatory response, referred to as “cytokine storm” [ 47 , 44 ]. Patients with certain chronic illnesses (e.g. diabetes, hypertension) suffer from a continuous low-grade inflammation facilitating the emergence of a cytokine storm, which in turn appears to be directly related to the severity of Covid-19 pneumonia cases and to subsequent death [ 47 ]. More specifically, patients with diabetes appear to have an impaired adaptive immune response characterized by an initial delay of Th1 cell-mediated immunity and a late hyperinflammatory response. In the absence of an immunostimulant, diabetes is associated with an increased pro-inflammatory cytokine response marked by increased secretion of IL-1, IL-6, IL-8 and TNF-α, which in turn play a more deleterious role in Covid-19 infection [ 44 , 45 ]. When specifically focusing on cancer, ACE2 and TMPRSS2 expression is found higher in cancer patients, and coagulopathy is a potential risk observed in a number of cancer patients [ 48 ]. Different hypotheses have been put forth regarding the differences in clinical outcomes between Covid-19 patients with solid vs. hematologic cancers. A study has found that the principal cause of elevated mortality risk from Covid-19 in solid cancer patients is cancer progression [ 49 ]. In contrast, the same study suggests that in haematological cancer patients, there was a particularly striking expression of exhaustion markers by CD8+ T cells. Exhausted T cells, in turn, may compromise virus clearance [ 49 ].

These links between Covid-19 and some of the chronic illnesses mentioned above have implications on the impact of current medical treatments for certain chronic illnesses on the probability of developing severe Covid-19. However, the results presented in studies covered in this literature review reveal that there is no evidence to support this hypothesis currently. In view of lack of robust evidence for either benefit or harm, it is reasonable for patients to continue using ACE inhibitors and ARB, as recommended by European Society of Cardiology Council on Hypertension, European Society of Hypertension and American Heart Association [ 44 ]. Moreover, there are several studies about the protective effect of statins in pneumonia [ 44 ]. Statins are known to increase ACE-2 levels and may protect against viral entry of SARS CoV-2. However, this increase in ACE-2 could be counterintuitive in the current context. Nevertheless, statins are known to inhibit Nuclear factor kappa B (NFkB) activation and might help in blunting the cytokine storm [ 44 ].

Similarly, to the case of diabetes, the literature review on the link between medications prescribed for managing hypertension and severity of Covid-19 finds no conclusive evidence. In a review by Hessami et al. [ 28 ] in 9 studies that were included, with a total of 10.900 Covid-19 cases, the random-effects analysis showed a combined OR for severity 0.76 (95% CI 0.39–1.49). Moreover, in their study there was a high heterogeneity indicating that there was no association between use of ACEI/ARB and Covid-19 severity. Continuation of ongoing treatment, coupled with self-management and remote interventions has also been suggested in the context of other chronic illnesses such as asthma [ 50 ].

Conclusions and policy implications

There are a few conclusions that stem from this comprehensive literature review on the link between NCDs and Covid-19. First, patients with certain chronic illnesses such as diabetes, hypertension (and other cardiovascular diseases), chronic respiratory illnesses, chronic kidney and liver conditions are more likely to be affected by Covid-19. This is further attested by the high prevalence of some of these chronic illnesses (such as diabetes and hypertension) among Covid-19 patients. More importantly, once they do get infected by the virus, patients with chronic illnesses have a much higher likelihood to either develop a more severe illness than an average patient; moreover they are more likely to die relative to patients who do not have chronic illnesses. Our literature review presents evidence on this obtained both from case- controlled studies as well as from other literature reviews that we distilled. Third, while the research on the reasons behind the high susceptibility of NCD patients to Covid-19 is still ongoing, researchers have hypothesised two main channels: (i) increased ACE2 (angiotensin-converting enzyme 2) receptor expressions, which facilitates the entry of the virus into the host body; and (ii) hyperinflammatory response, referred to as “cytokine storm”. Our literature review points out that these transmission mechanisms are at play when it comes to all Covid-19/NCD linkages. Finally, the literature review does not find any evidence that diabetes or hypertension related medications exacerbate the overall Covid-19 condition in chronic illness patients. Based on this there are a few implications/policy recommendations that stem from this research. First, it is recommended that patients continued with existing treatment for chronic illnesses, especially as there is no evidence that certain medications (e.g. for managing diabetes or hypertension) are associated with worse Covid-19 clinical outcomes. Second, there should be a greater emphasis on telemedicine and virtual visits. With physical distances no longer a factor, virtualizing the care provided by diabetes educators, dieticians, and specialized mental health professionals could improve access further than what was previously possible with in-person encounters [ 51 ]. Third, through the virtual visits there should also be an improvement in patient education and self-management [ 52 ]. Fourth, given the ongoing Covid-19 vulnerabilities among people with NCDs, prioritizing them for the vaccination process should also figure high on the agenda on health authorities. Finally, all of the steps above have to be done in resource-constrained setting, with resources being diverted to Covid-19 needs. Thus and going beyond just covering the immediate needs to patients, health system strengthening, while putting particular emphasis on primary healthcare, could go long way in providing effective and safe management of chronic illnesses [ 53 ].

Availability of data and materials

Not applicable.

Abbreviations

Acute respiratory distress syndrome

Noncommunicable disease

Acute myocardial infarction

Confidence interval

Odds ratios

Intensive care unit

Coronary heart disease

Chronic obstructive pulmonary disease

Angiotensin-converting enzyme 2

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Acknowledgements

The paper was produced by the Saudi Public Health Authority, in collaboration with technical support from the World Bank. The authors are grateful for the overall support provided by Rekha Menon, World Bank Practice Manager, Health Nutrition and Population, Middle East and North Africa region, and Issam Abousleiman, World Bank Country Director for GCC countries.

This paper was funded under the Reimbursable Advisory Services Program on Health, Nutrition and Population (P172148) between the World Bank and the Ministry of Finance, Saudi Arabia.

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Additional file 1: table a1..

Covid-19 and diabetes: overview of the papers included in this literature review. Table A2. Covid-19, hypertension and cardiovascular diseases: overview of the papers included in this literature review. Table A3. Covid-19, COPD and other chronic respiratory illnesses: overview of the papers included in this literature review. Table A4. Covid-19 and chronic kidney disease: overview of the papers included in this literature review. Table A5. Covid-19 and cancer: overview of the papers included in this literature review. Table A6. Covid-19 and chronic liver disease: overview of the papers included in this literature review. Table A7. Covid-19 and asthma: overview of the papers included in this literature review.

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Nikoloski, Z., Alqunaibet, A.M., Alfawaz, R.A. et al. Covid-19 and non-communicable diseases: evidence from a systematic literature review. BMC Public Health 21 , 1068 (2021). https://doi.org/10.1186/s12889-021-11116-w

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Article Contents

1. introduction, 2. materials and method, 3. impact on mode choice, 4. impact on trip purposes, 5. sociodemographic characteristics, 6. policy implications, 7. conclusions, conflict of interest statement.

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Impact of COVID-19 on daily travel behaviour: a literature review

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Tonmoy Paul, Rohit Chakraborty, Nafis Anwari, Impact of COVID-19 on daily travel behaviour: a literature review, Transportation Safety and Environment , Volume 4, Issue 2, June 2022, tdac013, https://doi.org/10.1093/tse/tdac013

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The coronavirus disease 2019 (COVID-19) pandemic made a perceptible impact on daily travel behaviour worldwide, especially through mode shifts and changes in trip frequencies with possible long-term repercussions. Non-therapeutic interventions adopted worldwide (e.g. lockdowns and travel restrictions) to reduce viral contagion need to be understood holistically because it is challenging for people to follow through these policies and stay home in developing nations. In this context, it is important to have a clear idea of how COVID-19 is shaping the mobility pattern and what policies must be taken (if not yet) to minimize viral transmission as well as develop a sustainable transportation system. To this end, this study presents a systematically analysed review of 56 international literatures from academic sources (Google Scholar, Scopus and Web of Science) on the impacts of COVID-19 on travel behaviour and focuses on policymaking measures. This article illustrates the modal shift, variation in frequencies of different trips and how sociodemographic characteristics have influenced the mobility pattern in response to COVID-19. Innate changes in travel patterns compared to the pre-COVID-19 era were observed. A noticeable apprehension on viral transmission in public transit has reduced public transit usage while increasing that of private vehicles. This poses challenges to develop sustainable transportation. This study concludes by discussing intervention measures to support transportation planners and policymakers to deal with the current pandemic as well as any future pandemics.

The coronavirus disease 2019 (COVID-19) pandemic has been declared a major global public health issue by the World Health Organization (WHO) [ 1 ]. The outbreak not only affects human health but also disrupts the economy, social activities, mobility styles and habitual travel behaviours all over the world, aggravating people's living standards [ 2 ]. To mitigate the virus transmission, a range of strategies involving lockdowns, restrictions on out-of-home activities and safety guidelines of maintaining physical distances have been implemented in many countries [ 3 ]. Although it is still uncertain whether the implemented strategies are ideal for both developed and developing countries, they have caused a clear declination in global air pollution [ 4 ], bringing back blue skies and cleaner air.

Because most people live and work in cities, they are vulnerable to various natural and man-made disasters [ 5 ]. Hence, to minimize the impacts and ensure safe and sustainable transportation simultaneously across the planet, it is necessary to understand clearly how travel patterns are influenced by the pandemic and what actions are required to minimize the negative impacts. Nevertheless, the advancements in the transportation sector in recent years have made travel a major factor in rapid disease transmission worldwide [ 6 ]. Consequently, an overwhelming number of studies on COVID-19 and transportation have already appeared in the scientific literature after the outbreak. It is to be noted that similar public health crises have occurred earlier including the Ebola outbreak, the H1N1 influenza virus, the Zika virus and SARS. In response, numerous studies have been carried out to investigate travel pattern changes caused by the outbreaks [ 7–10 ]. However, the effect of these outbreaks was limited to particular geographic areas, whereas the present COVID-19 pandemic has affected the whole world [ 11 ]. Hence, a comprehensive literature review is highly essential to delineate the existing knowledge and findings of the impact of COVID-19 on travel behaviour and mobility style all around the world and highlight the gaps that need to be further studied. This study has attempted this feat through a holistic review of previous literature, whose process is outlined in Fig.  1 . According to Fig.  1 , this review article mainly aims to illustrate the global findings on daily transportation and hence has not included long-distance discretionary travel using modes such as ships, planes, etc. In addition, this study includes discussion on various local and national policies that can guide transport planners and policy makers in decision making. This can ensure a safe and sustainable trip worldwide while accomplishing greater community goals under such crucial circumstances.

Flowchart of the aims and objectives of the study.

This study has used academic literature relevant to COVID-19 and daily travel behaviour, obtained from three broad and the most appreciated scholarly databases: Web of Science, Google Scholar and Scopus. Initial search results using keywords ‘COVID-19' and ‘transport’ revealed approximately 8000 studies from January 2020 to May 2021 on the COVID-19 topic. However, many of these are focused on disciplines such as pharmaceutical sciences, nursing, medicine and issues related to patient transportation safety and healthcare professionals’ occupational safety. Inclusion criteria applied to finalize the relevant articles comprised of the following:

1. Source: The relevant articles were obtained from three highly credible scholarly databases.

2. Geographic location of the studies: In this review, the aim is to have a clear idea of how COVID-19 has influenced daily travel behaviour across the world. Hence studies from both developed and developing countries were considered.

3. Publication type: The attention was on peer-reviewed articles only. In most of the Literature Review Papers (LRPs), a minimum of 30 papers and a maximum of 100 papers are usually cited in the field of transport [ 12 ].

After filtering, screening and checking the abstracts of the articles to ensure their relevance, 32 English-written research papers published in peer-reviewed international journals were selected in our first submission. After an update in August 2021, in total 51 academic papers were considered relevant. In the third phase, 55 articles are selected in October 2021. Finally, updating in December 2021, 56 research articles were selected to be reviewed in detail. However, most of the papers selected were found in all three databases and the duplicated papers were removed. From all of the phases, a total of 94 papers were considered, of which 38 duplicate papers were removed and finally 56 papers were selected to be reviewed in detail. The dominance of the themes of the selected papers can be observed from the Keyword Co-occurrence Network (KCN) in Fig.  2 obtained from VOSviewer. This is a software tool for text mining and constructing and visualizing bibliometric networks. The text mining function of the software is used to extract keywords from titles, abstracts and citation contexts, which creates a co-occurrence network and displays it in a two-dimensional map [ 13 ]. The gap between two keywords is approximately inversely proportional to the relatedness between them, where relatedness is measured in terms of co-occurrence of keywords. The keywords are presented in clusters and are assigned to clusters based on their co-occurrence. Also, the area covered by each cluster is proportional to the amount of co-occurrence of the keywords under that cluster [ 14–16 ]. The KCN generated in this article contains 19 clusters. Fig.  2 reveals that ‘covid-19' is the most dominant key term, followed by ‘mobility patterns’, ‘travel behaviour’, ‘mobility’. The keywords closer to one another mean a higher rate of co-occurrence. So, keywords like ‘epidemic control’, ‘behavioural change’ and ‘expert survey’ are separated by large distances because of their lower rate of co-occurrence in keywords from our selected articles.

Keyword co-occurrence network.

A wide range of issues were meticulously tabulated and analysed with the help of Microsoft Excel. The tabulation results are introduced in Table  1 , which depicts the location, medium of data collection and the response count of the selected papers. Out of the 56 papers, 17 are within 2020 while the remaining are from 2021. Because the world continues to struggle with the COVID-19 crisis, research is continuously being done worldwide to improve understanding of the COVID-19 pandemic and mitigation of virus transmission to ensure safe transport of people. This literature review comprises an ever-growing body of studies carried out in both the developed countries and developing countries to understand the nature of the COVID-19 pandemic and explore solutions and policies to mitigate the devastating effects of this virus and ensure transport safety for the public. Among the reviewed papers, the majority of studies are from China and India, followed by Germany, the USA and Bangladesh, while few papers have used data from several countries worldwide. However, a global survey can pose limitations because of geographical variations [ 17 ]. Almost all of the studied literature has extracted data using the web-based questionnaire survey and through social media. This is because a web-based survey can reach a large number of people within a short period [ 18 ] and would ensure comfortable survey participation during the pandemic. However, the online survey system has drawbacks, such as lack of privacy, difficulties in survey design and inadequate participants [ 19 ]. König and Dreßler [ 20 ] conducted both household surveys and telephone interviews while Beck and Hensher [ 21 , 22 ] performed both online and field surveys for two separate studies. Exceptions to this practice include Aloi et al. [ 23 ] and Jenelius and Cebecauer [ 24 ], who collected data through traffic counters and transport authorities. Other than [ 25–27 ], all of the survey-related studies collected more than 300 responses.

Key trip purposes and online activities during COVID-19.

Some of the studies reviewed in this article have some limitations. For example, the data obtained in some studies are for a short period and do not create a deeper pool of data sets [ 28 ]. Moreover, some studies collected data in only one weather. Weather or climate plays a vital role in activity pattern change, particularly activity pattern change is more noticeable in warmer conditions [ 22 ]. It should be considered that not all studies measured all potentially relevant variables that could have controlled the travel behaviour change [ 29 ]. While most studies concentrated in single country may not represent the overall travel pattern change across the world, others that collected data through a global survey have high scatter and variation in data due to geographical location [ 17 ]. The socioeconomic conditions are diverse for different countries [ 3 ] and different countries had different levels of restrictions and different percentages of the infected population [ 17 ]. Table A1 displays the location, medium of data collection and response count of studied literature. This paper has segregated its review into four sections, namely, (i) mode choice, (ii) trip purpose, (iii) sociodemographic characteristics and (iv) policy implications, which are discussed in the subsequent sections.

The present pandemic has created striking changes in travel mode choice around the world. Some of the changes are in response to restrictive measures imposed by the governments that involve complete and partial lockdowns, whereas others are driven because of safety concerns and/or by the obligation to slow down the spread of the virus for the betterment of society. Table A2 presents in detail the modal usage changes and preferences during the COVID-19 pandemic. The summarized results from Table A2 are presented in Figs.  3 and  4 , respectively, where Fig.  3 depicts the comparison of the most and the least preferred modes during the pandemic. On the other hand, Fig.  4 elucidates the largest decrease and largest increase in the mode usage due to COVID-19 considered in the studies reviewed. It can be seen that, in almost all regions, public transport (usually bus, train, bus rapid transit (BRT), minibus) has expectedly been the least preferred mode to travel. The preferences for ride-sharing vehicles and ride-hailing services have decreased as well. This is because although the ride-hailing services may reduce the number of passenger contacts, smaller confined spaces and shorter social distances in cars may increase the chance of virus transmission (especially for drivers) [ 30 ]. A few studies have assessed the mode choice behaviour during the COVID-19 pandemic by performing statistical tests and developing models including exploratory factor analysis, multinomial logistic regression [ 17 ] and multiple discrete choice extreme value (MDCEV) models [ 2 ]. Mode choice has varied even during the COVID-19 period depending on the difference in soci-demographics [ 17 ], vehicle ownership [ 30 ], the status of employment [ 26 ] and purpose of the trip [ 2 ]. Apart from these factors, travel time saving, comfort and cost also affect mode choice, but these variables have less priority during the pandemic [ 17 ].

Mode preference summary from papers reviewed.

Mode usage change summary from papers reviewed.

Numerous studies have demonstrated a shift in respondent's preference from public transport to other modes during the pandemic [ 11 , 20 ]. Some studies have investigated mode shift using inertia analysis [ 2 , 11 , 31 ]. Among the most preferred/usage modes during the pandemic period, private cars have become the most preferred mode in many parts of the world including developing nations like Bangladesh and India [ 32 , 33 ]. For example, Zhang et al. [ 34 ] found a modal shift of 64.8% on average from public transport to private cars. This trend can be attributed to people's perception of reduced physical contact and infection chances when travelling via cars [ 25 ]. However, the benefits of sustainable transportation cannot be replaced by private vehicles. Moreover, high car usage can worsen traffic congestion [ 30 ]. Although active transportation mode (walking and cycling) has been observed along with private transportations, the actual percentage of bicycle usage is very low. Eisenmann et al. [ 35 ] observed an insignificant increase from 6% to 9% for the mono-modal group, while Politis et al. [ 36 ] noticed a disparaging rise in bicycle usage from 1.09% to 2.01%. Hence, the usage of these modes should be encouraged more [ 34 ] as walking and cycling aid people in maintaining higher well-being levels [ 25 ]. In addition, personal vehicle (car and motorcycle) owners are less likely to choose rickshaw (non-motorized transport, NMT) as the mode of choice for shopping trips in Bangladesh [ 33 ]. So, for people not owning personal vehicles during COVID-19, a rickshaw can be a suitable mode of transport as it is pollution-free and cost-effective for short-distance movement. For instance, Anwari et al. [ 11 ] observed a decent usage of NMT in their study. Some of the studies have investigated mode shifts to online/virtual medium [ 2 , 33 ], caused by an increase in work-from-home facilities and the ease of access as well as the prevalence of online shopping. However, it is possible to get infected via delivery people [ 2 ]. On the other hand, in Bangladesh, remote shopping is not that significant even during the pandemic situation because developing countries like Bangladesh have a weak e-commerce framework [ 33 ].

The most fundamental and dominating factor to generate a trip is its purpose. People make trips because they have activities to perform outside the home, and the types of activities determine the frequency of trip demand [ 37 ]. In general, people choose to travel either for commute purposes or for different discretionary purposes [ 2 ]. Based on the objectives of the studies, different authors categorized trips into different purposes. For example, Khaddar and Fatmi [ 25 ] analysed shopping trips, recreational activity trips and trips for buying household errand. Parady et al. [ 38 ] considered shopping and leisure trips for their study. During such a crisis, people may be able to reduce less important trips, although they are bound to travel for essential purposes. Table  1 represents the key purposes for which people all around the world have to generate trips even during the COVID-19 pandemic and for which people use the virtual medium as an alternate to make trips.

Shopping trips have been observed to be among the most highly participated ones during the pandemic. Shopping trips can be considered as trips for buying essential grocery items or as non-mandatory luxurious shopping [ 38 ]. Parady et al. [ 38 ] found contrasting results in their study because both essential trips (shopping) and non-essential shopping trips (dining outside) remained significant during the pandemic. Trips for commute purposes refer to travel between one's place of residence and place of work or study [ 3 ]. However, trips for some particular purposes have remained high using only a specific mode of transport. For example, Bhaduri et al. [ 2 ] found high discretionary trips using personal vehicles, and Molloy et al. [ 39 ] observed high shopping trips using bicycles only. In a few studies, although the trip reduction is the highest for particular purposes, the frequency remains large. For instance, Politis et al. [ 36 ] found the largest reduction in trips to be for home-based others (HBO) trips (shopping, leisure, etc.), although the rate of trips remained higher than home-based work (HBW) and non-home based (NHB) trips. Similarly, Politis et al. [ 40 ] observed the highest decrease in commute trips, yet a substantial percentage of people have continued to make these trips during the pandemic. On the other hand, Anke et al. [ 44 ] revealed that certain trip purposes have remained unchanged during the pandemic situation, while video conference usage was noticeable for work purposes. Similarly, Hiselius and Arnfalk [ 46 ] noticed a negligible change in work trips for the studied group, although the sample size of respondents seemed inadequate. Additionally, work trips remained as a prime trip purpose during the pandemic in the East Asian countries. In addition, Istanbul, a European city, has shown similar characteristics.

Online facility usage has varied from country to country. For instance, Italians and Swedish people heavily used the virtual medium for work purposes, while Indians used it for entertainment purposes [ 47 ]. Low work trip frequencies during the pandemic in several studies [ 17 , 22 ] can be attributed to job losses and an increase in work-from-home facilities. However, work at home has both benefits and limitations. Based on the study by Shamshiripour et al. [ 48 ], high productivity has been attributed to reduced/eliminated commuting times and a casual home environment. On the other hand, low productivity has been attributed to frequent distractions at home and a lack of comfortable workspace [ 48 ]. Hence, the home environment can either improve or deteriorate the work experience, depending on how well people have adjusted to the new normal. There has also been an increase in the time spent on the internet for social interactions, news and entertainment [ 50 ].

Sociodemographic characteristics play a vital role in travelling. While the exact effect on trips during the pandemic can vary from country to country, a few trends can be observed because of very limited choices [ 2 ]. Table  2 portrays the demographic groups who are at high risk of infection, caused by their high travel frequencies during the COVID-19 pandemic. Studies from Greece and Canada reveal that males and commuters are at high risk, respectively [ 25 , 36 ]. The risk is higher if the trip is made using shared vehicles or public transport, where a large group of unknown people travel together and cannot maintain physical distance measures. Based on both the studies from Germany, public transport users are at high risk of infection. Eisenmann et al. [ 35 ] mentioned that more than 60% of respondents feel uncomfortable travelling on public transport despite being forced to ride it. Although a decent percentage of people worked from home during the pandemic [ 2 ], a large portion still had to make trips to their workplaces. This might be due to the nature of the job or because their work does not support work-from-home practices [ 22 ]. Several researchers found increased daily trip preference among low-income holders because of their manual labour work, which increased their risk of virus contamination [ 21 , 45 , 50 ]. Moreover, Molloy et al. [ 39 ] reported that 20% of participants worked for short hours, despite trivially influencing daily trips. Healthcare personnel and people working in retail stores commuted daily during the pandemic [ 48 ].

Demographic groups having high infection risk.

Various studies show that males are making comparatively more daily trips than females are and are therefore at more risk of virus contagion [ 2 , 11 , 22 ]. Consequently, males have higher infection and death rates [ 54 ]. Interestingly, Khaddar and Fatmi [ 25 ] noticed that individuals living in a high-income household are more likely to be working out of the home, whereas middle-aged people from low-income households are not working outside of the home. On the other hand, Beck and Hensher [ 21 ] observed that younger respondents are more prone to having commuting trips, trips for education and childcare, food shopping and general shopping than middle-aged and older respondents are prone to. Hence, the younger respondents are at greater risk of infection than the middle-aged and older respondents. On the other hand, Anwari et al. [ 11 ] observed that 51–60-year-olds are frequent travellers. People from low-income groups in several studies are not able to access work-from-home facilities, open spaces to maintain a safe distance in the workplace, or are unable to use private cars to make trips [ 21 ]. As a result, low-income people face greater risks of virus contagion than higher-income groups do.

The COVID-19 pandemic has ushered in unprecedented challenges worldwide. Mobility patterns have changed unconventionally in response to reduce virus transmission and mitigate the associated ramifications of the pandemic. While some habits may be reverted, other changes can transcend into a new regular way of living. The question is ‘Is the world ready to adapt to the new normal and its behavioural habit in the post-pandemic situation?’ To dispel the doubt, priority must be given to appropriate transport planning and policy measures that reflect sustainable mobility objectives and accomplish the greater community goals under such crucial circumstances [ 3 ].

In response to the pandemic, social distancing measures were taken by imposing lockdowns in many parts of the world including China, Italy, Spain and Bangladesh, while less-rigid social distancing measures were taken in other countries like the Netherlands, Sweden and Japan. However, the result of lockdowns and restrictions on movement may be ineffective in countries with high population density, poor transportation infrastructure and a large informal economy [ 55 ]. Public transport is a major transport mode, accommodating many captive users. As public transport has been associated with increased risk of viral transmission, the services have been reduced and users are facing constraints to use them as a travel mode. As a result, out-of-home activities and manual labour work become inaccessible to low-income people who do not own cars. Work from home cannot act as an alternative to blue-collar jobs. Thus, transport planners and operators should prioritize safe transportation of workers and craftsmen during this pandemic through dynamic planning. In response to reduction of public transport services and reduced trust in its usage, affluent people are shifting to private vehicles. Nevertheless, a private vehicle is not a sustainable solution to transportation as it creates greater traffic congestion and occupies a larger portion of the roadway for transporting the same number of people than public transport does [ 3 ]. Hence, policymakers need to be cautious about the likely decline in usage of public transport and emphasize the improvements of public transport strongly by upgrading both the safety and level of service of buses, trams and transits. As an immediate response, the city of Manila, Philippines introduced a separated lane for Bus Rapid Transit without imposing additional fares to attract more commuters and maintain high service frequencies [ 56 ]. The internal design of buses can be modified and rearranged while using dividers to facilitate physical distancing among passengers as they board and descend from them [ 2 ]. Contactless payment like mobile financial services (MFS) can be implemented to prevent virus transmission through banknote payments in buses and trains. It is quite challenging to rebuild trust in public transport as many governments have used the media to request people to avoid using public transport [ 11 ]. However, if the right measures are taken, public transport can be COVID-safe [ 57 ]. According to a study by the University of Colorado Boulder, the risk of being infected in a well-ventilated metro with minimal talking and movement is 0% after 70 minutes. Moreover, the result is even lower for a bus ride [ 58 ]. Advancing these scientific studies can restore trust in public transport services. In the case of ride-hailing services, provision of face masks and facilities for sanitization of both drivers and passengers may help to resolve user concerns [ 3 , 11 , 17 ]. For countries like Bangladesh, where a rickshaw is available as a non-motorized vehicle, such provisions can play a vital role in the access of these captive users. Besides, virus transmission among commuters can be reduced by educating commuters, raising awareness about COVID-19, providing them with coronavirus updates, and updating them on the impact of COVID-19 on public transit [ 55 ].

Several studies revealed a rise in walking activity during the COVID-19 pandemic among people who cannot afford to run cars or use public transport [ 59 ]. The ongoing pandemic created unemployment and affected economic stability [ 34 ]. Many economically backward regions do not have sufficiently well-maintained pedestrian facilities [ 60 ]. Hence, reducing public transit services in these regions may entice people to walk more in poor pedestrian facilities without maintaining proper social distancing procedures, which can increase the risk of virus exposure. Thus, the government needs to improve walkway facilities in the cities. For example, footpath width can be increased to increase social distancing among pedestrians. However, relying on supply management only will not be effective as substantial areas of footpaths are occupied by street vendors, on-street parking and other hindrances. Thus, urban planners need to focus on safe and smooth walkability. In addition to pedestrian activity, cycling activity was also noticeable in many countries during the pandemic. However, a few studies [ 27 , 47 ] on the opposite end of the spectrum have observed an insignificant increase in active transport (walking and cycling) despite the potential of bicycles to reduce air pollution and help maintain a healthy lifestyle. This might be because many cities around the world lack proper pedestrian and bicycle infrastructure [ 17 ], even though there are other influencing factors like cultural, climatic and topographic conditions. Hence, transport authorities should give attention to building and maintaining safe and adequate bicycle lanes to promote cycling among the youth and to attract the private vehicle riders to shift to bicycles. Moreover, adequate bike racks and necessary cycling-friendly facilities should be established at locations like malls, workplaces, restaurants, etc. that have high trip attractions. Although cycling facilities in the previous year have been expanded including new or expanded bike lanes and paths in large European and American cities [ 61 ], bike-sharing has suffered in many cities because of increased contact risk [ 62 ]. Further research needs to address ways to sanitize bicycles when transferring usage from one person to another. Usually, commuters have to make trips in the morning peak period even during the COVID-19 pandemic [ 63 ]. This may still create crowding situations and stimulate virus transmission. Hence, policymakers should dynamically plan by combining a range of strategies involving regulation of flexible operating hours of various managerial departments and essential businesses to cope with the increased demands of transport and shortage of options due to social distancing. Besides, the possibilities of work-from-home facilities should be explored further to shift more commuters into the virtual medium. All meetings, conferences and desk jobs should be encouraged to be performed online. Apart from work purposes, online facilities have been very popular for shopping. Shamshiripour et al. [ 48 ] mentioned that more than half the respondents would reportedly do online grocery shopping more frequently even long after the pandemic. Thus, helplines and psychological assistance services can be widened for all age groups and occupations to use the internet to meet a variety of social needs. However, developing countries usually have a large proportion of people who do not have access or have limited usage knowledge about Information and Comminucations Technologies (ICT) tools. Such countries should focus on ensuring how people can still participate in activities that have largely shifted to ICT solutions to reduce unnecessary travel demand [ 11 ]. In this modern age, artificial intelligence and machine learning can assist in the understanding of travel patterns and behaviour while facilitating dynamic future planning [ 64 ]. This will reduce virus exposure and road congestion.

Studies revealed that male trip-makers travel more compared to females even during the pandemic [ 3 , 11 ]. This is because in developing countries like Bangladesh, most males have to work outside to earn for the family, whereas females look after the home [ 17 ]. Besides, males predominantly perform labour-intensive jobs and are hence more susceptible to COVID-19 infection. Thus, local authorities need to create awareness among men and take necessary action so that males take extra safety precautions during their pandemic trips. In addition, national authorities and policymakers should focus on the highly exposed age groups of people who make trips during the pandemic to minimize the virus contagion.

This article presents a review of the global findings on changes in transportation behaviour due to the COVID-19 pandemic along with an in-depth discussion on policymaking. Through a meticulous collection of research articles related to travel pattern changes during the present pandemic, this article presents a series of findings that include a brief discussion on mode shift and preferences during the pandemic, use of online facilities as an alternate of trip making, prime trip purposes during the pandemic, category of people at high risk of COVID-19 infection based on their travel behaviour and policy implications to provide insights for transport planners and policymakers. The article aims to showcase the scenario of daily travel all over the world due to the COVID-19 crisis that may help researchers conduct case studies under such circumstances in the future.

Previous studies showed reduced usage of public transportation but increased reliance on private cars [ 51 , 37 ]. Restriction on public transit usage is viewed as an emergency, the response to which, at least in the short term, is an increased reliance on private modes. Non-motorized vehicle usage and walking prevalence increased mostly in European countries. Despite this pandemic situation, we must act now to move beyond ensuring the survival of public transport by developing the infrastructure of public transportation, which will be effective in emergencies like this. Moreover, observed preference for active transports (bicycling, walking) in few studies demands more attention of the infrastructure planners to develop enough facilities, attract people to these modes and reduce traffic congestion [ 3 ]. Flexible operating hours for commute and development in internet facilities for work purposes could minimize infection risks and decrease traffic congestions. Policymakers should emphasize the accessibility of online facilities because apart from work purposes, online shopping (especially grocery shopping) experienced increased internet usage in almost all studies. Furthermore, local authorities should provide extra security for males in developing countries where they are the main earning members, but cannot significantly reduce physical trips (especially for commute).

However, various aspects of the COVID-19 pandemic still need further investigation. Researchers are uncertain when the present pandemic will be over and are concerned about the varying impacts of different waves of COVID-19 infection [ 65 ]. First, it is important to compare and contrast the travel pattern change as the first, second and third waves of the virus manifest impact over different time frames. After every wave of impact, while some people may adapt to the ‘new normal’ and shift the trips to online activity, others may again increase the use of public transport due to their poor financial condition and escalate the risk of virus contagion. It is quite impossible to implement lockdowns months after months, as people who earn their living through physical activities and manual labour have to suffer because of the absence of work and inability to make trips to their work destination. The investigation of the overall scenario of the COVID-19 influence level on daily travel behaviour throughout the different waves of the pandemic is essential as this would help transport policymakers plan strategically to meet the travel demand in the post-pandemic condition. Although Beck and Hensher [ 22 ] studied the travel pattern change in Australia during the lockdown and after the easing of the restrictions, further research is required until the pandemic ceases. Second, as the production and the supply of vaccines have begun in many countries, the mobility pattern can be compared among the ‘before vaccination period’, ‘during vaccination period’ and ‘after vaccination period’. As no vaccine is 100% effective [ 66 ], the virus may spread even after the completion of vaccination, especially because newer variants/mutations of the coronavirus may resist vaccines better [ 67 ]. Moreover, vaccinated people may try to return to their previous way of life and make discretionary trips without wearing any masks or maintaining social distancing while travelling to crowded locations. This may put unvaccinated people at risk, because the vaccine cannot protect people against transmission or sickness, but can only reduce the severity of the disease in the body [ 68 ]. Moreover, many countries may not get an adequate dosage of the vaccine on time because of vaccine diplomacy [ 69 ]. Besides, online activities may decline and the frequency of long-distance trips may rise again. Third, a comparison of travel behaviour is necessary between rural and urban people. Usually, in cities, the high population density can create greater havoc than in rural areas and hence serious movement restriction is required in cities and towns [ 70 , 3 ]. Usually, rural people are well self-subsistent and have to make less grocery trips. They can easily collect fruits and vegetables from farms and fishes from local ponds. On the contrary, urban people especially in developing countries have to make trips to buy groceries. Hence, the present pandemic may engage the urban to involve in subsistence through the creation of individual mini gardens on rooftops and in verandas [ 71 ].

Preparedness of the transportation sector across the world is required to deal with any future pandemic while minimizing the damage. Worldwide collaboration of researchers along with local and global policymakers could bring more impactful results. As this study has highlighted different types of changes in transportation behaviour during the pandemic across the world and analysed the measurements taken by the authorities to contain the virus contagion through public transport, it will provide insights for future researchers to compare and choose a definite and more effective method and estimate changes in activities and travel behaviour in the post-pandemic situation.

No conflict of interest exits in the submission of this manuscript, and the manuscript is approved by all authors for publication.

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Strategies to strengthen the resilience of primary health care in the COVID-19 pandemic: a scoping review

• Ali Mohammad Mosadeghrad 1 ,
• Mahnaz Afshari 2 ,
• Parvaneh Isfahani 3 ,
• Farahnaz Ezzati 4 ,
• Mahdi Abbasi 4 ,
• Shahrzad Akhavan Farahani 4 ,
• Maryam Zahmatkesh 5 &
• Leila Eslambolchi 4  

BMC Health Services Research volume  24 , Article number:  841 ( 2024 ) Cite this article

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Metrics details

Primary Health Care (PHC) systems are pivotal in delivering essential health services during crises, as demonstrated during the COVID-19 pandemic. With varied global strategies to reinforce PHC systems, this scoping review consolidates these efforts, identifying and categorizing key resilience-building strategies.

Adopting Arksey and O'Malley's scoping review framework, this study synthesized literature across five databases and Google Scholar, encompassing studies up to December 31st, 2022. We focused on English and Persian studies that addressed interventions to strengthen PHC amidst COVID-19. Data were analyzed through thematic framework analysis employing MAXQDA 10 software.

Our review encapsulated 167 studies from 48 countries, revealing 194 interventions to strengthen PHC resilience, categorized into governance and leadership, financing, workforce, infrastructures, information systems, and service delivery. Notable strategies included telemedicine, workforce training, psychological support, and enhanced health information systems. The diversity of the interventions reflects a robust global response, emphasizing the adaptability of strategies across different health systems.

Conclusions

The study underscored the need for well-resourced, managed, and adaptable PHC systems, capable of maintaining continuity in health services during emergencies. The identified interventions suggested a roadmap for integrating resilience into PHC, essential for global health security. This collective knowledge offered a strategic framework to enhance PHC systems' readiness for future health challenges, contributing to the overall sustainability and effectiveness of global health systems.

Peer Review reports

The health system is a complex network that encompasses individuals, groups, and organizations engaged in policymaking, financing, resource generation, and service provision. These efforts collectively aim to safeguard and enhance people health, meet their expectations, and provide financial protection [ 1 ]. The World Health Organization's (WHO) framework outlines six foundational building blocks for a robust health system: governance and leadership, financing, workforce, infrastructure along with technologies and medicine, information systems, and service delivery. Strengthening these elements is essential for health systems to realize their objectives of advancing and preserving public health [ 2 ].

Effective governance in health systems encompasses the organization of structures, processes, and authority, ensuring resource stewardship and aligning stakeholders’ behaviors with health goals [ 3 ]. Financial mechanisms are designed to provide health services without imposing financial hardship, achieved through strategic fund collection, management and allocation [ 4 , 5 ]. An equitable, competent, and well-distributed health workforce is crucial in delivering healthcare services and fulfilling health system objectives [ 2 ]. Access to vital medical supplies, technologies, and medicines is a cornerstone of effective health services, while health information systems play a pivotal role in generating, processing, and utilizing health data, informing policy decisions [ 2 , 5 ]. Collectively, these components interact to offer quality health services that are safe, effective, timely, affordable, and patient-centered [ 2 ]

The WHO, at the 1978 Alma-Ata conference, introduced primary health care (PHC) as the fundamental strategy to attain global health equity [ 6 ]. Subsequent declarations, such as the one in Astana in 2018, have reaffirmed the pivotal role of PHC in delivering high-quality health care for all [ 7 ]. PHC represents the first level of contact within the health system, offering comprehensive, accessible, community-based care that is culturally sensitive and supported by appropriate technology [ 8 ]. Essential care through PHC encompasses health education, proper nutrition, access to clean water and sanitation, maternal and child healthcare, immunizations, treatment of common diseases, and the provision of essential drugs [ 6 ]. PHC aims to provide protective, preventive, curative, and rehabilitative services that are as close to the community as possible [ 9 ].

Global health systems, however, have faced significant disruptions from various shocks and crises [ 10 ], with the COVID-19 pandemic being a recent and profound example. The pandemic has stressed health systems worldwide, infecting over 775 million and claiming more than 7.04 million lives as of April 13th, 2024 [ 11 ]. Despite the pandemic highlighting the critical role of hospitals and intensive care, it also revealed the limitations of specialized medicine when not complemented by a robust PHC system [ 12 ].

The pandemic brought to light the vulnerabilities of PHC systems, noting a significant decrease in the use of primary care for non-emergency conditions. Routine health services, including immunizations, prenatal care, and chronic disease management, were severely impacted [ 13 ]. The challenges—quarantine restrictions, fears of infection, staffing and resource shortages, suspended non-emergency services, and financial barriers—reduced essential service utilization [ 14 ]. This led to an avoidance of healthcare, further exacerbating health inequalities and emphasizing the need for more resilient PHC systems [ 15 , 16 , 17 ].

Resilient PHC systems are designed to predict, prevent, prepare, absorb, adapt, and transform when facing crises, ensuring the continuity of routine health services [ 18 ]. Investing in the development of such systems can not only enhance crisis response but also foster post-crisis transformation and improvement. This study focuses on identifying global interventions and strategies to cultivate resilient PHC systems, aiding policymakers and managers in making informed decisions in times of crisis.

In 2023, we conducted a scoping review to collect and synthesize evidence from a broad spectrum of studies addressing the COVID-19 pandemic. A scoping review allows for the assessment of literature's volume, nature, and comprehensiveness, and is uniquely inclusive of both peer-reviewed articles and gray literature—such as reports, white papers, and policy documents. Unlike systematic reviews, it typically does not require a quality assessment of the included literature, making it well-suited for rapidly gathering a wide scope of evidence [ 19 ]. Our goal was to uncover the breadth of solutions aimed at bolstering the resilience of the PHC system throughout the COVID-19 crisis. The outcomes of this review are intended to inform the development of a model that ensures the PHC system's ability to continue delivering not just emergency services but also essential care during times of crisis.

We employed Arksey and O'Malley's methodological framework, which consists of six steps: formulating the research question, identifying relevant studies, selecting the pertinent studies, extracting data, synthesizing and reporting the findings, and, where applicable, consulting with stakeholders to inform and validate the results [ 20 ]. This comprehensive approach is designed to capture a wide range of interventions and strategies, with the ultimate aim of crafting a robust PHC system that can withstand the pressures of a global health emergency

Stage 1: identifying the research question

Our scoping review was guided by the central question: "Which strategies and interventions have been implemented to enhance the resilience of primary healthcare systems in response to the COVID-19 pandemic?" This question aimed to capture a comprehensive array of responses to understand the full scope of resilience-building activities within PHC systems.

Stage 2: identifying relevant studies

To ensure a thorough review, we conducted systematic searches across multiple databases, specifically targeting literature up to December 31st, 2022. The databases included PubMed, Web of Science, Scopus, Magiran, and SID. We also leveraged the expansive reach of Google Scholar. Our search strategy incorporated a bilingual approach, utilizing both English and Persian keywords that encompassed "PHC," "resilience," "strategies," and "policies," along with the logical operators AND/OR to refine the search. Additionally, we employed Medical Subject Headings (MeSH) terms to enhance the precision of our search. The results were meticulously organized and managed using the Endnote X8 citation manager, facilitating the systematic selection and review of pertinent literature.

Stage 3: selecting studies

In the third stage, we meticulously vetted our search results to exclude duplicate entries by comparing bibliographic details such as titles, authors, publication dates, and journal names. This task was performed independently by two of our authors, LE and MA, who rigorously screened titles and abstracts. Discrepancies encountered during this process were brought to the attention of a third author, AMM, for resolution through consensus.

Subsequently, full-text articles were evaluated by four team members—LE, MA, PI, and SHZ—to ascertain their relevance to our research question. The selection hinged on identifying articles that discussed strategies aimed at bolstering the resilience of PHC systems amidst the COVID-19 pandemic Table 1 .

We have articulated the specific inclusion and exclusion criteria that guided our selection process in Table 2 , ensuring transparency and replicability of our review methodology

Stage 4: charting the data

Data extraction was conducted by a team of six researchers (LE, MA, PI, MA, FE, and SHZ), utilizing a structured data extraction form. For each selected study, we collated details including the article title, the first author’s name, the year of publication, the country where the study was conducted, the employed research methodology, the sample size, the type of document, and the PHC strengthening strategies described.

In pursuit of maintaining rigorous credibility in our study, we adopted a dual-review process. Each article was independently reviewed by pairs of researchers to mitigate bias and ensure a thorough analysis. Discrepancies between reviewers were addressed through discussion to reach consensus. In instances where consensus could not be reached, the matter was escalated to a third, neutral reviewer. Additionally, to guarantee thoroughness, either LE or MA conducted a final review of the complete data extraction for each study.

Stage 5: collating, summarizing and reporting the results

In this stage, authors LE, MZ, and MA worked independently to synthesize the data derived from the selected studies. Differences in interpretation were collaboratively discussed until a consensus was reached, with AMM providing arbitration where required.

We employed a framework thematic analysis, underpinned by the WHO's health system building blocks model, to structure our findings. This model categorizes health system components into six foundational elements: governance and leadership; health financing; health workforce; medical products, vaccines, and technologies; health information systems; and service delivery [ 2 ]. Using MAXQDA 10 software, we coded the identified PHC strengthening strategies within these six thematic areas.

Summary of search results and study selection

In total, 4315 articles were found by initial search. After removing 397 duplicates, 3918 titles and abstracts were screened and 3606 irrelevant ones were deleted. Finally, 167 articles of 312 reviewed full texts were included in data synthesis (Fig.  1 ). Main characteristics of included studies are presented in Appendix 1.

PRISMA Flowchart of search process and results

Characteristics of studies

These studies were published in 2020 (18.6%), 2021 (36.5%) and 2022 (44.9%). They were conducted in 48 countries, mostly in the US (39 studies), the UK (16 studies), Canada (11 studies), Iran (10 studies) and Brazil (7 studies) as shown in Fig.  2 .

Distribution of reviewed studies by country

Although the majority of the reviewed publications were original articles (55.1 %) and review papers (21 %), other types of documents such as reports, policy briefs, analysis, etc., were also included in this review (Fig.  3 ).

An overview of the publication types

Strengthening interventions to build a resilient PHC system

In total, 194 interventions were identified for strengthening the resilience of PHC systems to respond to the COVID-19 pandemic. They were grouped into six themes of PHC governance and leadership (46 interventions), PHC financing (21 interventions), PHC workforce (37 interventions), PHC infrastructures, equipment, medicines and vaccines (30 interventions), PHC information system (21 interventions) and PHC service delivery (39 interventions). These strategies are shown in Table 3 .

This scoping review aimed to identify and categorize the range of interventions employed globally to strengthen the resilience of primary healthcare (PHC) systems in the face of the COVID-19 pandemic. Our comprehensive search yielded 194 distinct interventions across 48 countries, affirming the significant international efforts to sustain healthcare services during this unprecedented crisis. These interventions have been classified according to the WHO’s six building block model of health systems, providing a framework for analyzing their breadth and depth. This review complements and expands upon the findings from Pradhan et al., who identified 28 interventions specifically within low and middle-income countries, signaling the universality of the challenge and the myriad of innovative responses it has provoked globally [ 178 ].

The review highlights the critical role of governance and leadership in PHC resilience. Effective organizational structure changes, legal reforms, and policy development were crucial in creating adaptive healthcare systems capable of meeting the dynamic challenges posed by the pandemic. These findings resonate with the two strategies of effective leadership and coordination emphasized by Pradhan et al. (2023), and underscore the need for clear vision, evidence-based policy, and active community engagement in governance [ 178 ]. The COVID-19 pandemic posed significant challenges for PHC systems globally. A pivotal response to these challenges was the active involvement of key stakeholders in the decision-making process. This inclusivity spanned across the spectrum of general practitioners, health professionals, health managers, and patients. By engaging these vital contributors, it became possible to address their specific needs and to design and implement people-centered services effectively [ 41 , 42 , 43 ].

The development and implementation of collaborative, evidence-informed policies and national healthcare plans were imperative. Such strategies required robust leadership, bolstered by political commitment, to ensure that the necessary changes could be enacted swiftly and efficiently [ 41 , 45 ]. Leaders within the health system were called upon to foster an environment of good governance. This entailed promoting increased participation from all sectors of the healthcare community, enhancing transparency in decision-making processes, and upholding the principles of legitimacy, accountability, and responsibility within the health system [ 10 ]. The collective aim was to create a more resilient, responsive, and equitable healthcare system in the face of the pandemic's demands.

In the wake of the COVID-19 pandemic, governments were compelled to implement new laws and regulations. These were designed to address a range of issues from professional accreditation and ethical concerns to supporting the families of healthcare workers. Additionally, these legal frameworks facilitated the integration of emerging services such as telemedicine into the healthcare system, ensuring that these services were regulated and standardized [ 38 , 40 , 61 ]. A key aspect of managing the pandemic was the establishment of effective and transparent communication systems for patients, public health authorities, and the healthcare system at large [ 60 , 61 ]. To disseminate vital information regarding the pandemic, vaccination programs, and healthcare services, authorities leveraged various channels. Public media, local online platforms, and neighborhood networks were instrumental in keeping the public informed about the ongoing situation and available services [ 53 , 60 , 86 ]. For health professionals, digital communication tools such as emails and WhatsApp groups, as well as regular meetings, were utilized to distribute clinical guidelines, government directives, and to address any queries they might have had. This ensured that healthcare workers were kept up-to-date with the evolving landscape of the pandemic and could adapt their practices accordingly [ 60 , 144 ].

Healthcare facilities function as complex socio-technical entities, combining multiple specialties and adapting to the ever-changing landscape of healthcare needs and environments [ 179 ]. To navigate this dynamic, policy makers must take into account an array of determinants—political, economic, social, and environmental—that influence health outcomes. Effective management of a health crisis necessitates robust collaboration across various sectors, including government bodies, public health organizations, primary healthcare systems, and hospitals. Such collaboration is not only pivotal during crisis management but also during the development of preparedness plans [ 63 ]. Within the health system, horizontal collaboration among departments and vertical collaboration between the Ministry of Health and other governmental departments are vital. These cooperative efforts are key to reinforce the resilience of the primary healthcare system. Moreover, a strong alliance between national pandemic response teams and primary healthcare authorities is essential to identifying and resolving issues within the PHC system [ 29 ]. On an international scale, collaborations and communications are integral to the procurement of essential medical supplies, such as medicines, equipment, and vaccines. These international partnerships are fundamental to ensuring that health systems remain equipped to face health emergencies [ 63 ].

To ensure the PHC system's preparedness and response capacity was at its best, regular and effective monitoring and evaluation programs were put in place. These included rigorous quarterly stress tests at the district level, which scrutinized the infrastructure and technology to pinpoint the system’s strengths and areas for improvement [ 43 ]. Furthermore, clinical audits were conducted to assess the structure, processes, and outcomes of healthcare programs, thereby enhancing the quality and effectiveness of the services provided [ 63 ]. These evaluation measures were crucial for maintaining a high standard of care and for adapting to the ever-evolving challenges faced by the PHC system.

Financial strategies played a critical role in enabling access to essential health services without imposing undue financial hardship. Various revenue-raising, pooling, and purchasing strategies were implemented to expand PHC financing during the pandemic, illustrating the multifaceted approach needed to sustain healthcare operations under strained circumstances [ 9 , 19 ].

In response to the COVID-19 pandemic, the Indian government took decisive action to bolster the country's healthcare infrastructure. By enhancing the financial capacity of states, the government was able to inject more funds into the Primary Health Care (PHC) system. This influx of resources made it possible to introduce schemes providing free medications and diagnostic services [ 50 ]. The benefits of increased financial resources were also felt beyond India's borders, enabling the compensation of health services in various forms. In Greece, it facilitated the monitoring and treatment of COVID-19 through in-person, home-based, and remote health services provided by physicians in private practice. Similarly, in Iran, the financial boost supported the acquisition of basic and para-clinical services from the private sector [ 21 , 65 ]. These measures reflect a broader international effort to adapt and sustain health services during a global health crisis.

The COVID-19 pandemic presented a formidable challenge to the PHC workforce worldwide. Healthcare workers were subjected to overwhelming workloads and faced significant threats to both their physical and mental well-being. To build resilience in the face of this crisis, a suite of interventions was implemented. These included recruitment strategies, training and development programs, enhanced teamwork, improved protective measures, comprehensive performance appraisals, and appropriate compensation mechanisms, as documented in Table 3 . To address staffing needs within PHC centers, a range of professionals including general practitioners, nurses, community health workers, and technical staff were either newly employed or redeployed from other healthcare facilities [ 63 ]. Expert practitioners were positioned on the frontlines, providing both in-person services and telephone consultations, acting as gatekeepers in the health system [ 49 , 63 ]. Support staff with technological expertise played a crucial role as well, assisting patients in navigating patient portals, utilizing new digital services, and conducting video visits [ 102 ]. Furthermore, the acute shortage of healthcare workers was mitigated by recruiting individuals who were retired, not currently practicing, or in training as students, as well as by enlisting volunteers. This strategy was key to bolstering the workforce and ensuring continuity of care during the pandemic [ 109 ].

During the pandemic, new training programs were developed to prepare healthcare staff for the evolving demands of their roles. These comprehensive courses covered a wide array of critical topics, including the correct use of personal protective equipment (PPE), the operation of ventilators, patient safety protocols, infection prevention, teamwork, problem-solving, self-care techniques, mental health support, strategies for managing stress, navigating and applying reliable web-based information, emergency response tactics, telemedicine, and direct care for COVID-19 patients [ 74 , 95 , 100 , 108 , 110 , 112 , 117 ].

Acknowledging the psychological and professional pressures faced by the primary healthcare workforce, health managers took active measures to safeguard both the physical and mental well-being of their employees during this challenging period [ 124 ]. Efforts to protect physical health included monitoring health status, ensuring vaccination against COVID-19, and providing adequate PPE [ 63 , 72 ]. To address mental health, a variety of interventions were deployed to mitigate anxiety and related issues among frontline workers. In Egypt, for instance, healthcare workers benefited from psychotherapy services and adaptable work schedules to alleviate stress [ 126 ]. Singapore employed complementary strategies, such as yoga, meditation, and the encouragement of religious practices, to promote relaxation among staff [ 133 ]. In the United States, the Wellness Hub application was utilized as a tool for employees to enhance their mental health [ 132 ]. In addition to health and wellness initiatives, there were financial incentives aimed at motivating employees. Payment protocols were revised, and new incentives, including scholarship opportunities and career development programs, were introduced to foster job satisfaction and motivation among healthcare workers [ 63 ].

The resilience of PHC systems during the pandemic hinged on several key improvements. Enhancing health facilities, supplying medicines and diagnostic kits, distributing vaccines, providing medical equipment, and building robust digital infrastructure were all fundamental elements that contributed to the strength of PHC systems, as outlined in Table 3 . Safe and accessible primary healthcare was facilitated through various means. Wheelchair routes were created for patients to ensure their mobility within healthcare facilities. , dedicated COVID-19 clinics were established, mass vaccination centers were opened to expedite immunization, and mobile screening stations were launched to extend testing capabilities [ 23 , 33 , 63 , 140 ].

In Iran, the distribution and availability of basic medicines were managed in collaboration with the Food and Drug Organization, ensuring that essential medications reached those in need [ 89 ]. During the outbreak, personal protective equipment (PPE) was among the most critical supplies. Access to PPE was prioritized, particularly for vulnerable groups and healthcare workers, to provide a layer of safety against the virus [ 63 ]. Vaccines were made available at no cost, with governments taking active measures to monitor their safety and side effects, to enhance their quality, and to secure international approvals. Furthermore, effective communication strategies were employed to keep the public informed about vaccine-related developments [ 32 , 83 ].

These comprehensive efforts underscored the commitment to maintaining a resilient PHC system in the face of a global health every individual in the community could access healthcare services. To facilitate this, free high-speed Wi-Fi hotspots were established, enabling patients to engage in video consultations and utilize a range of e-services without the barrier of internet costs crisis. Significant enhancements were made to the digital infrastructure. This expansion was critical in ensuring that [ 30 , 54 ]. Complementing these measures, a variety of digital health tools were deployed to further modernize care delivery. Countries like Nigeria and Germany, for instance, saw the introduction of portable electrocardiograms and telemedical stethoscopes. These innovations allowed for more comprehensive remote assessments and diagnostics, helping to bridge the gap between traditional in-person consultations and the emerging needs for telemedicine [ 141 , 180 ].

Throughout the COVID-19 pandemic, targeted interventions were implemented to bolster information systems and research efforts, as outlined in Table 3 . Key among these was the advancement of a modern, secure public health information system to ensure access to health data was not only reliable and timely but also transparent and accurate [ 33 , 45 , 49 ]. The "Open Notes" initiative in the United States exemplified this effort, guaranteeing patient access to, and editorial control over, their health records [ 141 ]. Management strategies also promoted the "one-health" approach, facilitating the exchange of health data across various departments and sectors to enhance public health outcomes [ 10 ].

In addition to these information system upgrades, active patient surveillance and early warning systems were instituted in collaboration with public health agencies. These systems played a pivotal role in detecting outbreaks, providing precise reports on the incidents, characterizing the epidemiology of pathogens, tracking their spread, and evaluating the efficacy of control strategies. They were instrumental in pinpointing areas of concern, informing smart lockdowns, and improving contact tracing methods [ 33 , 63 , 72 ]. The reinforcement of these surveillance and warning systems had a profound impact on shaping and implementing a responsive strategy to the health crisis [ 10 ].

To further reinforce the response to the pandemic, enhancing primary healthcare (PHC) research capacity became crucial. This enabled healthcare professionals and policymakers to discern both facilitators and barriers within the system and to devise fitting strategies to address emerging challenges. To this end, formal advisory groups and multidisciplinary expert panels, which included specialists from epidemiology, clinical services, social care, sociology, policy-making, and management, were convened. These groups harnessed the best available evidence to inform decision-making processes [ 30 ]. Consequently, research units were established to carry out regular telephone surveys and to collect data on effective practices, as well as new diagnostic and therapeutic approaches [ 31 , 89 ]. The valuable insights gained from these research endeavors were then disseminated through trusted channels to both the public and policymakers, ensuring informed decisions at all levels [ 36 ].

The COVID-19 pandemic acted as a catalyst for the swift integration of telemedicine into healthcare systems globally. This period saw healthcare providers leverage telecommunication technologies to offer an array of remote services, addressing medical needs such as consultations, diagnosis, monitoring, and prescriptions. This transition was instrumental in ensuring care continuity and mitigating infection risks for both patients and healthcare workers, highlighting an innovative evolution in healthcare delivery [ 170 , 181 ].

Countries adapted to this new model of healthcare with varied applications: Armenia established telephone follow-ups and video consultations for remote patient care, while e-pharmacies and mobile health tools provided immediate access to medical information and services [ 29 ]. In France and the United States, tele-mental health services and online group support became a means to support healthy living during the pandemic [ 147 , 158 ] . New Zealand introduced the Aroha chatbot, an initiative to assist with mental health management [ 139 ].

The implementation and effectiveness of these telehealth services were not limited by economic barriers, as underscored by Pradhan et al. (2023), who noted the key role of telemedicine in low and middle-income countries. These countries embraced the technology to maintain health service operations, proving its global applicability and utility [ 178 ]. The widespread adoption of telemedicine, therefore, represents a significant and perhaps lasting shift in healthcare practice, one that has redefined patient care in the face of a global health crisis and may continue to shape the future of healthcare delivery [ 170 , 178 , 181 ].

The study highlighted PHC strengthening strategies in COVID-19 time . Notably, the adaptations and reforms spanned across governance, financing, workforce management, information system, infrastructural readiness, and service delivery enhancements. These interventions collectively contributed to the robustness of health systems against the sudden surge in demand and the multifaceted challenges imposed by the pandemic and resulted.

Significantly, the findings have broader implications for health policy and system design worldwide. The pandemic has highlighted the critical need for resilient health systems that are capable of not only responding to health emergencies but also maintaining continuity in essential services. The strategies documented in this review serve as a template for countries to fortify their health systems by embedding resilience into their PHC frameworks (Fig.  4 ). Future health crises can be better managed by learning from these evidenced responses, which emphasize the necessity of integrated, well-supported, and dynamically adaptable health care structures.

A model for strengthening the resilience of the primary health care system

Looking ahead, realist reviews could play a pivotal role in refining PHC resilience strategies. By understanding the context in which specific interventions succeed or fail, realist reviews can help policymakers and practitioners design more effective health system reforms, as echoed in the need for evidence-based planning in health system governance [ 9 ] ​​. These reviews offer a methodological advantage by focusing on the causality between interventions and outcomes, aligning with the importance of effective health system leadership and management [ 50 , 182 ] ​​. They take into account the underlying mechanisms and contextual factors, thus providing a nuanced understanding that is crucial for tailoring interventions to meet local needs effectively [ 28 , 86 ] ​​, ultimately leading to more sustainable health systems globally. This shift towards a more analytical and context-sensitive approach in evaluating health interventions, as supported by WHO's framework for action [ 2 , 10 ] ​​, will be crucial for developing strategies that are not only effective in theory but also practical and sustainable in diverse real-world settings.

Limitations and future research

In our comprehensive scoping review, we analyzed 167 articles out of a dataset of 4,315, classifying 194 interventions that build resilience in primary healthcare systems across the globe in response to pandemics like COVID-19. While the review's extensive search provides a sweeping overview of various strategies, it may not capture the full diversity of interventions across all regions and economies. Future research should focus on meta-analyses to evaluate the effectiveness of these interventions in greater detail and employ qualitative studies to delve into the specific challenges and successes, thus gaining a more nuanced understanding of the context. As the review includes articles only up to December 31, 2022, it may overlook more recent studies. Regular updates, a broader linguistic range, and the inclusion of a more diverse array of databases are recommended to maintain relevance and expand the breadth of literature, ultimately guiding more focused research that could significantly enhance the resilience of PHC systems worldwide.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Abbreviations

Primary Health Care

World Health Organization

Sustainable Development Goals

Universal Health Coverage

Personal Protective Equipment

General Practitioner

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We would like to thank Dr. Arshad Altaf for his invaluable comments on the earlier drafts of this work.

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Mosadeghrad, A.M., Afshari, M., Isfahani, P. et al. Strategies to strengthen the resilience of primary health care in the COVID-19 pandemic: a scoping review. BMC Health Serv Res 24 , 841 (2024). https://doi.org/10.1186/s12913-024-11278-4

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The impact of covid-19 on university library services: a systematic literature review.

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The impact of COVID-19 on university library services is a less researched area. For the systematic literature review, the researchers searched Scopus, Web of Science, and Google Scholar. Initially, the researchers found 903 potentially relevant citations. From 903, 427 duplicate citations were removed. The remaining 476 articles were rechecked for relevance. There remained 34 full-text papers that were assessed for eligibility. Only 13 of these studies fulfilled the eligibility criteria to provide information on university library services in the pandemic era. PRISMA guidelines are followed in this study.

The findings of this systematic literature review contribute towards a better understanding of the impact of coronavirus on university library services. These are also useful for academic librarians to facilitate their patrons by improving their electronic resources during the pandemic situation of COVID-19. This study provides guidelines and systematic steps for evaluating the impact of the pandemic situation on university library services. This review also aids university libraries in making decisions on the adoption of digital and electronic services to support students’ e-learning programs. Through exploration and reflection, this review contributes to a newly emerging body of knowledge on university library services during the outbreak of coronavirus.

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Assessing the Impact of COVID-19 Vaccination Programs on the Reduction of COVID-19 Cases: A Systematic Literature Review

Affiliations.

• 1 Department of Environmental Health, Faculty of Public Health, Universitas Indonesia, Depok, West Java, Indonesia.
• 2 Research Center for Climate Change, Universitas Indonesia, Depok, West Java, Indonesia.
• PMID: 39070079
• PMCID: PMC11276414
• DOI: 10.5334/aogh.4484

Background: Vaccination is the most effective way to prevent serious illness and death from COVID-19 among the various preventive interventions available. Objective: This review aimed to assess the actual effectiveness of COVID-19 vaccines in curbing the transmission and incidence of COVID-19 cases, to examine the role of different vaccine types in controlling the COVID-19 pandemic, as well as to identify the key factors influencing the efficacy of COVID-19 vaccines in containing the spread of the virus. Methods: The suggestions made by the PRISMA Framework were adhered to. To find the publications for the 2020-2023 timeframe, searches were performed through the PubMed databases, EMBASE, Scopus, and ProQuest. For the review, 17 reports satisfied the inclusion requirements. Ad26.CoV2.S or ChAdOx1-S, Gam-COVID-Vac(GAM), Sinovac Life Sciences Co., Oxford-AstraZeneca, Pfizer-BioNTech, and viral vector vaccines are among the vaccines that act on various variations. They dealt with the Delta, B.1.1.519, Omicron, and Alpha variations. Findings: Vaccinations against various Variants resulted in fewer COVID-19 infections, fewer deaths, and fewer hospitalizations. The emergency of the Delta variant, persons over 60, and vaccine hesitancy were the main issues affecting the effectiveness of COVID-19 vaccinations in containing the virus's spread. Conclusion: The collective evidence strongly supports the conclusion that COVID-19 vaccination plays a crucial role in mitigating the spread of the virus and reducing the severity of illness among those who contract the virus.

Keywords: COVID-19; reduction cases; severity illness; systematic review; vaccine efficacy.

Copyright: © 2024 The Author(s).

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Study profile.

• Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 2020;382:1969–1973. 10.1056/NEJMp2005630. - DOI - PubMed
• Forni G, Mantovani A. COVID-19 vaccines: Where we stand and challenges ahead. Cell Death Differ. 2021;28:626–639. 10.1038/s41418-020-00720-9. - DOI - PMC - PubMed
• Dubé E. Addressing vaccine hesitancy: The crucial role of healthcare providers. Clin Microbiol Infect. 2017;23:279–280. 10.1016/j.cmi.2016.11.007. - DOI - PubMed
• Dooling K, Marin M, Wallace M, et al. The Advisory Committee on Immunization Practices’ Updated Interim Recommendation for Allocation of COVID-19 Vaccine — United States, December 2020. MMWR Morb Mortal Wkly Rep. 2021;69:1657–1660. 10.15585/mmwr.mm695152e2. - DOI - PMC - PubMed
• Mathieu E, Ritchie H, Rodés-Guirao L, et al. Coronavirus Pandemic (COVID-19). Our World Data. 2020. Accessed October 31, 2023. https://ourworldindata.org/coronavirus .

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Published on 29.7.2024 in Vol 10 (2024)

This is a member publication of University College London (Jisc)

Preferences for COVID-19 Vaccines: Systematic Literature Review of Discrete Choice Experiments

Authors of this article:

• Yiting Huang 1, 2 * , MPH   ; 
• Shuaixin Feng 3 * , MPH   ; 
• Yuyan Zhao 1 * , BMed   ; 
• Haode Wang 4 , PhD   ; 
• Hongbo Jiang 1, 5 , PhD  

1 Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China

2 Department of Medical Statistics, School of Basic Medicine and Public Health, Jinan University, Guangzhou, China

3 Outpatient department of Baogang, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China

4 School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom

5 Institute for Global Health, University College London, London, United Kingdom

*these authors contributed equally

Corresponding Author:

Hongbo Jiang, PhD

Department of Epidemiology and Biostatistics, School of Public Health

Guangdong Pharmaceutical University

Department of Epidemiology and Biostatistics, School of Public Health Guangdong Pharmaceutical University

No. 283 Jianghai Road, Haizhu District

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Phone: 86 0 203 405 5355

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Background: Vaccination can be viewed as comprising the most important defensive barriers to protect susceptible groups from infection. However, vaccine hesitancy for COVID-19 is widespread worldwide.

Objective: We aimed to systematically review studies eliciting the COVID-19 vaccine preference using discrete choice experiments.

Methods: A literature search was conducted in PubMed, Embase, Web of Science, Scopus, and CINAHL Plus platforms in April 2023. Search terms included discrete choice experiments , COVID-19 , and vaccines and related synonyms. Descriptive statistics were used to summarize the study characteristics. Subgroup analyses were performed by factors such as high-income countries and low- and middle-income countries and study period (before, during, and after the pandemic wave). Quality appraisal was performed using the 5-item Purpose, Respondents, Explanation, Findings, and Significance checklist.

Results: The search yield a total of 623 records, and 47 studies with 53 data points were finally included. Attributes were grouped into 4 categories: outcome, process, cost, and others. The vaccine effectiveness (21/53, 40%) and safety (7/53, 13%) were the most frequently reported and important attributes. Subgroup analyses showed that vaccine effectiveness was the most important attribute, although the preference varied by subgroups. Compared to high-income countries (3/29, 10%), a higher proportion of low- and middle-income countries (4/24, 17%) prioritized safety. As the pandemic progressed, the duration of protection (2/24, 8%) during the pandemic wave and COVID-19 mortality risk (5/25, 20%) after the pandemic wave emerged as 2 of the most important attributes.

Conclusions: Our review revealed the critical role of vaccine effectiveness and safety in COVID-19 vaccine preference. However, it should be noticed that preference heterogeneity was observed across subpopulations and may change over time.

Trial Registration: PROSPERO CRD42023422720; https://tinyurl.com/2etf7ny7

Introduction

Although the World Health Organization has declared the end of COVID-19 as a public health emergency [ 1 ], the persistence of this disease as a global threat should not be overlooked or underestimated [ 2 ]. Vaccination has been regarded as one of the most effective strategies against COVID-19 and reduced global COVID-19 mortality, severe disease, symptomatic cases, and COVID-19 infections [ 2 , 3 ]. Furthermore, studies have shown that COVID-19 vaccine also had a preventive effect against post–COVID-19 condition [ 4 - 6 ].

Despite significant progress made with vaccination efforts, achieving high vaccination coverage remains a challenge due to disparities in vaccine distribution and vaccine hesitancy [ 7 - 9 ]. Disparities in vaccine distribution have been observed between different countries, with vaccination rates varying markedly between high- and low-income countries [ 10 ]. In addition, COVID-19 vaccine hesitancy has been reported across countries [ 11 ], and booster hesitancy has also become a growing concern for public health officials [ 12 ]. Vaccine hesitancy can change over time and in response to different circumstances. Notably, vaccine hesitancy tends to increase when population-level side-effect studies are released after emergency approvals [ 13 ]. These challenges underline the need for well-designed vaccination programs to ensure equitable access and high uptake.

Designing a successful vaccination program, including vaccine selection, rollout, and accessibility, is crucial [ 14 , 15 ]. A thorough understanding of individual needs and preferences will allow us to better tailor vaccination programs, which will facilitate the appeal and uptake of COVID-19 vaccines [ 16 , 17 ]. One approach increasingly used to elicit preferences for vaccines and vaccination programs is the discrete choice experiment (DCE) [ 18 , 19 ]. DCEs are scientific research methods that assess preferences by presenting respondents with a series of hypothetical scenarios. In these scenarios, individuals choose among different alternatives which are characterized by specific attributes. By analyzing these choices, researchers can identify the relative importance of each attribute and estimate utility functions [ 20 , 21 ]. DCEs provide valuable insights into decision-making processes and allow for objective evaluation of attribute-based benefits [ 22 - 24 ]. Published studies have been conducted to identify and review choice-based experiments that assess vaccine preferences [ 18 , 19 ]. However, it is important to note that the nature of various vaccines is different, and the preference for vaccines of COVID-19 was not specifically included in these studies.

The COVID-19 vaccines were developed under emergency conditions where there were no peer-reviewed systematic reviews of DCEs on COVID-19 vaccine preference data to inform global decision-making. The diversity in COVID-19 vaccine preferences may be attributed to disparities in vaccine development and production, vaccination scheduling and management, public trust and uptake, as well as vaccine prioritization strategies across various countries and regions [ 25 ]. Moreover, new mutant variants are more likely to infect new individuals, highlighting the need for more effective booster vaccines [ 26 , 27 ]. This study provides empirical evidence on the development, implementation, and follow-up of the COVID-19 vaccine and provides references for vaccine decision-making of other infectious diseases.

We conducted our review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines ( Multimedia Appendix 1 ) [ 28 ]. This study was registered in the international prospective register of systematic reviews (PROSPERO CRD42023422720).

Search Strategy

A literature search was conducted in PubMed, Embase, Web of Science, Scopus, and CINAHL Plus platforms in April 2023. Search terms included discrete choice experiments , COVID-19 , and vaccines and related synonyms. Further details are provided in Multimedia Appendix 2 .

Eligibility Criteria

The inclusion and exclusion criteria are detailed in Textbox 1 .

Inclusion criteria

• Study focus: Focused on preferences for COVID-19 vaccine (product, service and distribution, policy intervention, etc)
• Article or study type: First-hand discrete choice experiment (DCE) data analysis research

Exclusion criteria

• Study focus: No preferences for COVID-19 vaccine reported
• Article or study type: Not DCE research; nonoriginal research (including secondary reports, systematic reviews, conference abstracts and presentations, correspondence, editorials, and commentaries); theoretical articles; protocols; book chapters; and duplicates

Data Screening and Extraction

Two reviewers (YH and SF) independently performed a 2-stage screening process to identify eligible studies. In the first stage, titles and abstracts were screened to exclude irrelevant studies using the web-based tool Rayyan (Rayyan Systems, Inc [ 29 ]). In the second stage, full-text versions of selected papers were assessed to ensure that the inclusion criteria were met. Both reviewers compared the selected papers at each stage to ensure agreement. Any discrepancy or uncertainty between the reviewers was addressed through discussion until a consensus was reached. If not, a third (senior) reviewer (HJ) was consulted to resolve the disagreement.

The extracted data were recorded and managed in Microsoft Excel (Microsoft Corp) software. Full texts were extracted and reviewed independently by 2 authors (YH and YZ), and any disagreements were resolved by a third reviewer (HJ). Data extraction was performed for 3 specific aspects, focusing on their relevance and importance for the analysis of the DCE: (1) study information (author, publication year, study period, country, population, and sample size); (2) information on the DCE methodology (survey administration, attribute and level selection, pilot-tested, experimental study design, choice sets per respondent, options per choice set, inclusion of an opt-out option, and statistical models); and (3) information on the DCE results (number of attributes, included attributes classified into 4 categories [outcome, process, cost, and other], and the most important attribute).

Choice-based experiments use different definitions for similar attributes [ 19 ]. To address this issue, the attributes were initially grouped into 4 main categories: outcomes, process, cost, and other. The outcomes category encompassed the outcomes or consequences of vaccine administration, such as safety and effectiveness. The process category included activities related to the delivery and administration of vaccines, such as service delivery, dosing, and visits. The cost category focused on the financial aspects of vaccines. Any attributes that did not fit into these 3 categories were classified as other , such as disease risk, incentives or penalties for vaccination, vaccine advice or support, and so on. The classification of outcome, process, cost, and other attributes depended on the aim and design of the studies. It should be noted that vaccine effectiveness and safety were phrased differently in different studies. To facilitate a comparison between studies, efficacy [ 11 , 30 - 41 ], protection rate [ 42 , 43 ], and decreased deaths [ 44 ] were summarized as vaccine effectiveness, whereas side effects [ 11 , 26 , 31 , 35 , 37 , 40 , 41 , 43 , 45 - 61 ], rare but serious risks [ 62 ], and the likelihood of having a flare [ 62 ] were summarized as vaccine safety ( Multimedia Appendix 3 [ 11 , 26 , 30 - 74 ]).

High-income countries (HICs) and low- and middle-income countries (LMICs) were classified according to the World Bank [ 75 ]. LMICs encompass low-income, lower-middle–income, and upper-middle–income countries. On the basis of previous literatures [ 63 , 76 , 77 ], we hypothesized that individuals’ preferences for vaccines may vary depending on the status of the pandemic. Therefore, we sought to explore how COVID-19 vaccine preferences differed during different study periods. To do this, we used data from the surveillance website [ 78 ] to define the pandemic periods based on daily COVID-19 cases. The first group, before the pandemic wave , referred to the period before the outbreak of the pandemic, when the number of incident cases was low. The second group, during the pandemic wave , represented the peak of the pandemic or was characterized by a rapid increase in the number of incident cases. The third group, after the pandemic wave , was when the number of incident cases decreased and remained low ( Multimedia Appendix 4 [ 11 , 26 , 30 - 74 ]).

Quality Appraisal

The 5-item Purpose, Respondents, Explanation, Findings, and Significance (PREFS) checklist, developed by Joy et al [ 79 ], is widely accepted and used to assess the reporting quality of preference studies [ 18 , 80 - 84 ]. It evaluates studies based on criteria such as the study’s purpose, respondent sampling, explanation of assessment methods, inclusion of complete response sets in the findings, and use of significance testing.

Data Synthesis and Analysis

This review used a combination of text and summary tables to effectively convey information about the characteristics and results of the included studies. Descriptive statistics were used to summarize the study characteristics. The findings were synthesized in a narrative format, providing an overview of the included studies, highlighting the key features of the study designs, and presenting the main findings of the COVID-19 vaccine preference studies. Subgroup analyses were performed by independent factors such as HICs or LMICs and study period (before, during, and after the pandemic wave).

Study Selection

The search yielded a total of 623 records. After title and abstract screening, 513 (82.3%) records were excluded. An additional 63 (10.1%) studies were excluded after full-text assessment. Finally, 47 (7.5%) studies met the eligibility criteria and were included in the review ( Figure 1 ).

Study and Sample Characteristics

We included 47 studies from 29 countries. Among them, 5 (11%) studies were conducted in multiple countries, with 4 studies conducted in both HICs and LMICs and 1 study conducted in >1 HICs. In addition, 22 (47%) studies were conducted in HICs, while 21 (45%) studies were conducted in LMICs. China stood out with the highest number of preference-based DCEs for COVID-19 vaccines, with 19 (40%) studies. The United States followed closely with 9 (19%) studies, followed by France (n=5, 11%), the United Kingdom (n=4, 9%), Germany (n=4, 9%), and Spain (n=3, 6%). Australia, Canada, India, Italy, Japan, the Netherlands, and South Africa had 2 (4%) studies each. All other countries had only 1 (2%) study ( Figure 2 ). The studies were published between the years 2020 and 2023, with sample sizes ranging from 194 to 13,128 participants. The median number of participants per study was 1456 (IQR 872-2109).

Most participants were adults, although the specific focus varied. Most studies (36/47, 77%) involved general population samples, whereas some studies (11/47, 23%) included specific groups of participants. These included 5 studies conducted in universities using web-based tools, including 3 studies with university students and 2 studies with both students and staff. In addition, 3 studies involved health care workers (Chinese intensive care unit clinicians, health care workers, and health care and welfare workers); 2 studies involved parents with children aged <18 years, and 1 study involved people with chronic immune-mediated inflammatory diseases ( Table 1 ).

a ICU: intensive care unit.

b NR: not reported.

The Implementation of DCEs

Among these 47 studies, researchers commonly used a multifaceted approach to identify and select attributes and levels. Among the studies reviewed, 23 (49%) studies reported a literature review with qualitative assessments such as expert interviews and public surveys. A total of 25 (53%) studies reported a pilot DCE survey. In terms of survey administration, most studies (40/47, 85%) reported that the DCE was conducted through web-based surveys ( Table 2 ).

a NR: not reported.

b CDC: Center for disease control and prevention.

c UKZN: the University of KwaZulu-Natal.

Attributes in DCE Studies

Of the 286 attributes identified in the 47 studies, 126 (44.1%) were categorized as outcome attributes, followed by 82 (28.7%) as process attributes, and 22 (7.7%) as cost attributes. The remaining 55 (19.2%) attributes were categorized as other attributes ( Table 3 and Multimedia Appendix 3 ).

a Attribute is significant ( P <.05).

b Not available.

c The corresponding coefficients and P values are not provided.

The Most Important Attribute Reported in DCE Studies

In total, 2 of the 5 multicountry studies did not report preferences for each country and were therefore excluded from the synthesis of the most important attribute. A total of 53 data points on COVID-19 vaccine preferences were collected from the study population of the corresponding country. In the outcome category, among the 30 attributes examined, effectiveness emerged as the most prominent, accounting for 40% (21/53) of the studies [ 31 , 35 , 36 , 38 - 42 , 48 , 50 - 52 , 57 , 58 , 60 - 62 , 64 - 67 ]. Safety was addressed in 13% (7/53) of the studies [ 33 , 43 , 47 , 56 , 59 , 68 , 69 ], while protection duration was mentioned in 4% (2/53) [ 11 , 50 ]. In the process category, 13 attributes were identified. Brand (1/53, 2%) [ 32 ], region of vaccine manufacturer (1/53, 2%) [ 34 ], and halal content (1/53, 2%) [ 53 ] were associated with vaccine production. In addition, waiting time for COVID-19 vaccination (1/53, 2%) [ 70 ] and vaccine frequency (1/53, 2%) [ 71 ] were considered. Furthermore, 3 (6%) studies on vaccine distribution prioritized vaccination for the medical risk group (1/53, 2%) [ 72 ], those who had a higher COVID-19 mortality risk (6/53, 11%) [ 63 ], and those who had the potential capacity to spread the virus (1/53, 2%) [ 72 ]. In the cost category, personal vaccination cost accounted for 6% (3/53) [ 31 , 37 , 41 ]. Among the other attributes (7/53, 13%), disease risk threat was of particular importance, including possible trends of the epidemic (1/53, 2%) [ 30 ] and COVID-19 mortality rate (1/53, 2%) [ 55 ]. In addition, incentives and penalties for vaccination were identified, including quarantine-free travel (1/53, 2%) [ 33 ] and mandatory testing at own expense if not vaccinated (1/53, 2%) [ 44 ]. Vaccine advice or support included vaccination invitation sender (1/53, 2%) [ 73 ] and recommenders (1/53, 2%) [ 46 ]. The proportion of friends and family members who had received the vaccine (1/53, 2%) [ 26 ] was also among the other attributes influencing decision-making ( Table 2 ).

Although effectiveness remained the most important attribute, it is worth noting that variations in preferences were also observed among different subgroups. A higher proportion of studies conducted in LMICs (4/24, 17%) than in HICs (3/29, 10%) prioritized on safety ( Multimedia Appendix 5 ). In addition, COVID-19 mortality risk was the second most important attribute (6/29, 21%) after effectiveness in HICs. Cost was considered to be another most important attribute (3/24, 13%) in LMICs. Interestingly, many other attributes also became more important as the pandemic progressed. Protection duration (2/24, 8%) emerged as one of the most important attributes during the pandemic wave. COVID-19 mortality risk (5/25, 20%) and cost (3/25, 12%) were considered as the most important attributes after the pandemic wave ( Multimedia Appendix 6 ).

Study Quality

The overall reporting quality was deemed acceptable but there is room for improvement. The PREFS scores of the 47 studies ranged from 2 to 4, with a mean of 3.23 (SD 0.52). No study scored 5. Most studies scored 3 (32/47, 68%) or 4 (13/47, 28%), while 2 studies (2/47, 4%) scored 2 ( Multimedia Appendix 7 [ 11 , 26 , 30 - 74 ]).

Principal Findings

This systematic review synthesizes existing data on preference for COVID-19 vaccine using DCE, with the aim of informing improvements in vaccine coverage and vaccine policy development. We identified 47 studies conducted in 29 countries, including 21 HICs and 8 LMICs. HICs had an adequate supply of vaccine since the early emergency availability of COVID-19 vaccine, and HICs had 1.5 times more doses of COVID-19 vaccinations than LMICs by September 2023 [ 85 ]. In total, 19 (40%) studies were conducted in China and 9 (19%) in the United States, demonstrating their significant contribution to the research and their leadership in vaccine research and development. Vaccine effectiveness and safety were the most important attributes in DCEs, although preferences differed among subgroups.

Recent years have seen new trends in the design, implementation, and validation of the DCE. For example, most studies (40/47, 85%) reported that the DCE was administered through web-based surveys, which have become a quick and cost-effective way to collect DCE data [ 66 ]. Almost half of the studies (25/47, 53%) did not report a pilot test. However, piloting in multiple stages throughout the development of a DCE is conducive to identifying appropriate and understandable attributes, considering whether participants can effectively evaluate the full profiles, and producing an efficient design [ 21 , 86 , 87 ].

Overall, vaccine effectiveness and safety have emerged as the most commonly investigated attributes in the outcome category. Despite heterogeneity in preferences across subpopulations, effectiveness remains the primary driver for COVID-19 vaccination across the studies [ 31 , 35 , 36 , 38 - 42 , 48 , 50 , 51 , 57 , 58 , 60 - 62 , 64 - 67 ], similar to the previous findings [ 18 ]. A study conducted in India and Europe found that respondents’ preference for the COVID-19 vaccine increased with effectiveness and peaked at 95% effectiveness [ 45 ]. Another study conducted among university staff and students in South Africa found that vaccine effectiveness not only was a concern but also significantly influenced vaccine choice behavior [ 64 ]. Interestingly, a nationwide stated choice survey in the United States found a strong interaction between effectiveness and other attributes [ 58 ]. These findings support the ongoing efforts to maximize vaccine effectiveness while emphasizing the importance of communicating information on vaccine effectiveness to the target population for promotion [ 62 ].

Safety has also been identified as a crucial factor influencing the acceptance of COVID-19 vaccine [ 33 , 43 , 47 , 56 , 59 , 68 , 69 ]. One study indicated that the likelihood of the general public choosing vaccines with low or moderate side effects increased by 75% and 63%, respectively, compared with vaccines with high side effects. While the likelihood changed within a 30% range when most attributes other than effectiveness and safety were changed [ 69 ]. In addition, respondents in Australia expressed a willingness to wait an additional 0.04 and 1.2 months to reduce the incidence of mild and severe adverse events by 1/10,000, respectively [ 56 ].

Similar to the results of previous systematic reviews of DCEs for various vaccines [ 18 , 19 ], the most common predictors of COVID-19 vaccine acceptance are effectiveness and safety, particularly during the rapid development and rollout of COVID-19 vaccines, which essentially boils down to trust in the vaccine [ 31 ]. Respondents expressed the importance of having a safe and effective COVID-19 vaccine available as soon as possible, but the majority preferred to wait a few months to observe the experience of others rather than be the first in line [ 43 ]. Therefore, collaborating to enhance vaccine effectiveness while reducing the risk of severe side effects could be a highly effective strategy to address vaccine hesitancy and augment vaccine desirability. Dissemination of this important vaccine-related information by governments and health care institutions, along with effective communication by health care professionals, can help build public trust and ultimately increase vaccination rates [ 69 ]. However, these inherent vaccine attributes are typically beyond the control of a vaccination program, and given the ongoing mutations of SARS-CoV-2, it is challenging to predict the effectiveness of the vaccines currently in development [ 66 ]. Global collaboration between scientists and pharmaceutical companies is therefore essential to improve vaccine effectiveness and minimize side effects [ 41 ].

Vaccine production, including its origin, brand, vaccine frequency, and content, are key considerations in the process category. Vaccine brand also has a significant impact on vaccine choice [ 32 ], independent of effectiveness and safety, due to factors such as reputation, country of origin, technological advances, and reported side effects associated with the brands [ 35 ]. For vaccine origin, some studies found that participants preferred domestic vaccines to imported vaccines, which may depend on the availability or the approval of vaccines in different countries [ 31 , 41 , 50 ] or the incidence of side effects among different types of COVID-19 vaccines [ 37 ]. However, some studies found that imported vaccines were more likely to be accepted than domestically produced vaccines, which may be attributed to less trust in domestically produced vaccines [ 57 , 66 ]. A study on vaccine preferences among the Malaysian population found that the composition and production process of the COVID-19 vaccine, which complied with Islamic dietary requirements (ie, halal content) was an important factor for many Malaysians when deciding whether to be vaccinated. This underscores the substantial influence of religion on vaccine choice [ 53 ].

Vaccine frequency was emphasized to play an important role in the choice of COVID-19 vaccine among the US public, while the 90% efficacy with low side effect rate of the COVID-19 vaccine was set. The prospect of vaccinating once to get lifelong immunity was very attractive, reflecting the fact that people were effort minimizers [ 71 ]. This is similar to the nature of the 2 studies referenced in the outcome attribute, where the protection duration is prioritized. Given the threat of COVID-19, people expect the protection duration to be as long as possible [ 11 , 50 ].

When vaccine supply is limited, people tend to prioritize vaccination for those who are more susceptible to the disease, have higher mortality rates from infectious diseases, or have greater potential to spread the virus. A study in Iran found that individuals tend to prioritize vaccination for those in the community with higher potential for virus transmission [ 57 ]. In addition, results from a study in 6 European countries revealed unanimous agreement among respondents that candidates with higher mortality and infection risks should be prioritized for vaccination [ 63 ]. While another study conducted among Belgians also found that respondents would prioritize populations at higher medical risk [ 72 ].

Cost was another important factor influencing COVID-19 vaccine preferences, mostly related to out-of-pocket costs [ 31 , 37 , 41 ]. In 2 studies comparing public preferences for COVID-19 vaccines in China and the United States, vaccine efficacy emerged as the most important driver for the American public, whereas the cost of vaccination had the greatest impact on the Chinese public. This difference was likely due to the relatively stable pandemic situation in China at the time and the lower perceived risk of COVID-19. As a result, the Chinese population was more price sensitive and reluctant to pay for vaccination [ 31 , 37 , 41 ].

For the other category, several different attributes were highlighted, depending on the specific population or situation. When people perceive the threat of a disease, their desire to be vaccinated becomes more urgent. In a study among health care workers in China, participants’ expectations about the future development of COVID-19 had a greater impact on their decision to be vaccinated than their perceived risk of infection or actual case rates, which may have been influenced by their previous experience with seasonal influenza vaccination [ 30 ]. The mortality rate of COVID-19 was considered the most influential factor in the uptake of COVID-19 booster shots in Vietnam. This study was conducted during a pandemic wave in Vietnam, which may have led to an increased perception of public health risks and a greater inclination toward COVID-19 vaccination [ 55 ]. To achieve herd immunity, government authorities can implement policies of incentives and penalties for vaccination to encourage population-wide uptake. A study conducted in the Netherlands revealed that respondents particularly disliked policies that penalized those who were not vaccinated, such as mandatory testing at their own expense if they were not vaccinated [ 44 ]. Instead, they favored policies that rewarded vaccination, such as giving vaccinated individuals additional privileges through a vaccination passport. This finding is consistent with a study in Hong Kong, which found that quarantine-free travel was considered the most important motivator among university students and staff, given their frequent engagement in international travel [ 33 ].

The source of vaccine information also influences vaccine decision-making [ 30 ]. Variation in the sender of vaccination appointment invitation via SMS text messaging and recommenders may potentially influence the public’s willingness to vaccinate against a disease [ 30 , 46 , 73 ]. Furthermore, the acceptance of vaccines was observed to change as the firsthand information about vaccine side effects and effectiveness was provided by friends and family in India [ 26 ].

In HICs, COVID-19 mortality risk was the second most important attribute after effectiveness, as respondents in all 6 high-income European countries from a study of public preferences for COVID-19 vaccine distribution prioritized candidates with higher mortality risks [ 63 ]. However, individuals from LMICs appeared to be more concerned about vaccine safety than those from HICs. This may be related to greater confidence in vaccine safety in HICs due to the earlier initiation and higher rates of COVID-19 vaccination [ 85 ]. In contrast, in some LMICs, vaccine safety was reported as the main reason influencing the willingness to vaccinate due to the rapid development of the COVID-19 vaccines [ 26 , 43 , 47 , 59 , 68 , 69 , 74 , 88 ].

Interestingly, the preference for COVID-19 vaccines may also have changed as the pandemic progressed [ 63 ]. Similarly, effectiveness remained the most important attribute in all periods, possibly due to the continuing severity of the pandemic and the fear of the possible emergence of new coronavirus strains [ 43 ]. Before the pandemic wave, the information on vaccine effectiveness was limited [ 26 ], but people still considered vaccine effectiveness to be the most important driver of vaccination. However, during the pandemic, the public’s perception of the health risk increased. As vaccines were introduced and used, people seemed to become more concerned about the duration of vaccine protection and preferred a longer vaccine protection [ 11 , 50 ]. After the pandemic wave, as the pandemic situation gradually stabilized, cost, combined with their perception of the risk of susceptibility, became more important in their preferences. However, despite this shift, most of the public still believed that people who are at higher risk of infection or death should be vaccinated first [ 63 ].

Limitations

Our study had several limitations. First, not all studies used the same attributes and levels, which limited our ability to perform a quantitative synthesis and directly compare the estimates of model parameters. Instead, we qualitatively synthesized and summarized the range of attributes that may be useful in the formative stage of attribute selection in future DCE surveys investigating the preference for COVID-19 vaccine. Second, although DCEs have been shown to be a valid method for eliciting preferences, the experiment may not represent real market choices but rather hypothetical scenarios with plausible and realistic attributes. However, it offers opportunities to evaluate vaccines that are not yet available in the market or to specific population [ 68 ]. Third, the commonly used classification of outcome, cost, and process was used in order to better explain the public’s preference for vaccine attributes. However, several attributes could not be properly classified, and a fourth category (ie, other attributes) had to be added [ 19 ]. Meanwhile, the variety of attributes included may make it difficult to appropriately name and interpret this category as a whole. Fifth, the PREFS checklist is limited to 5 questions and fails to elicit several criteria that should be reported in DCE studies. Also, it does not provide sufficient tools to assess the biases in a DCE, such as selection bias and nonresponse bias [ 79 , 89 ]. Finally, although there was no specific theoretical framework to structure our qualitative analysis from the 4 identified categories, our classification was based on previous studies [ 18 , 19 , 82 , 90 , 91 ] and our own findings. This synthesis led us to categorize attributes into 4 main classes, providing a clear structure for analyzing and presenting participants’ vaccine preferences and making it easier to compare their preferences across different studies.

Conclusions

In conclusion, this systematic review synthesized the global evidence on preferences for COVID-19 vaccines using the DCE methodology. Vaccine effectiveness and safety were found to be the main drivers for COVID-19 vaccination, highlighting the importance of global collaboration to improve vaccine effectiveness and minimize side effects, as well as the importance of communicating this vaccine-related information to the public to maximize the uptake of COVID-19 vaccines. The subgroup analyses emphasized the importance of differences in vaccine preference of specific populations and time periods in optimizing the acceptance of COVID-19 vaccines. These findings may serve as valuable insights for government agencies involved in the social mobilization process for COVID-19 vaccination. However, the response to the pandemic is a continuous learning process [ 92 ]. It is crucial for policy makers to consider preference evidence when designing policies to promote vaccination.

Acknowledgments

The authors have not received a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability

All data relevant to the study are included in the article or uploaded as supplemental information. Data sets of this study are available upon reasonable request to the corresponding author.

Authors' Contributions

YH, SF, and YZ are joint first authors. HJ conceived the study and its methodology. YH, SF, and YZ designed, refined, and implemented the search strategy; screened articles for inclusion; and extracted and curated the data. All authors contributed to the interpretation of the results. YH, SF, and YZ wrote the initial draft of the manuscript. HJ and HW critically reviewed the manuscript. HJ supervised the study design and provided overall guidance. All authors approved the final draft of the manuscript. HJ had full access to all the data used in this study, and all authors had final responsibility for the decision to submit for publication.

Conflicts of Interest

None declared.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist.

Search strategies.

Attributes included in each category.

The detailed distribution of the study period across countries.

Preference for COVID-19 vaccines among high-income countries and low- and middle-income countries (n=53).

Preference for COVID-19 vaccines in the different study periods (n=53).

Assessment of 47 included studies quality using the Purpose, Respondents, Explanation, Findings, and Significance checklist.

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Abbreviations

Edited by A Mavragani; submitted 19.01.24; peer-reviewed by T Ricks, I Saha; comments to author 11.04.24; revised version received 01.05.24; accepted 26.05.24; published 29.07.24.

©Yiting Huang, Shuaixin Feng, Yuyan Zhao, Haode Wang, Hongbo Jiang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 29.07.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Public Health and Surveillance, is properly cited. The complete bibliographic information, a link to the original publication on https://publichealth.jmir.org, as well as this copyright and license information must be included.

• Scoping Review
• Open access
• Published: 29 July 2024

Impact of COVID-19 on the neglected tropical diseases: a scoping review

• Caitlin Brigid Butala 1 , 2 ,
• Roo Nicola Rose Cave 1 ,
• Jenna Fyfe 1 ,
• Paul Gerard Coleman 1 ,
• Guo-Jing Yang 3 &
• Susan Christina Welburn   ORCID: orcid.org/0000-0002-9903-7086 1 , 2 , 3 , 4  

Infectious Diseases of Poverty volume  13 , Article number:  55 ( 2024 ) Cite this article

187 Accesses

Metrics details

This study investigates the impact of the COVID-19 pandemic on the prevalence, management, and control of the neglected tropical diseases (NTDs) highlighting the current or prospective impact of COVID-19 on research and development funding for, and execution of, NTD programmes. This review was conducted to determine if, and how, NTDs were affected by COVID-19, and whether those effects will delay the elimination goals of the Sustainable Development goals.

Using open-source available data from policy and documentation from official websites of the relevant stakeholders including but not limited to World Health Organization (WHO) documents and policies, government foreign aid documents, and the Policy Cures G-Finder reports, this scoping review explored ongoing challenges to supporting research and development (R&D) for the NTDs and in maintaining NTD control programs; examined the constraints posed for NTD management by the pandemic from disruptions to healthcare services, reduction of finance and explored the potential long-term implications and consequences for those poorer, neglected populations in low and middle income-countries (LMICs). This was done by a scoping review literature search, publications were subject to an initial practical screening step to ensure the most relevant publications were selected for full screening, with the focus on scoping the designated topic of the impact of COVID-19 on NTDs. We further undertook an evaluation of the socio-economic factors exacerbating the impact of COVID-19 on NTD burden.

Multiple disruptions and setbacks, likely to affect NTD programmes and progress towards their elimination targets were identified in this study. R&D funding for the NTDs and AIDs and TB has declined since the funding high point of 2019, and for malaria since the high point of 2018. Significant changes in allocation of R&D funding within the NTDs are observed post pandemic, likely because of prioritization among donors. Diseases for which the least R&D investment was reported in place, prior to the pandemic (mycetoma, taeniasis/cysticercosis, trachoma and Buruli ulcer) have been particularly impacted post pandemic. We identified specific NTDs including schistosomiasis, leprosy, and rabies that have been affected by the COVID-19 pandemic and disruptions caused to on ongoing NTD control and elimination programs. Pandemic restrictions disrupted essential medical supply manufacturing and distribution impacting immunization programs and hindered efforts to control the spread of infectious diseases. NTD programmes have experienced numerous setbacks including delays in mass drug administration programs (e.g. for schistosomiasis), cancelled or delayed vaccination programs (e.g. for rabies) and closure of testing facilities has resulted in reduced diagnosis, treatment, and disease elimination for all NTDs. Lockdowns and clinic closures causing disruption to essential healthcare services restricted NTD surveillance and treatment programs. Community fears around contracting COVID-19 exacerbated the constraints to service delivery. Disparities in global vaccine distribution have widened with LMICs facing limited access to vaccines and disruption to immunization programs. Finally, the pandemic has led to increased poverty with poor and marginalized communities, impacting nutrition, healthcare access and education all of which have long term implications for NTD management and control.

Conclusions

The COVID-19 pandemic profoundly impacted global health research and global health equity. Attention and funding were diverted from all sectors, significantly affecting research and development efforts set out in the World Health Organization’s NTD elimination Roadmaps. Ongoing changes to funding, economic crises, logistics and supply chain disruptions as well as deepening poverty has put a strain on already weak healthcare systems and exacerbated LMIC healthcare challenges. In particular, the delays and constraints to NTD management and elimination programs will have long-reaching consequences highlighting the need for global cooperation and renewed investment to put the NTD roadmap back on track. Targets and milestones are unlikely to be met without significant investment for recovery, in place.

Graphical Abstract

Neglected tropical diseases (NTDs) affect poorer people in low-middle-income countries (LMIC). This NTD group has grown to include 21 types of disease which are considered neglected in comparison with tuberculosis, malaria and HIV/AIDS, also known as the Big 3 [ 1 ]. The Big 3 receive the bulk of funding in research and development dollars and the bulk of media coverage [ 2 ]. These 21 diseases can cause lifelong disabilities and impairments but historically garner less attention and funding than the Big 3; Tuberculosis, Malaria, and Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS). The NTDs have lower mortality rates than the Big 3, but can lead to lifelong disfigurements, permanent changes to health, and the ability to work [ 3 ]. The reported lower global burden of NTDs is also reflects underreporting which is common amongst patients with NTDs due to stigma from the diseases or lack of reporting [ 4 ]. NTD programs are funded though governmental and non-governmental organizations (NGOs); these groups work together to fund intervention programs to stop the transmission of the diseases, as well as fund basic research and new treatments. Several high-income-countries (HIC) are at the forefront of foreign aid funding, usually pledging a commitment over several years. Global Aid funding to eliminate NTDs along with malaria, HIV, and tuberculosis aims to reach the World Health Organization (WHO) Roadmap 2020–2030 [ 5 ].

In 2019 the new coronavirus, SARS-CoV-2 made its debut in the world of global infectious diseases and took precedence in terms of funding, research, and public awareness. SARS-CoV-2 caused the disease now known as COVID-19, an infection in the upper respiratory tract that can cause serious illness and death [ 6 ]. COVID-19 became a global pandemic that has altered almost every aspect of daily life and at the time of writing (April 2024) has caused almost 7 million deaths worldwide, and 772.38 million cases [ 7 ]. COVID-19 has understandably been prioritized, this was particularly crucial in the early days of the pandemic as scientists, public health experts and governments tried to understand the new disease. This focus also impacted the research and development world, eating into funds that were previously designated for NTDs, the big three, and other common infectious diseases.

Research into treatments for COVID-19, the development of vaccines and research into the repurposing of existing drugs to treat severe COVID-19 have been very successful, but the cost has been high [ 8 , 9 , 10 ]. Academic research grants related to COVID-19 were abundant with the total amount exceeding USD 2.6 million [ 7 , 11 ]. Governments and private donors contributed more money to these grants accounting for an increased portion of funding. The Global Health report states that in total an estimated USD 243.8 billion has been committed to COVID-19, although only USD 139.1 billion has been disbursed and of that only USD 13.7 billion has been for health-related work [ 12 ]. COVID-19 has had a crippling effect on NTDs from several fronts and angles. Like many aspects of eliminating NTDs, this is a multi-dimensional problem that requires a complex solution. This aims to inform a commentary on the impact COVID-19 has had on the research and development efforts set out in the WHO’s NTD elimination Roadmaps.

This study analyzed and evaluated a wide range of sources to obtain evidence-based information to explore the challenges posed by the pandemic in maintaining existing NTD control programs, the disruptions to healthcare services, reduction of R&D finance and the potential long-term implications and consequences for those poorer, neglected populations in LMICs disproportionately affected by the NTDs. We aimed to identify specific NTDs affected by the COVID-19 pandemic, and disruptions caused to ongoing NTD control and elimination programs. We further undertook an evaluation of the socio-economic factors exacerbating the impact of COVID-19 on NTD burden, using open-source available data.

This scoping review was conducted in full accordance with the JBI methodology for scoping reviews. Search strategies included database searches, hand searches and application of snowball methodologies as outlined below following specific inclusion and exclusion criteria as outlined below. Full details of the research methodology can be found in Additional file 1 .

Search strategy

Database searches.

Searches were run in the following databases: PubMed, Web of Science, JSTOR, Science Direct, and Google Scholar.

The searches were constructed by combining search terms from Additional file 2 . For the NTD and Big 3 searches respectively one or more search term was used from each word group. Words within a word group were combined with OR, AND, and, were used between word groups. The initial searches for the 20 NTDs included by WHO between 2000‒2003 were performed in November and December of 2020 with follow up searches in June 2021, September 2022, and December 2023. An additional search was undertaken in April 2024 following the addition of noma, officially included as the 21st NTDs in late December 2023, but no additional sources were identified.

Publications were subject to an initial practical screening step to ensure the most relevant publications were selected for full screening, with the focus on scoping the designated topic of the impact of COVID-19 on NTDs. Practical screening assessed the topic of the publication as well as date of publication.

In total 553 publications were extracted for title and abstract and full text screening (see Additional file 2 ). Figure  1 shows a flow diagram of the inclusion and exclusion process.

Flow diagram of search profile for scoping review

Hand searches

The literature/data included in this study were found using open-source available data from policy and documentation. Official websites of the relevant stakeholders such as NGOs, LMIC governments, philanthropic groups and countries giving foreign aid were searched for news or policy updates to their NTD work.

Information was also obtained by searching through government foreign aid policies, grant proposal and awards, NGO annual report statements, and often news articles obtained through Google Search. While news articles are not typically used in journals or academic work, this information is not available from academic sources yet, and wherever possible academic articles were used instead of news articles. When selecting these sources, key words were used, including any projects mentioning water, sanitation, and hygiene (WASH), NTD, Neglected Tropical Diseases, or any specific disease name on the WHO NTD list in relation to COVID-19 or budget cuts.

In total 222 information sources were compiled through this method to be screened.

Snowball method

A subsequent search of the bibliographies of the articles selected for full review was also conducted using a snowball method, using the same inclusion and exclusion criteria applied to the original search. The search and subsequent analysis were carried out by the primary author of this review. 11 articles and sources were found through this method for screening as seen in Fig.  1 .

Inclusion and exclusion criteria

From the database, snowball and hand searches 786 publications were extracted for title and abstract and full text screening.

Inclusion criteria was health policy makers, health programs, ministries of health, NGOs, philanthropists, Official Development Aid donor countries that are working in connection with NTDs; health policies, programmes, interventions, diagnostics, treatments, and management focused on NTDs; work contributing to the management, monitoring, or elimination of NTDs where the impact of COVID-19, negative, positive, or neutral must be discussed.

Exclusion criteria were papers including health policies, health programmes, interventions, diagnostics, treatments, management not addressing diseases listed as NTDs where there was discussion of work on NTDs but with no information or discussion of finance and the impact of funding on NTDs and/or COVID-19.

Analysis of yearly research and development funding data (USD) for NTDs

To explore changes in funding profiles over time, pre and post COVID-19, for the NTDs, a quantitative analysis of yearly research and development (R&D) funding data, in US dollars, was undertaken in which data was extracted from the Policy Cures G-Finder Report on January 31, 2024, for the following diseases: mycetoma, taeniasis, cysticercosis, trachoma, Buruli ulcer, leprosy, lymphatic filariasis, Chagas, soil transmitted helminths, schistosomiasis, human African trypanosomiasis (HAT), dengue, leishmaniasis. The funding for taeniasis and cysticercosis was combined due to the data being combined in the G-Finder data portal. The soil transmitted helminth funding was the combined funding for whipworm (trichuriasis), roundworm (ascariasis), hookworm (anclyostomiasis and necatoriasis) and strongyloidiasis. All data was then graphically represented as a line plot or alluvial plot produced in in R (version: R 4.3.1 GUI 1.79 Big Sur ARM build, https://cran.r-project.org/ ) with R Studio (version: 2023.06.1 + 524, 2023.06 Mountain Hydrangea, Built on July 6, 2023 from 547dcf86, https://github.com/rstudio/rstudio/commits/547dcf861cac0253a8abb52c135e44e02ba407a1 ) using) using ggplot2 and ggalluvial packages shown in Figs.  2 and 3 .

R&D funding for all NTDs compared to the Big 3 from 2017 to 2022. Note: Tracking of NTD Research and Development funding in comparison to HIV/AIDS, malaria and tuberculosis funding for the years 2017‒2022. R&D funding data for all NTDs from 2007–2022 can be found in Additional file 2

Alluvial plot illustrating the research and development funding spent (USD) for 14 neglected tropical diseases (NTDs) between 2017 and 2022. The colours represent the NTDs and the alluviums are arranged in decreasing order of proportion of the overall of funding demonstrated by the width of the alluviums. The diseases represented are as follows: mycetoma, taeniasis/cysticercosis, trachoma, Buruli ulcer, leprosy, lymphatic filariasis, Chagas, soil transmitted helminths, schistosomiasis, human African trypanosomiasis, dengue, leishmaniasis. The crossing of alluviums over time shows the changing prominence of allocated funding for each disease. The COVID-19 Pandemic is highlighted. The 4 least funded NTDs of the 14 for which data is available (mycetoma, taeniasis/cysticercosis, trachoma, Buruli ulcer) are magnified in the top panel to allow greater clarity. Note: R&D funding data for all NTDs 2007–2022 can be found in Additional file 2

Using open-source available data from policy and documentation from official websites of the relevant stakeholders including but not limited to World Health Organization (WHO)_ documents and policies, government foreign aid documents, and the Policy Cures G-Finder reports, this scoping review explored ongoing challenges to supporting research and development (R&D) for the NTDs and in maintaining NTD control programs; examined the constraints posed for NTD management by the pandemic from disruptions to healthcare services, reduction of finance and explored the potential long-term implications and consequences for those poorer, neglected populations in LMICs and evaluated the socio-economic factors exacerbating the impact of COVID-19 on NTD burden.

Of the 786 publications, 102 were included for the scoping review analysis. Of the 684 excluded, 14 were retained for background only.

The impact of COVID-19 on NTDs

In 2019 the new coronavirus, SARS-CoV-2 knocked even the Big 3 to a lower status. SARS-CoV-2 is a novel coronavirus that causes COVID-19, an infection in the upper respiratory tract that can cause serious illness and death. COVID-19 is a global pandemic that has altered almost every aspect of daily life and at the time of writing has caused more than 6.88 million deaths worldwide [ 11 ]. COVID-19 has understandably been prioritized and taken over the research and development world as well, eating into funds that were previously designated for NTDs. Research into treatments for COVID-19, the development of vaccines and the repurposing of existing drugs has been very successful, but the cost has been high. Academic research grants related to COVID-19 were abundant with the total amount exceeding USD 2.6 million [ 11 ]. Governments and private donors contributed more money to these grants accounting for an increased portion of funding. The Global Health report states that in total an estimated USD 243.8 billion has been committed to COVID-19, although only USD 139.1 billion has been disbursed and of that only USD 13.7 billion has been for health-related work [ 9 , 13 ]. Furthermore, the USD 786.6 million contributed to development assistance for pandemic preparedness in 2021 was a 64.8% increase from the 2019 contribution. More than 97% of this 2021 funding lacked the geographical detail to be disaggregated to global, regional, or national services. Pandemic preparedness development assistance funding peaked in 2020 at USD 1049.6 million, future results will determine if funding continues to decrease [ 9 , 14 , 15 , 16 , 17 , 18 ].

Funding for R&D for NTDs rerouted to COVID-19 research

Overall, funding for COVID-19 and future pandemic preparedness has dwarfed R&D funding for the NTDs. In terms of R&D funding, an estimated 98.12% of the total USD 5.9 billion initially allocated to COVID-19 research has largely been publicly funded by central governments [ 14 ]. Of USD 9.18 billion pledged or funded, the bulk of this money has been for vaccine developments (USD 5.5 billion), therapeutic treatments research (USD 1.3 billion), diagnostics (USD 804 million), basic research (USD 212 million), with USD 1.3 billion for unspecified categories [ 15 ]. Bill and Melinda Gates Foundation has donated USD 1.75 billion to COVID-19; most allocated to development of vaccines, diagnostics, and treatment drugs [ 16 ]. The Wellcome Trust, in the first year of COVID-19 awarded 28 grants totaling GBP 24 million [ 17 ]. World Report, shows that for all coronaviruses considered and/or COVID-19, a USD 183 million spend since 2020 [ 18 ].

The largest private single source of funding for COVID-19 is from the Bill and Melinda Gates Foundation, who are the biggest single private funder for NTD research. The Foundation has clearly stated that funds spent on COVID-19 research has not been diverted from other pledged projects, and are the only funder to have made an open statement about their funding intentions [ 19 ]. R&D funding for the NTDs and AIDs and TB has declined since the funding high point of 2019, and for Malaria since the high point of 2018 (see Fig.  2 ).

Notably, R&D funding for NTDs after the London Declaration in 2012, a pledge from governments, industry, and philanthropists to commit to “ control, eliminate or eradicate 10 diseases by 2020 and improve the lives of over a billion people ” did not improve as anticipated post declaration, and in the case of several NTDs R&D funding decreased after 2012 (see Additional information file 2). This is representative of the R&D funding, not intervention, or control programming and funding may have been targeted at control rather than R&D although arguably for the NTDs R&D and control are intwined. For the years of 2012–2017 R&D funding is observed to rise and fall but post 2017 there is consistent rise in funding leading to record funding level in 2018 and 2019, however, as observed in Fig.  2 , funding levels fell again thereafter.

Data shows that funding for R&D for the NTDs is varied, changing year to year as a grouping and as individual diseases. As shown in the alluvial plot (Fig.  3 ), funding for R&D for the NTDs has in the main remained relatively stable, but the proportions of the overall funding allocated to an individual disease can be observed to shift from year to year, especially in pre- and post- pandemic periods.

Out of the 15 NTDS that the G-Finder lists within its data portal, 3 diseases have been newly added to the NTDs. Snakebite envenoming is an outlier due to its inclusion into the NTD group in 2017, which shows an increase over the 5 years based on the inclusion and increased awareness that may follow inclusion. Scabies and Mycetoma showed similar albeit smaller increases since their inclusion to the NTD group in 2017. Nine diseases (dengue, Chagas, leishmaniasis, human African trypanosomiasis, onchocerciasis, taeniasis, Buruli ulcer, trachoma and soil transmitted helminths) all showed decreased R&D funding post COVID-19 pandemic as would be expected. Three diseases showed small increases in R & D funding between 2020 and 2021: schistosomiasis (up by 6.5%), lymphatic filariasis (up 1.55%) and leprosy (up 10.4%). Larger increases in funding were observed between 2021 and 2022 for schistosomiasis (increased by 29%), lymphatic filariasis (increased by 35%) and leprosy (increased by 27%). R&D funding for schistosomiasis, leprosy, and lymphatic filariasis has rebounded since 2020 reaching their peaks levels for the previous 5 years in 2022. Chagas R&D funding increased in 2022 but not to pre-2020 level funding. Funding for the remaining 8 NTDS has continued to decrease in the post-COVID-19 era.

Despite record funding for NTDs, every year the funding gap between the amount donated and the amount needed to meet and maintain target goals towards elimination within the roadmap widens [ 20 ]. The costs needed to reach elimination targets increase as the numbers of people affected decrease. This is due to having to travel to reach more rural areas, maintain a longer cold chain to transport vaccines and medicines and the fact that cost/benefit goes down as you decrease the number of people being treated. The converse of this scenario can also lead to an increase in costs, these higher costs are connected to increasing populations at risk due to an increase in poverty, increase in vector habitat due to climate change, and an increase in populations [ 21 , 22 , 23 , 24 ].

UK foreign AID budget cuts

Governmental funding of NTD research and control programs is vital to ending transmission and the eventual elimination of NTDs. HICs donate money through their foreign aid budgets to fund NTD programs, and LMIC fund programs through their governmental budgets. Until recently, the USA and the UK have been the biggest governmental donors to foreign aid budgets.

In November 2020, after declaring that the United Kingdom, through UKAID, would continue to fund NTDs, the UK announced that the UKAID budget would be cut dramatically from 0.7% of the gross national income to 0.5% [ 25 ]. There has been speculation as to whether the budget cuts were due to ‘Brexit’ or the pandemic, however, the reason given by the government for the cuts was the “economic hurricane” of the pandemic and the amount of money that the UK government had spent on the pandemic [ 26 ]. Figure  4 shows the timeline of announced budget cuts and the effects on NGO programs. This budget cut meant that many NGOs that were already recovering from time away from their programs due to travel restrictions and lockdowns installed in response to COVID-19, now also face financial shortages that will affect their ability to supply aid in NTD endemic countries. NGOs contribute money, labor, and organizational infrastructure in areas they work in to improve the health of patients and affected individuals in those communities, without NGO interventions, much of the work of eliminating NTDs would be expected to fall further behind.

Timeline of UK foreign aid budget cuts

A key part of core funding for NTDs is the provision of infrastructure for water and sanitation. Water, sanitation and hygiene (WASH) is important as access to clean water and appropriate sanitation is vital for the elimination of several NTDs [ 27 , 28 ]. Different aid groups and diseases have been affected by the UK cuts, with clean water, sanitation and hygiene budget being cut by 80% [ 29 ]. The executive director of the Water Witness International group came forward to suggest that the UK should be held responsible for the cholera outbreak in Malawi which has killed 1210 people after the UK cut the WASH aid budget of the country by GBP 90 million [ 30 ]. The UK has since contributed GBP 500,000 to the Malawi relief fund, but the total funding needed is GBP 14 million [ 30 ]. While the UK is not the only country that donates money through aid programs, it was the 2nd largest contributor, with this cut dropping it 4th, below France and Germany in the ranking of donors. Other countries and pharmaceutical donors may decide to stop funding aid or donating medicine, knowing that the medicines will expire before being distributed. The Trump administration in the USA proposed several cuts to foreign aid since 2016, ranging from a 20‒30% decrease in foreign spending. In no year during that period did the proposed budget cuts pass, however, it may have contributed to the UK government’s willingness to reduce their aid budget.

Filling the void

Considering the UK foreign aid budget cuts, several independent philanthropic donors have stepped in to fill the void. The Bill and Melinda Gates Foundation, the Children’s Investment Fund Foundation, the ELMA Foundation, and the Open Society Foundations have pledged GBP 94 million to cover part of, but not all the cuts to the budget. This amount will help to cover the immediate costs to keep some clinics open and drug disbursement until the budget is restored or other funding can be found by NGOs [ 31 ]. The chief executive of the Children’s Investment Fund Foundation said: “These life-saving treatments are cost-effective investments. If they go unfunded this year, British taxpayer generosity will be wasted as clinics are closed and essential drugs expire and are thrown away” [ 31 ]. Despite the GBP 94 million supplement from private donors, some programs will still have to close due to lack of funding. One such programme, Accelerating the Sustainable Control and Elimination of Neglected Tropical Diseases (ASCEND), will close their doors and cancel lifesaving programs. ASCEND has been working on visceral leishmaniasis (VL) in Ethiopia, Kenya, Sudan, South Sudan, Uganda, Nepal and Bangladesh, and the closing of that program is projected to result in an additional 20,000‒30,000 deaths from VL [ 32 ].

COVID-19 impacts on supply chains

COVID-19 restrictions alongside budget cuts resulted in donated medicines sitting in warehouses in LMIC and expiring because the NGO workers could not enter the countries or could not pay to have workers already in the country distribute those medicines [ 33 ]. Distribution requires transportation, translators, cold chain storage for some vaccines. Mass drug administration (MDA) programs, which often rely on schools to administer the drugs to children, have already been delayed a year in many cases due to school closures, and now risk further delays. The NTD Modelling Consortium presented models that a 12-month delay of MDA will set the elimination of the disease back another three years. Due to these budget cuts, many programs are facing two to three years setback, causing a 6-to-9-year elimination delay. These MDA programs have subsequently resumed in some NTD endemic countries. However, these programs face continue to face challenges due to ongoing resource shortages. It is also reported that post COVID-19 pandemic some communities are reticent to engage with health care services due to transmission fears [ 34 , 35 ].

COVID-19 has also had a considerable effect on supply chains and manufacturing of drugs, through lockdowns preventing the manufacturing and shipping of produced goods. Vials used for vaccines are made from borosilicate glass and need to be made to certain specifications, but the current vial making glass companies were focused on providing enough vials to contain vaccines [ 36 ]. At two doses per person, that is fifteen billion vials, for COVID-19 vaccines alone, not including those required for “routine” vaccines globally. This represents the bulk of the global production of vials which runs between 15 and 20 billion [ 36 ]. This shortage has also affected blood testing in the UK, in August 2021, the NHS had to suspend some blood testing due to lack of testing vials [ 37 ].

In October 2021, WHO reported there was a more than 2 billion shortfall on syringes, specifically the 0.5 ml auto-disable syringes used for COVID-19 vaccines and routine immunization vaccines and the 0.3 ml auto-disable syringes used for the Pfizer BioNtech COVID-19 vaccine. This shortage will not only impact the ability of LICs to vaccinate for COVID-19 but other lifesaving vaccinations like measles, malaria, and polio (which all require the 0.5 ml syringe); while rabies post exposure requires a larger 1.0 ml syringe, although these can be given without the auto-disable syringe, WHO recommends single use to prevent cross contamination and infections [ 38 , 39 , 40 ]. This has become even more urgent as wild poliovirus has been reported in Malawi for the first time since 2016, and vaccination will be essential to prevent further spread of polio [ 41 ].

COVID-19 also affected supplies of personal protection equipment which prevent the spread of disease, as well as hand sanitizers and soaps, both of which are crucial to stopping the spread of half of all NTDS. For a large part of 2020 there were not enough face masks being produced leading people to make their own masks at home out of cloth or face shields out of recycled plastic bottles. These masks were less effective than medical supply masks or K95 masks leading to greater risk of infection [ 42 ]. The Federal Drug Administration (FDA) of the United States maintains a medical supply shortage list that continues to have basic medical necessities like surgical gloves and gowns listed as in short supply [ 43 ].

Consequences of the COVID-19 pandemic to progress for TB and malaria

TB setbacks and similar will cost in the long run to catch up to where we were. Tuberculosis (TB), one of the Big 3, has seen quantifiable setbacks to treatment and elimination projects around the globe [ 44 , 45 ]. This can be used as a canary in a coal mine to determine funding health for more neglected NTDs, if the Big 3 are losing funding and being setback by the pandemic we can extrapolate the effects on the remaining NTDs. TB is closely linked to NTDs through the Millennium Development Goals (MDGs) and the Sustainable Development Goals (SDGs) [ 46 , 47 ].

TB receives more funding both in research and development dollars and in donations from NGOs and foreign aid than all the NTDS, save malaria and HIV/AIDS. On any given year since the GFinder reports began in 2007, TB has received more than double the research and development dollars than the next closest non- big 3 NTD (diarrheal diseases) [ 48 , 49 ]. Human African trypanosomiasis, leishmaniasis, and other diseases receive so little funding as to be labeled “unspecified diseases” on the GFinder reports [ 48 ].

Limited studies available on co-infections of TB and COVID-19 are often contradictory, with one study suggesting that a latent TB infection boosts the immune system and helps lessen the severity of COVID-19 infections, with another suggesting that the effects of COVID-19 more than double a person’s chances of dying from COVID-19 [ 50 , 51 ]. There are no contraindications on treating TB and COVID-19 at the same time. TB management NGOs have recommended sending TB patients home with enough medicine to continue to treat at home removing the need to risk contracting COVID-19 while seeking treatment for TB [ 52 , 53 ].

COVID-19 has affected both active case finding and treatment of already diagnosed cases. This is represented by the numbers in India, National TB Programmes (NTP) report an approximately 80% decline in the daily TB notifications, reporting new cases to health authorities [ 54 ]. A survey conducted by the Global Coalition of TB Activists shows that 40% of NTP are being used as COVID-19 response centers [ 55 ]. This creates a lack of space, workers, time, and lab space to diagnose new cases of TB, or to treat those already diagnosed cases.

This contributed to people not seeking treatment for their ongoing TB infections, fearing COVID-19 infections in the hospitals and clinics that usually serve TB patients but are now also treating COVID-19 patients [ 56 ]. Although the connections are still being studied, the comorbidities of TB and COVID-19 and the severity of subsequent infections present a unique hazard. Since both diseases cause similar symptoms of difficulty breathing and coughing, the scarification of lungs of TB patients stands to be further damaged by COVID-19, as well as making patients more susceptible to infection [ 57 ].

TB clinics had to close due to lockdowns in several endemic countries, this delayed treatment of people willing and able to receive treatment, contributing to more transmission, reactivation of TB in patients, longer time of treatment and further TB complications [ 58 , 59 ]. Stopping treatment, whether due to inability to obtain medicine or by choice, also increases the likelihood of drug resistance, a growing problem even with rigorous treatments. TB is fatal if left untreated, and even in the pre COVID-19 era roughly 4000 people died per day of TB [ 53 ].

TB is not an outlier in the NTD community, if one of the most well-known, and well-funded “other diseases” featured in the MDGs is being affected financially and with disruptions of treatment, it signals worse indications for the neglected of the neglected diseases. Global cessation of TB transmission has been a goal since the beginning of the MDGs, which has carried through to the SDGs [ 60 ]. COVID-19 has presented new unforeseen challenges to this goal and has set progress back by several years due to interruptions of treatment, active case finding and diagnostics. According to the Global fund annual report for 2021, TB cases were down 18% which on the surface seems encouraging but the reason for the decrease is less testing and less active case finding meaning that more people are living with the disease instead of receiving treatment [ 61 ]. The percentage of countries reporting disruptions to TB diagnosis and treatment increased from 40% (of 124 countries) in 2020 to 51% (of 98 countries) in 2021 [ 62 ].

As is the case for TB, malaria as one of the Big three receives more attention and funding than any neglected tropical disease by at least two-fold in any given year. Even with this advantage, malaria has faced setbacks in terms of progress towards elimination and reducing cases and deaths. In 2019 there were an estimated 227 million cases of malaria worldwide, already up from the 2015 low of 224 million. In 2020, that number has increased to 241 million cases, predominately attributed to the service disruptions caused by COVID-19 [ 63 ]. These disruptions include control programs to distribute insecticide treated bed nets, indoor residual spraying, and seasonal malaria chemotherapy campaigns. in 2020 there were 37 of 64 (58%) responding endemic countries reporting disruptions to diagnosis and treatment, this dropped to 23 of 59 responding countries in 2021. Insecticide treated net distribution disruption is still at 19 endemic countries reporting disruptions, 14 countries reporting disruption of indoor residual spraying [ 62 ]

The number of countries reporting disruptions has decreased between 2020 and 2021, however there are still many endemic countries reporting disruptions at various severity levels, and all disruptions affect the ability to reach the Global Technical Strategy Target for 2030 [ 64 ].

Consequences of COVID-19 for control and elimination of the NTDs

In the early stages of the pandemic between March and August of 2020, several models were developed to predict the outcome of delays and cancellations of NTD programs over time. Schistosomiasis MDA programs were modelled showing that the delay towards elimination as a public health problem would only be delayed for the same amount of time as the delay of the distribution of medicine. This does not account for areas with higher transmission or programs that are in later stages of running where the risk is losing the long-term benefit of multiple rounds of MDA to stop transmission [ 65 , 66 ].

Leprosy was severely affected by the COVID-19 pandemic. Brazil has the second highest burden of leprosy in the world and has a high burden of COVID-19 [ 24 ]. There was a 41.4% reduction in the number of reported cases of leprosy between 2019 and 2020 as a direct result of cases not being identified, from closure of testing facilities and from fear of contracting COVID-19 keeping patients away from health care facilities [ 66 , 67 ]. Delaying in treatment for leprosy has a direct impact on the severity of the disease and increase the likelihood of permanent disability [ 67 , 68 ]. From a survey sent to forty-four leprosy centers, 16/20 or 80% responded that leprosy diagnostic services were reduced, only one responded that they had been closed; 7/8 (87%) of leprosy reconstructive surgery centers had suspended their services and active case finding 3/13 (23%) had been reduced, and 10/13 (77%) had been closed [ 69 , 70 ]. In addition to the closing of active case finding and surgery centers, travel restrictions have had an impact on leprosy. Clinics in many places were sending patients home with 2 to 3 months of multi drug therapy (MDT) although reaction treatments of prednisolone or clofazimine have been unavailable or given out in regular one-month doses for those needing treatment [ 69 , 70 ].

The impact on rabies programs around the world has been felt since the beginning of the pandemic. Based on a survey of 87 groups consisting of NGOs, government offices, and academics contributing from 47 countries, the threat is not only from the cancellation or postponement of dog vaccination programs [ 71 ]. Several countries have reduced their procurement of human rabies vaccines in 2020 and predict even lower procurement plans for 2021 and beyond [ 71 ]. If post exposure vaccines are not available, and bite centers are closed, people may go home and not seek further treatment as in a case in the Philippines where a patient went home untreated and died [ 71 ]. In 25% of responding countries staff who routinely conduct rabies surveillance were reassigned to COVID-19 response [ 72 ].

GAVI’s Vaccine Investment Strategy helps lower income countries obtain vaccines, in particular the human pre-exposure rabies vaccine; but this has been on hold due to COVID-19. In 2020 financial resources allocated to rabies were reduced by 60% and only 5% of reporting countries completed dog vaccination campaigns. Cities in Argentina, Cuba, Mexico, and Brazil all cancelled or postponed with no scheduled repeat day dog vaccination campaigns [ 73 , 74 , 75 , 76 ]. Haiti cancelled their dog vaccination campaign and the funds that were set aside for the campaign were diverted to COVID-19 [ 77 ]. In Arequipa Peru, due to cancellations, dog vaccine coverage was down to 12.3%, far lower than the 70% needed to stop transmission [ 78 ]. Models predicted that based on the decrease in dog vaccinations in Arequipa the rates of rabies cases would grow exponentially within months. December 2020 through March 2021 has tracked with the model predictions, with higher-than-average cases despite lower surveillance being performed [ 71 ]. Rabies is a disease that can be readily controlled by through dog vaccines, but the delays in the dog vaccination programs and the inability to obtain human rabies vaccines means that more people, often children under 15 years old, will be exposed and potentially die from rabies.

Healthcare service disruption

While there is limited data on impacts of COVID-19 on progress towards control and elimination of the NTDs, day to day control of NTDs sits squarely at the healthcare interface and universally health care systems have been challenged by the COVID-19 pandemic. Many health systems in LMIC were already struggling pre-pandemic, with limited physical resources and a lack of physicians and nurses. The chronic and growing shortage of healthcare providers in LMIC due to increased work hours, low resources, and migration to HIC is not a new problem, but has been exacerbated by COVID-19, increasing workload, and causing burnout amongst doctors and nurses [ 79 , 80 , 81 , 82 ]. In Zimbabwe, even before the pandemic, there were strikes of medical professionals due to lack of protective equipment and basic tools such as gloves, bandages, and syringes [ 83 , 84 ]. Doctors strikes and nursing shortages are affecting basic care as well as surveillance on NTDs. When there are a fraction of nurses performing the same tasks that were once done by a large team, underreporting of NTDs will be exacerbated with cases being undiagnosed [ 85 ].

Lockdown policies, albeit implemented in exceptional circumstances, kill people through disruption of health services and deprivation of livelihoods [ 86 ]. There have already been reported increases in maternal deaths during labor, as well as an increase in measles; essential healthcare being suspended or delayed and disrupting access to routine healthcare and/or preventative health care. With preventative campaigns postponed, cancelled, or shortened, the resulting increase in NTD cases and DALYs more generally have and will continue to derail progress towards elimination and meeting the targets set by the WHO 2030 Roadmap [ 86 ].

The WHO created a Pulse survey administered in 159 countries; in multiple configurations since July 2020 to assess the initial impacts of COVID-19 on healthcare systems [ 66 , 87 ]. In addition to clinic closures and staff shortages respondents reported: disruptions due to essential medicines being out of stock (22% of 111 responding countries); unavailability of hospitals beds (19% of 111 responding countries); insufficient staff, often due to COVID-19 redeployment (66% of 112 responding countries; insufficient personal protective equipment in 26% of 111 countries [ 88 ].

More telling regarding the NTDs was the impact in health seeking behavior from within the community. Demand for services were lower than expected due to community fears and mistrust in seeking healthcare (57% of 112 responding countries), patients were observed to be not presenting for outpatient care (57% of 111 responding countries). There were perceptions that financial difficulties were affecting attendance (43% of 112 responding countries) in addition to access to care being prevented by travel restrictions (36% of 112 of responding countries) [ 88 ].

COVID-19 and its consequences present an ongoing constraint to the management of NTDs

The lack of vaccine equity is ongoing despite the best efforts of WHO and partners. In 2022, 116 countries were still short of the target of 70% of the population vaccinated against COVID-19 [ 89 ] despite China having donated 1.3 billion of doses of their vaccines Sinovac and Sinopharm [ 20 ] and pledging 2 billion vaccine doses by the end of 2021 [ 90 ]. The pressure to vaccinate against COVID-19 has been intense, but this has drawn resource away from pre-pandemic vaccine programmes. By contrast COVAX, a WHO joint initiative with the Center for Epidemic Preparedness and Innovation (CEPI), Gavi- the Vaccine Alliance and UNICEF who are committed to facilitate donations of vaccines to countries in need but given vaccine shortages, brought about by the COVID-19 pandemic they were unable to reach their goal of 20% of the world’s population vaccinated by the end of the 2022 despite having successful distributed 1.99 billion vaccines to 146 countries so far, with more than 2 billion vaccines allocated for distribution by 2023 [ 91 , 92 , 93 , 94 ]. COVAX is unable to fulfill many of its 2021 pledges due to the purchasing of additional vaccines by HIC. The CEO of Pfizer, Albert Bourla, cited vaccine hesitancy in Africa as the reason for poor uptake of COVID-19 vaccination [ 95 ] despite communities in Africa being comfortable with childhood vaccination programmes that have eliminated smallpox and are very close to eliminating polio through vaccinations [ 96 ] and the reasons behind vaccine hesitancy remain debatable [ 97 , 98 ]. Inequality persists with wealthy countries administering booster shots while poorer countries have insufficient vaccine to cover even 15% of their population [ 2 , 99 ] and governments not wishing to accept short expiry vaccines [ 92 , 100 ]. Ramping up of production of vaccines in the Global south remains an ambitious goal [ 101 , 102 ]. The prioritization of profit over human health and lives has a direct impact on NTDs as the same pharmaceutical companies are the groups most capable of creating the next antibiotic, anti-malarial, anti-parasitic drugs needed to eliminate NTDs, particularly those that are becoming increasingly drug resistant.

Poverty exacerbation due to COVID-19

It is estimated that as many as 97 million people in 2020 fell into poverty because of COVID-19. While lower than the predicted 119 million this is a “historically unprecedented increase in global poverty” [ 103 , 104 ] derailing progress towards the SDGs and undoing 5 years of progress towards poverty elimination with LMIC hit harder. With an increase in poverty comes an increase in the diseases of poverty.

The NTDs are diseases of poverty, affecting poor rural communities that are often dependent on tourism, the neglected zoonotic diseases affect communities dependent on wildlife and animal trade for their livelihoods. In sub-Saharan Africa (SSA), Kenya, Nigeria, Uganda, and Ghana are in the top ten countries in Africa that account for the most tourism dollars. In SSA T&T contribution to the GDP declined by 46.5% between 2019 and 2020, resulting in a USD 48.8 billion loss to the GDP and 5.7 million jobs lost [ 105 ]. People living in poverty have been required to make hard choices between taking unnecessary health risks and providing for their families [ 106 ].

Lockdowns have had an unprecedented negative impact on children of school age particularly in LMIC. While school closures were global, although in HIC many schools and children were able to continue education online via online platforms, an estimated 1.5 billion children were left without access to education [ 107 ]. Globally, only one in three children has access to internet at home, making online education unattainable [ 108 ]. It is anticipated that as many as 5 million children will not be able to return to school due to teen pregnancy, lack of school fees, or needing to help the family by working [ 109 , 110 ].

Uganda and the Philippines had two of the longest school shutdowns due to COVID-19 and since many MDA programs are delivered to children in schools, this creates a delay in the treatment and elimination of diseases [ 108 ]. In Uganda schools only reopened in January of 2022 after two years of closures; 15.5 million Ugandan students lost two years of education as many lack the resources to participate in online schooling. These children will also lose out on any future MDA programs that will be restarted by the schools, contributing to millions of missed opportunities to end transmission of NTDs. In addition to the missed educational opportunities which impact the children’s future ability to move ahead in life, as many as 370 million children lost their access to the only reliable meal of the day which was provided by the schools [ 107 ].

The COVID-19 pandemic profoundly impacted global health research and global health equity. Countries affected by one or more Neglected Tropical Disease were as expected, have been affected by economic crises, lockdowns, vaccine inequities, and disruption to health services supply shortages all which impact on their ability to manage the NTDs and follow pathways to elimination and control. Attention and funding were diverted from all sectors, significantly affecting research and development efforts set out in the World Health Organization's NTD elimination Roadmaps. The direct impacts of COVID-19 can be seen from the restructuring of investments in research and development for the NTDs.

As is often the case, the bottom billion are the most affected the most by the global turmoil brought on by the COVID-19 pandemic and subsequent economic crises. Ongoing challenges in funding for the NTDs, for research and development will inevitably push back targets and impede development of new tools to manage these diseases. Economic crises, logistics and supply chain disruptions as well as deepening poverty have put a strain on already weak healthcare systems and exacerbated delivery of programmes aimed at alleviating the suffering caused by the NTDs. In particular, the delays and constraints posed to NTD management and elimination programs will have long-reaching consequences. The shortage in medical staff, doctors, nurses, and community health care workers will continue to impact LMICs’ ability to care for the most neglected and underserved portions of the global population.

Not only does an increase in global poverty set back progress in our ability to tackle the NTD’s but it also creates a situation where more people are at risk for developing NTDs; with vector control programmes and MDA suspended.

COVID-19 has shed light on issues with infrastructure, and the need for robust health care systems to be ready for the next pandemic. It has also emphasized the importance of global action for health. COVID-19 will remain an issue for so long as countries are unable to vaccinate their populace and provide adequate consistent healthcare. Poverty and NTDs are intertwined in so many ways that eliminating one is extremely unlikely without eliminating the other.

Availability of data and materials

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Accelerating the Sustainable Control and Elimination of Neglected Tropical Diseases

HIV/AIDS, malaria and tuberculosis

Center for Epidemic Preparedness and Innovation

Foreign Commonwealth and Development Office

Federal Drug Administration

Gross Domestic Product

High Income Countries

Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome

Low- Middle- Income Countries

Mass Drug Administration

Multi Drug Therapy

Medical Research Council

National Institutes of Health

Neglected Tropical Disease

Policy Cures Research and Development Tracker

Research and Development

Sustainable Development Goals

Sub Saharan Africa

Tourism and travel

Water, Sanitation and Hygiene

World Health Organization

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This research was supported by the National Institute for Health Research (NIHR) Global Health Research programme (16/136/33) using UK aid from the UK Government. The views expressed in this publication are those of the author(s)and not necessarily those of the NIHR or the Department of Health and Social Care (SCW, CBB). This work was supported by the Zhejiang University Education Foundation Emergency Research Fund (SCW), Zhejiang University and the University of Edinburgh (CBB).

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Butala, C.B., Cave, R.N.R., Fyfe, J. et al. Impact of COVID-19 on the neglected tropical diseases: a scoping review. Infect Dis Poverty 13 , 55 (2024). https://doi.org/10.1186/s40249-024-01223-2

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The pandemic of Covid-19 has compelled numerous companies worldwide to use several growing online communication platform technologies fully. Educational institutions are among the organizations that have urged students and educators to communicate through a variety of online communication platforms in order to maintain an ongoing educational process. However, the Covid-19 pandemic has created challenges for the worldwide education sector when using these expanding technologies. The challenges were highlighted in many recent studies. However, compared with other developing countries, fewer studies were conducted in Malaysia. This study aimed to identify the challenges faced by educators and learners in online learning impacted by Covid-19 through a literature review. The challenges mentioned are lack of facilities, lack of social interaction among students and educators, poor internet connection, motivation issues, assessment and evaluation process. This literature review implies that they could facilitate relevant authorities such as educational institution administrators, officers serving the Ministry of Higher Education and policymakers in designing effective measures to tackle the challenges.

Impact of Covid-19 , Online Learning , Language Learning , Challenges in E-Learning

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1. Introduction

Covid-19 pandemic declared by the World Health Organization (WHO) in 2019 has impacted people’s lives. The infectious new coronavirus named SARS-CoV-2 was discovered in late 2019 causing the deadly Coronavirus disease (Covid-19). Due to its contagious nature and fast spread, WHO and governments across the globe put an effort to subdue it. Despite widespread public education on avoiding and halting its spread, the disease has spread internationally to 210 nations and territories, with 342,821,624 confirmed cases of Covid-19 and a death toll of 5,592,617 (Worldometer, 2022) . These fast-growing numbers alarmed scientists and governments about the degree to which the disease might devastate the global economy and education (Owusu-Fordjour et al., 2020) , alerting them to act promptly to take preventive measures. To contain the spread of the deadly sickness, most governments temporarily closed all educational institutions and prohibited outdoor activities. In Malaysia, the number of Covid-19 cases reported daily increased fast, prompting the government to issue Movement Control Orders (MCOs) requiring residents of Malaysia to remain at home in order to mitigate the spread of the virus. As the sector is seeing today, the Covid-19 pandemic is compelling instructional establishments and universities to rework and adapt to far-flung and online gaining knowledge rapidly. As all public and private establishments in Malaysia will carry out coaching and gain knowledge online (Chung et al., 2020) , this surfaced the norm of gaining knowledge entirely virtually, embracing digital learning which began to replace traditional classrooms at the elementary to tertiary level. Most of the tertiary institutions have automated a new pattern of teaching and learning as they provide online courses in their digital classrooms facilitated by educators.

The academic community was resilient, adaptable, and proactive in addressing the obstacles faced during MCO. Chung et al. (2020) , an associate professor in UITM, conducted research and reported that lessons, projects, group work, presentations, and evaluations were created in two weeks and implemented using technology. They added that while it is undeniable that online learning is the best solution for ensuring learning continuity in the era of the new norm, there are some drawbacks such as a lack of interactions, observing students’ incomprehension through facial expressions, cracking jokes, students’ participation, and interaction. These can be accomplished more effectively through face-to-face learning. It is also noted that learners demonstrate a lack of human engagement and difficulty in learning in online study groups, and they prefer face-to-face study groups in comparison to online. Educators had to stay resilient in the face of these rapid changes and prepare classes with urgent notices, but many college learners found it struggling to learn online. Despite the Ministry of Education, the government, educational institutions, policies and preparations, the question of whether educators and learners in Malaysia are prepared for online learning continues. As online learning should be implemented by educators during the Covid-19 outbreak (to restrict student movement), and because it is being implemented for the first time by educators, researchers have identified opportunities to investigate the challenges faced by educators and learners in online teaching and learning (Bibi Noraini & Jihan, 2020) .

E-learning has become a norm in higher learning nowadays. Although the common is observed, it had brought several challenges to educators and learners, especially English educators and learners. Among the challenges faced is a lack of technological skills (Erlangga, 2022) students’ participation (Igai & Yunus, 2022) , internet connections (Razkane et al., 2021) and conducting online assessments (Hijazi & AlNatour, 2021) . Added to the point, Bernama (2022) highlighted that limited to no online teaching experience leads to trials frustrations and endless flaws, mentally draining for both English educators and learners, lack of motivation, difficulty dealing with communication in teaching grammar and lack of technical support.

As a result, this literature review documents the challenges in E-learning as part of Covid-19 impact on the education field. This literature review implies that they could facilitate relevant authorities such as educational institution administrators, officers serving the Ministry of Higher Education, and policymakers in designing effective measures to tackle the challenges.

2. Literature Review

2.1. The Impact of Covid-19 on the Education System

Thanks to various online platforms, the way educators provide high-quality education is changing dramatically (Tadesse & Muluve, 2020) . The use of these platforms has become a necessity in the past couple of years due to the restriction on physical gatherings imposed owing to the Covid-19 pandemic. Most countries have had to close schools, training institutes, and higher education institutions due to lockdown and social separation measures enforced in reaction to the Covid-19 outbreak (Preeti, 2020) . According to Tadesse and Muluve (2020) , the instructional machine and educators have embraced “Education in Emergency” through unique online systems. However, the troubles that educators and newcomers encounter, consisting of online learning, faraway training, and persevering with training, have grown to be a technique for this tremendous international pandemic (Adams et al., 2018) . In the dearth of choices, switching from conventional face-to-face training to online training is unique for newcomers and educators. They are being pressured to evolve into a machine they are unprepared for. Hence, this section will be enlightened through two (2) sub-sections which are the impact on the education environment and the impact on the educators and learners.

2.1.1. The Impact on the Education Environment

Learners, parents, and educators worldwide have felt the unanticipated rippling impact of the Covid-19 pandemic as schools have been shuttered to deal with this global medical emergency. While governments, frontline workers, and health authorities fight to contain the spread, educational institutions work to maintain a high standard of education for everyone during these challenging times (Krishnan et al., 2020) . They added that numerous students have experienced psychological and emotional anguish and have been unable to interact successfully at home or in a living space. Concerned authorities and many families opted for different strategies to give their children a better experience during this challenging time. Due to school closures and strict containment measures, more families have relied on technology and digital solutions to keep children engaged in learning, entertained, and connected to the outside world. However, not all children possess the necessary knowledge, skills, and resources to stay safe online (Siti Nurshahidah et al., 2020) .

Nevertheless, the use of technology for educational purposes became the new norm and projected several modifications in academic provision. The closing of educational institutions has resulted in several changes to their system, most notably in teaching and learning. As stated by Preeti (2020) it affected the learning and schooling structures and teaching and evaluation practices. She also cited that the closure of institutions had affected learners’ learning. One urgent action is necessary to maintain continuation in institutions and universities. The use of digital learning tools and platforms became one such action and many educational institutes started using them. Colleges and universities started continuing to provide education by means of learning management software and using open-source as a digital learning solution to operate online classrooms. It was an important step as higher education is vital in determining the country’s economic destiny, and the epidemic has heavily impacted the industry (Mohamed et al., 2022) .

2.1.2. The Impact on Educators and Learners

Movement restrictions not only impacted the learning of learners, but also affected the measurement of their learning. The lockdown brought changes to the lesson delivery mechanism as well as assessment and evaluation. Numerous examinations and evaluations have been canceled or postponed due to educational institution closures (Mohammad Izzamil et al., 2021) . Many colleges and universities have transitioned from conventional classrooms to online classrooms and from offline to online examinations by utilising online assessment tools (Chung et al., 2020) . However, online evaluation tools can have drawbacks. There are various measuring inaccuracies associated with online evaluation tools compared to conventional measurement (Bibi Noraini & Jihan, 2020) . However, assessment and evaluation are important as they are an integral part of education that measures learning outcomes. Moreover, it gives valid records for employees to compare candidates while recruiting graduates. Burgess and Sievertsen (2020) showed that companies utilise educational credentials such as grade point averages and degree categories to evaluate candidates. Thus, the lockdown affected how fresh graduates are placed in the job market.

New graduates’ matching efficiency (the matching between the fresh graduates with the target market of job specifications) is declining as disturbances in candidates’ outcomes increase, resulting in increased employment separation rates and slower earning growth. According to Preeti (2020) , this is both personally and societally expensive. Additionally, it is difficult to supervise how learners take online courses and to guarantee that they are not cheating on online tests (Basilaia & Kvavadze, 2020) . Adding to the point, online laboratory examinations, practical exams, and performance testing are not feasible. Learners who do not have access to the internet may have difficulties with tests and evaluations (Sahu, 2020) . According to Osman (2020) , assessing and evaluating learners’ performance in online learning is challenging for both educators and learners, mainly when teaching practicum and technical competence, and assessing practical skills is challenging. Learners’ assessments are conducted online, with educators, learners, and parents experiencing trial and error, ambiguity, and misunderstanding. Conducting online assessments takes a variety of forms, depending on the educator’s convenience and skill and the learners’ compatibility. According to Tadesse and Muluve (2020) , many schools and institutions have yet to develop effective methods to prevent plagiarism, owing to the enormous student population.

2.2. E-Learning

According to Shahzad et al. (2021) , technology such as artificial intelligence has transformed conventional education into contemporary learning. Thus, E-learning is a broader word that encompasses technology-based learning through websites, learning portals, video conferencing, YouTube, mobile applications, and a plethora of other free blended learning websites. However, the effectiveness of any information system is contingent upon the system’s users (Almaiah et al., 2020) . Currently, via the internet, E-learning is boosting students’ knowledge and the academic staff’s, as well as professional and industry people’s abilities (Adams et al., 2018) . Thus, in the context of an E-learning system, learners’ acceptance of E-learning is seen as a critical factor in determining success. This section will be expanded to a wider view through two (2) sub-sections which are E-learning in higher education and the pros and cons of E-learning to educators and learners.

2.2.1. E-Learning in Higher Education

Most institutions of higher education offer online courses to students on and off campus. This is true for education providers in Malaysia where the government invests heavily in higher education. According to a news source, Malaysian institutions, colleges, and polytechnics are using Massive Open Online Courses (MOOCS) to facilitate online teaching and learning. Radha et al. (2020) stated that the online education industry is predicted to increase at a 16.4 percent annual rate between 2016 and 2023. They stated that with the exponential rise of the internet, university teaching and learning paradigms would shift in the next decade to fifteen years. Though virtual education is a common topic of discussion, users’ use and acceptance of E-learning is a challenge for every educational institution, established or developing, in any country. According to Almaiah et al. (2020) , developed nations are likely to have less anxiety about their learners’ desire to embrace and utilise the E-learning system since necessary progressive steps have already been achieved as stated by Almaiah et al. (2020) . The problems associated with implementing E-learning systems in underdeveloped nations remain a reality owing to the developing countries’ digital divide (Almaiah et al., 2020) .

2.2.2. The Benefits and Challenges of E-Learning to Educators and Learners

E-learning enables educators to achieve a greater degree of coverage to properly transmit their message to their target listeners (Ab Wahab & Mohamad, 2022) . This guarantees that all learners get the same kind of instruction while using this form of instruction. However, E-learning has not yet gained equal status in different regions, mainly due to challenges in its practical usage. Despite the popularity of online education, many population segments deliberately avoid it, mainly because of a misleading image (Doucet et al., 2020) . According to Krishnan et al. (2020) , despite the growing popularity of online courses, most students choose conventional classroom instruction. In comparison to online education, physical classroom instruction is more natural, and students have the chance to argue, think, and discuss with their classmates and professors. They concluded in their results that face-to-face instruction is critical for practical learning since E-learning may encounter unanticipated technological difficulties at any moment. In addition to that, E-learning is always reliant on a stable internet connection with a high-bandwidth connection. It is not always successful, owing to a lack of connection and severe energy scarcity. E-learning is poorer in rural regions than in metropolitan ones, due to a lack of infrastructure required for online courses, which results in students being unable to attend virtual classrooms (Mohammad Izzamil et al., 2021) . However, E-learning is more pronounced these days due to the pandemic and many countries are trying out to adopt it to ensure continuity of learning.

E-learning platforms were critical throughout this pandemic, assisting schools and colleges in facilitating student learning when universities and schools were closed (Subedi et al., 2020) . While adjusting to new changes, assessing and assisting staff and student preparedness is necessary. Learners with a fixed mentality have difficulty adapting and adjusting, but learners who have a growth mindset readily adapt to a new learning environment. There is no one-size-fits-all methodology for online learning due to the diversity of disciplines and their associated demands. Diverse disciplines and age groups need distinct methods for online education (Doucet et al., 2020) . Additionally, online education enables physically challenged students to study more freely in a virtual setting that requires less mobility (Basilaia & Kvavadze, 2020) .

2.3. Challenges in E-Learning

1) Lack of ICT Infrastructure and Support

The current literature research highlighted several barriers to implementing an E-learning system. According to Almaiah et al. (2020) , the difficulties may be categorised into four categories: a) technology difficulties, b) individual difficulties, c) cultural difficulties, and d) course difficulties. It is discovered that these problems vary significantly throughout countries owing to diverse cultures, settings, and preparedness. For example, the primary barriers to E-learning system adoption in underdeveloped nations were a lack of ICT competence, inadequate network infrastructure, and a lack of content creation (Aung & Khaing, 2015) . Another research discovered that system features, internet experience, and computer self-efficacy are the primary impediments to effective E-learning system adoption in Pakistan (Kanwal and Rehman, 2017) . In similar research done in Kenya, three significant barriers to E-learning were identified: insufficient ICT infrastructure, a lack of technical skills, and budgetary restrictions (Tadesse & Muluye, 2020) . According to research conducted by Rahim & Chandran (2021) , the key challenges impeding the effective implementation of current E-learning programs include poor interface design, insufficient technical assistance, and a lack of IT skills.

A study conducted by Aboagye et al. (2020) as cited in Heng and Sol (2021) identified that key challenges faced in implementing E-learning are related to technological infrastructure and digital competence, socio-economic factors, assessment and supervision, and heavy workload and compatibility (as cited in Heng and Sol, 2021 ). Thus, the common problems in practicing E-learning are related to technological competence, technological infrastructure, lack of content creation, individual and cultural differences. Moreover, Heng & Sol (2021) stated that the lack of accessibility to the internet was a great challenge for learners of Southeast Asia. However, issues with the internet are not the only problem highlighted in the region. A study conducted in the Philippines identified the learning environment at home to be the greatest challenge (Barrot et al., 2021) . Similarly, a study conducted in Malaysia by Bibi Noraini and Jihan (2020) , revealed six significant challenges for universities, educators, and students when implementing E-learning methodologies: ICT infrastructure, required online skills, platform security, motivation for lecturers and students while using the online method, and context-specific.

2) Lack of Budget and Funding in some Higher Institutions

Furthermore, accessibility cost, flexibility, pedagogy, lifelong learning and educational policy are often the highlighted issues in E-learning (Alkhezzi & Ahmed, 2020) . Numerous nations have significant challenges in internet connectivity and the availability of digital gadgets. While economically disadvantaged students in many developing nations cannot afford online learning gadgets, online education exposes the learner to increasing screen time (Hove & Dube, 2021) . As a result, offline activities and self-exploratory learning have become critical for pupils. They added that lack of parental direction, particularly for young learners, is another issue, primarily when both parents work. There are practical concerns with physical workplaces favorable to various learning modes as they may have difficulties integrating online learning tools (Bibi Noraini & Jihan, 2020) . Institutions will need to budget for both per-learner and overall expenditures associated with online learning versus more conventional modes of instruction. Cost may become more bearable if courses can be leveraged over a larger learner (Ab Wahab & Mohamad, 2022) . Additionally, a school might shift some expenses to learners and parents by pushing them to purchase any essential multimedia equipment for online education, such as PCs, laptops, printers, or scanners (Bozkurt et al., 2020) . However, there are also restrictions on internet access in some places, creating further complications.

2.3.1. Challenges among Educators

Several of the challenges that educators and learners may face include familiarity with online tools, the capacity to optimize the benefits of the medium, teachers’ availability during times of need, and the ability to provide feedback and prompt responses from learners due to a limited number of computers, internet access, mobile network access, and a shortage of ICT-trained teachers in developing countries (Morgan, 2022) .

As educators, they face a variety of challenges in E-learning, including limited exposure to platform setup (zoom meetings, Google Hangout Meet, Telegram, and Google Classroom, among others), concerns about student participation, and a lack of assessment methods for determining course learning outcomes (Zhu et al., 2018) and a lack of expertise developing e-content (Bozkurt et al., 2020) . Additionally, educators are concerned about students’ devices and Internet access to participate in online classes. Technical difficulties encountered by learners participating in activities such as not having an email to create a new account, being unable to explore how to use tools on the platform, and not knowing how to search for uploaded assessments create another panic among educators (Bozkurt et al., 2020) . Moreover, in their study conducted during the Movement Control Orders in Malaysia, Abdul Rahman et al. (2021) noted that the inability of instructors to boost and sustain student participation also is a problem related to E-learning. They also highlighted that attracting and engaging students in the online learning process was the most challenging. This is also previously stated by Ab Wahab & Mohamad (2022) who discussed the absence of engagement from the teacher’s standpoint. They claimed that when educators are unable to see their learners’ faces, they cannot detect symptoms of attentiveness or inattention and hence are unable to intervene swiftly.

According to a study conducted by Bibi Noraini and Jihan (2020) , educators face six (6) significant challenges in online learning, including the following: 1) learners were less focused on online learning; 2) the platform/medium of instruction was unsatisfactory; 3) learners abandoned learning tools such as books and laptops in residential colleges, and 4) learners’ internet access was unsatisfactory to the point that lectures had to be extended from the scheduled time. There were four (4) strategies for overcoming these obstacles. 1) Institutions should provide more comprehensive and e-learning platforms for online learning; 2) educators and learners should have adequate internet access to ensure smooth and uninterrupted online classes; 3) educators should receive workshops or training on managing online classes; and 4) courses requiring mathematical computation, in addition to a more suitable teaching platform, the student population per group should be small enough to accommodate ten.

2.3.2. Challenges among Learners

Many previous researches have examined a variety of difficulties encountered by both learners and educators. Learners encountered numerous obstacles, including administrative concerns, social interaction, academic and technical abilities, motivation, time constraints, restricted access to resources, and technological difficulties (Barrot et al., 2021) . Learners encountered online education difficulties, including a lack of online student discipline, faculty resistance, and the high expenses connected with online production and delivery (Shahzad et al., 2021) . These difficulties are comparable to those identified in previous research, including unclear duties and responsibilities, a delay in receiving feedback from educators, a lack of technical support, a heavy reliance on technology, and poor learners performance and satisfaction (Chung et al., 2020) . Additionally, difficulties might occur due to a lack of desire and a feeling of alienation and isolation, as learners see themselves as an online component (Sahu, 2020) . Learners perceived it to be less appealing than other modes of instruction, unfriendly to learners, and insufficiently participatory to foster a sense of connection with educators and peers through social media platforms such as Facebook, WhatsApp, WeChat, and email (Haleem et al., 2020) . Meanwhile, various issues have been identified, including learners’ attitudes, personnel resources, time limits, lecturer self-efficacy, and technological difficulties (Zhu et al., 2018) .

The coronavirus lockdown may lead individuals to experience tension, dread, and anxiety, such as a fear of death or their families dying (Sahu, 2020) . This stress might hurt the learners’ mental and physical health. The pandemic may have had a significant impact on learners’ careers or may have prevented them from graduating this year’s higher education undergraduate students (Niranjan, 2020) . All learners may not have positive interactions with online learning apps and platforms (Haleem et al., 2020) , as some learners may be more active while others may take longer to get acquainted with the system. The loss of social connection and the difficulty of learners to create study groups, which they formerly enjoyed, are among some of the difficulties they now face. According to Tümen (2020) , who conducted a study titled “College Students” Views on Pandemic Distance Education: “A Focus Group Discussion”, while distance education can be beneficial during a pandemic, certain forms of distance education lack interaction between learners and educators, which has been a significant issue. The data indicate that most viewpoints expressed concerns about the adverse effects of virtual education on learners’ learning, including a lack of connection, communication difficulties with educators, tests, assignments, time management, and conventional educational traditions. Participants in the study mostly complained about not having enough opportunities to challenge lecturers. Parallel to this conclusion, the researchers discovered that learners could not raise questions as they arose, forcing them to wait for a further encounter with the lecturers (Ab Wahab & Mohamad, 2022) .

Abdul Rahman et al. (2021) who conducted an exploratory sequential sentimental analysis during MCO in Malaysia revealed that learners in rural areas had trouble joining their online classes and sometimes could not join at all due to a lack of access to the internet. They also pointed out that existence of a gap in free-flowing interaction, a lack of engagement among students, and a lack of understanding of self-directed learning, and some learners were uncertain about coping with their assignments and projects. Another study that studied the impact of Covid-19 on university students learning life during the first peak of the pandemic in Malaysia discovered that work and information overload received from instructors, inadaptability and unfamiliarity with the new online learning environment, and personal health challenges related to stress and anxiety as obstacles learners faced during E-learning phase amid the pandemic (Al-Kumaim et al., 2021) .

It is necessary to evaluate the learner’s anxiety about ODL activities. Before organizing ODL activities, educators must examine learners’ Internet access and computer skills, which might induce concern (Bozkurt et al., 2020) , especially in sub-rural and rural areas. Will students complete the tasks outlined in ODL activities independently, without physical connection with peers or lecturers, and how motivated will students be to complete their studies when faced with interruptions and problems at home? The factors mentioned earlier seem to significantly influence students’ preparedness for online learning and academic achievement (Shahzad et al., 2021) .

3. Implication and Conclusion

The Covid-19 pandemic has impacted the education arena globally, and many educational institutions face challenges due to this sudden outbreak which led to the new norm of nearly fully integrating technology into daily lives, especially in educational institutions. On the positive side, this pandemic has allowed all parties to explore and push the boundaries of educational institutions worldwide to upgrade their teaching approaches and facilities. In this paper, the researchers highlighted the impact of Covid-19 on the educational system which was seen from the angles of the educational environment and among educators and learners. Added to that is E-learning which was viewed on the pros and cons, a few challenges educators and learners face in online teaching and learning, such as lack of facilities, lack of technical skills, lack of social interaction among students and educators, poor internet connection, motivation issues by both parties, difficulties in assessing and evaluating students. Hence, the authorities need to address these issues to improve the affected education system.

The sudden strike of the virus had left a massive impact on the educational system and environment as a whole. To sum up the findings of the paper, it is found that many past studies highlighted the impact of Covid-19 on the education system which opened the doors to the problems which resulted in the challenges in E-learning. Movement restrictions not only impacted the learning of learners but also affected the measurement of their learning. The result of the restrictions forced educators and learners to switch from traditional learning to online learning as a new norm. One of the spotlights was more families have relied on technology and digital solutions to keep children engaged in learning, entertained, and connected to the outside world. However, not all children possess the necessary knowledge, skills, and resources to stay safe online. E-learning does not seem to always be fond of the winning side. Even though E-learning enables educators to achieve their objectives in teaching and assist schools and colleges in facilitating students’ learning, it has always been reliant on a stable internet connection with a high-bandwidth connection, and the rural lack of infrastructure required for online courses resulted in learners being unable to attend virtual classrooms. Online laboratory examinations, practical exams, and performance testing are not feasible as the focus goes down to the assessment. Learners who do not have access to the internet may have difficulties with tests and evaluations. The challenges in E-learning are a lack of ICT infrastructure and support among educators and learners and insufficient funding among educational institutions. The challenges between the educators and learners are interconnected to each other such as a limited number of computers, internet access, mobile network access, and a shortage of ICT-trained teachers.

It is vital that the findings of this paper could alert relevant authorities such as educational institution administrators, officers serving the Ministry of Higher Education and policymakers. They need to develop a good plan and carry out measures to overcome the challenges to ensure the effectiveness of online teaching and learning. Universities and educators need to create programs to make learners aware of the challenges and to inform them of how to overcome them, motivating them to embrace online learning. University administrators should include in their plans to upgrade their online platforms to better ones and provide training opportunities for lecturers to familiarize themselves with the E-learning systems, enhancing knowledge on creating content and delivering them digitally. These measures are crucial in preparing the stakeholders of the education field for E-learning and to be prepared for any plans of education in an emergency in the future.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

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Severe COVID-19-Related Acute Respiratory Distress Syndrome (ARDS) in Pregnancy: Prompt Delivery May Be Life-Saving—A Case Report and Review of Literature

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• Volume 6 , article number  82 , ( 2024 )

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• Mohini Sachdeva   ORCID: orcid.org/0000-0002-8181-5687 1 ,
• Kallol Kumar Roy 2 ,
• Rinchen Zangmo 2 ,
• Nilanchali Singh 2 &
• Juhi Bharti 2  

To assess if preterm termination of pregnancy improves maternal outcome in COVID-19 ARDS. A 35-year-old, woman at 36 weeks period of gestation with severe COVID-19-related ARDS, whose rapid deterioration despite starting steroids, antibiotics, low molecular weight heparin, and optimizing ventilatory support, led us to intervene with a preterm emergency cesarean section. The most important factor in consideration was the limitation of maternal respiratory management due to pregnancy and superimposed maternal metabolic acidosis with the risk of fetal acidosis. The rationale of delivery was to improve respiratory mechanics and decrease maternal oxygen requirement. Some studies have discussed the importance of preterm termination of pregnancy with severe COVID-19 ARDS and investigated its impact on feto-maternal outcomes. This aspect is important as ethical and physiologic considerations in pregnancy, obviate the use of a single protocol for all pregnant women. Timely termination of pregnancy may improve maternal outcome in severe COVID-19 ARDS.

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Mohini Sachdeva

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Sachdeva, M., Roy, K.K., Zangmo, R. et al. Severe COVID-19-Related Acute Respiratory Distress Syndrome (ARDS) in Pregnancy: Prompt Delivery May Be Life-Saving—A Case Report and Review of Literature. SN Compr. Clin. Med. 6 , 82 (2024). https://doi.org/10.1007/s42399-024-01710-5

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Gender differences in the relationship between medical students’ emotional intelligence and stress coping: a cross-sectional study

• Na Zhang 1 ,
• Xiaoyu Ren 1 ,
• Zhen Xu 2 &
• Kun Zhang 3  

BMC Medical Education volume  24 , Article number:  810 ( 2024 ) Cite this article

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Given the increasing stress levels among medical students due to the impact of COVID-19, it is crucial to effectively reduce their stress levels for their future development. To better understand medical students’ stress coping, this study investigated how their emotional intelligence is related to stress coping and whether this relationship is moderated by gender differences.

A cross-sectional study was conducted. A random sample of 744 medical students from Hebei Province, China, was investigated via an emotional intelligence scale and stress coping questionnaire from March–May 2023. The response rate was 93%. SPSS and Mplus statistical software were used for the data analysis.

The self-emotional appraisal of medical students had a significant negative effect on avoidant coping (β = -0.173, CI 95% = [-0.243, -0.099], p  < .001). However, the other dimensions of emotional intelligence (others’ emotional appraisal, use of emotion, and regulation of emotion) had a significant positive impact on the active coping of female medical students (β = 0.146, CI 95% = [0.082,0.214], p  < .001; β = 0.235, CI 95% = [0.167,0.304], p  < .001; β = 0.165, CI 95% = [0.084,0.247], p  < .001). In contrast to those of female medical students, other dimensions of emotional intelligence had a significant positive impact on the avoidant coping of male medical students (β = -0.161, CI 95% = [-0.284, -0.062]; p  < 0.01; β = 0.126, CI 95% = [0.043,0.246], p  < 0.001; β = 0.159, CI 95% = [0.054,0.277], p  < 0.05; β = -0.221, CI 95% = [-0.363, -0.129], p  < 0.001). Moreover, the use of emotion had a significant positive impact on the active coping of male medical students (β = 0.272, CI 95% = [0.182,0.382], p  < .001). Furthermore, gender differences had a moderating effect on the relationship between emotional intelligence dimensions and stress coping (β = 0.178; CI 95% = [0.068,0.292]; p  < 0.05). Others’ emotional appraisal has a greater impact on female students’ active coping. In addition, with increasing regulation of emotion ability, female medical students reduce avoidant coping (β = 0.169, CI 95% = [0.002,0.326]; p  < 0.05).

Conclusions

The current study revealed that gender is a significant moderator of the relationship between medical students’ emotional intelligence and stress coping. These findings may help medical colleges focus on gender differences when improving medical students’ ability to cope with stress.

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Introduction

College students are faced with many internal and external stresses that mainly come from academic, personal, and interpersonal relationships. Since COVID-19, the stress level of college students has increased [ 1 ]. This is especially true for medical students, who are more likely to encounter COVID-19-infected individuals [ 2 ]. Stress is regarded as a life crisis that affects the development of college students at all stages. High stress levels among medical students may lead to psychological problems such as depression, anxiety, and irritability [ 3 , 4 ], which can cause serious harm to their physical and mental health [ 5 ]. Furthermore, it will have a certain degree of influence on the career planning of medical students [ 6 ]. Therefore, effectively reducing the stress level of medical students is highly important for their future development.

As a special group, medical students are also facing the pressure of changing from being college students to being qualified medical workers [ 7 ]. Thus, medical students face more pressure than students from other majors [ 8 ]. Stress coping involves the different ways people deal with stress. Many medical students try to eliminate or reduce the impact of stressors by using effective or ineffective styles to cope with stress [ 9 ]. As an intermediary mechanism of stress and health, stress coping has important protective effects on individuals’ physical and mental health. As a new force in the field of health care, medical students’ effective stress coping and maintenance of mental health have a crucial impact on their social development.

Previous research on stress often coincides with research on emotion, which is experienced both physically and mentally [ 10 ]. Emotional intelligence is the ability to recognize one’s own and others’ emotions, to motivate one’s own emotions, and to manage one’s emotions in interpersonal relationships [ 11 ]. Emotional intelligence greatly affects individuals’ behavior and performance [ 12 ]. It helps students select the most appropriate stress coping style [ 13 ]. In previous studies, emotional intelligence was shown to buffer stress through active coping [ 14 , 15 ]. In other words, emotional intelligence minimizes the negative effects of stress and improves coping [ 16 ].

Gender has been shown to be an important factor that influences stress coping. Researchers have found that females tend to use behavioral coping more actively than males do [ 17 , 18 ]. However, some scholars believe that, based on the socialization hypothesis, females are more likely to use avoidant coping, while males are more likely to adopt active coping [ 19 , 20 ]. There is no consistent conclusion on the impact of gender on stress coping. These inconsistent findings highlight the need to consider gender differences when examining medical students’ stress coping.

Similarly, the study of emotional intelligence also emphasizes gender differences [ 21 ]. On the one hand, there are significant differences in the level of emotional intelligence between males and females [ 22 ]. On the other hand, gender has an important influence on the role of emotional intelligence [ 23 ]. Gender differences exist in both emotional intelligence and stress coping. However, to date, little research has been conducted on the potential role of gender as a moderator in the relationship between emotional intelligence and stress coping. As a moderator, the relationship between emotional intelligence and stress coping can still exist in the Chinese context, even in the absence of gender [ 15 , 24 ]. Therefore, whether there is a gender difference in the impact of emotional intelligence on stress coping among Chinese medical students is worth further exploration.

Therefore, this study explored the gender differences in stress coping in the field of health care and further explored the role of medical students’ gender as a moderator of emotional intelligence dimensions on stress coping. Thus, the influence mechanism of emotional intelligence on the stress coping of medical college students is clearer. At the same time, we expand the research on the influence of gender differences on stress coping.

• Stress coping

Individuals try to alleviate stress by reducing stressors, regulating negative emotions, and re-establishing their inner balance; in other words, they engage in coping [ 25 ]. The most commonly used definition of stress coping by Lazarus and Folkman is “constantly changing cognitive and behavioral efforts to manage specific external or internal demands that are far beyond the existing resources of the person” [ 26 ].

Researchers have typically divided coping into two styles: problem-focused coping and emotion-focused coping [ 27 , 28 ]. However, some researchers have divided coping from the perspective of behavior into two categories: active and avoidant coping [ 17 , 29 ]. Active coping involves considering ways to overcome stress and make plans for subsequent efforts, seeking social support and taking advantage of the situation by learning lessons from it [ 30 ]. Avoidant coping includes withdrawal and avoidance [ 31 , 32 ]. This division is more concise and easier to understand and analyze. Therefore, to better guide practice, we chose this division.

Many scholars have proposed that emotional intelligence and stress coping are inseparable [ 15 , 33 ]. An increasing number of articles have established a relationship between emotional intelligence and stress coping among students [ 16 , 34 ]. These studies seemingly indicate that students with greater emotional intelligence display better stress coping.

In this research, we used Lazarus and Folkman’s definition of stress coping to explore the relationship between emotional intelligence and stress coping among medical students of different genders.

Emotional intelligence and stress coping

Emotional intelligence is related to an individual’s ability to deal with stress [ 24 ]. Emotional intelligence is the ability of individuals to recognize, evaluate, manage and control their own or others’ emotions [ 35 ]. The Wong and Law Emotional Intelligence Scale (WLEIS) is one of the most widely used measures of trait emotional intelligence. According to this measure, emotional intelligence includes an individual's specific ability in four aspects: (1) self-emotional appraisal, (2) others’ emotional appraisal, (3) use of emotion, and (4) regulation of emotion. Specifically, self-emotional appraisal relates to the individual’s ability to understand their deep emotions and be able to express these emotions naturally; regulation of emotion is the ability of people to regulate their emotions, which will enable a more rapid recovery from psychological distress; use of emotion is the ability of individuals to make use of their emotions by directing them toward constructive activities and personal performance; and others’ emotional appraisal is the ability to perceive and understand the emotions of those people [ 36 ].

With regard to stress coping, Moradi confirmed that people’s level of emotional intelligence helps in predicting useful stress coping [ 37 ]. Similar results were found in subsequent studies. Goleman argued that emotional intelligence includes traits such as motivation, optimism, adaptability, and warmth [ 38 ]. This adaptive capacity, also known as resilience, enables people to recover from stressful situations in the face of adversity [ 39 ]. High emotional intelligence is related to good adaptability [ 40 ]. In other words, students with high emotional intelligence have greater adaptability when facing stress. Due to their future occupation, medical students face more stress, so adaptability is necessary for them. Students with greater adaptability show a greater tendency to adopt active coping when faced with pressure and mental health problems [ 41 ].

In a study of college students’ stress coping, Fteiha reported a positive correlation between emotional intelligence and active coping [ 33 ]. Similarly, Por reported that individuals with higher emotional intelligence scores engaged in more active coping [ 42 ]. Based on the above discussion, the first hypothesis for this study is as follows:

H1: Emotional intelligence has a positive impact on the active coping of medical students.

Emotional intelligence is the ability to address one’s emotions, and an individual with high emotional intelligence is generally optimistic [ 43 ]. Optimistic students can see the positive side of the undesirable status quo and adopt active coping [ 44 ] instead of avoidant coping to escape stress.

According to a study of first-year law students, those with greater positive affect were less likely to adopt avoidant coping [ 45 ]. Similarly, many studies have shown that individuals with low emotional intelligence use more avoidant coping [ 24 , 46 ]. Based on the above discussion, the second hypothesis of this study is as follows:

H2: Emotional intelligence has a negative impact on the avoidant coping of medical students.

Gender differences and stress coping

Gender is recognized as an important predictor of differences in stress coping. The majority of prior studies found different results. Women believe that they do not have sufficient resources to cope with stress and tend to adopt an active coping style by seeking support from others [ 47 ]. Carver reported that women coped with stress positively by seeking social support, while men coped negatively by using distracting means such as alcohol and drugs [ 48 ]. Similarly, a recent study of law enforcement officers revealed that female officers were significantly more likely to use active coping, including emotional and social support, than male officers were [ 49 ].

However, the results remain somewhat mixed. Due to gender stereotypes, males are often associated with reason, while females are associated with emotion. According to Howerton, females are more likely to adopt avoidance-centered avoidant coping [ 50 ]. Another study revealed that females engage in more avoidant coping and that males engage in more rational active coping [ 51 ]. However, recent research has suggested that there are no statistically significant differences in the methods of coping with psychological stress based on gender [ 24 ].

Gender differences in stress coping can be explained by variations in the types of situations that female and male students typically encounter. Being female may be socially associated with exposure to a specific set of gender-related stressors, such as discrimination, battering, rape, and sexual harassment [ 52 ]. This may mean that different types of stress coping are needed.

Mixed results for the impact of gender on stress coping were found in the previous literature. However, the majority of related research suggests that gender differences have an impact on stress coping. Hence, we clarify the impact of gender differences on the stress coping of medical students. We propose the third hypothesis of the study:

H3: Gender moderates the emotional intelligence and stress coping of medical students.

Above literature reviews indicated that stress coping can be affected by gender and emotional intelligence. This research aimed to compare the associations between emotional intelligence dimensions and stress coping among medical students of different genders.

Sample and data collection

The study was mainly built on a quantitative design and survey research. This research adopted cluster random sampling. Hebei Province, a major province for the enrollment of medical students, was selected as the sampling area. Then, three medical colleges (enrollment number > 1200) were randomly selected from Hebei, as the medical colleges specialize in training medical students.

During the period of March–May 2023, we conducted a survey on the senior students of the two schools with the largest number of students in the three medical colleges, basic medical school and nursing school. The third author distributed the survey questionnaires to 800 Chinese medical students. Written informed consent was obtained from the participants after the researchers explained the purpose, risks, and benefits of the study, as suggested in prior research. Participation was voluntary, and no personally identifiable information was collected. In addition, at the beginning of the questionnaire, there was a cover letter containing information concerning purpose, anonymity, and confidentiality. The letter also included instructions and fill-in methods for those medical student participants.

The distribution of the questionnaires was completed in the classroom. The survey instrument included demographic conditions, the emotional intelligence scale and the stress coping scale and was distributed to each student by the researchers with the assistance of teachers. The questionnaires took approximately 20 min to complete. A questionnaire recovery box was set up in the college, and the participants completed the questionnaire and put into the box by themselves. After 56 invalid questionnaires were excluded, 744 valid questionnaires were finally collected, yielding an effective response rate of 93%.

All the measures were prepared in Chinese. The emotional intelligence scale was initially developed by Law K [ 53 ], and we used a Chinese version of the scale. To avoid distortion in the translation, the scale was independently translated back to English by two professionals and compared with the original English version. The scale has good reliability and validity in the Chinese context [ 54 , 55 ].

Emotional intelligence. Students’ emotional intelligence was measured using the questionnaire adapted from Law K, which consisted of four dimensions: self-emotion appraisal, other-emotion appraisal, use of emotion and regulation of emotion [ 53 ]. The survey included 16 items rated on a five-point scale (from 1 ‘strongly agree’ to 5 ‘strongly disagree’). High scores indicate good emotional intelligence, and low scores indicate poor emotional intelligence. Sample items included “I truly understand what I feel”, “I always know my friends’ emotions from their behavior”, and “I always tell myself I am a competent person”. The internal reliability of this questionnaire was sufficiently high (α = 0. 859).

Stress coping. Students’ stress coping ability was measured using the Chinese version of the questionnaire adapted from Frydenberg, which consisted of two dimensions: active coping and avoidant coping [ 56 ]. The survey included 13 items rated on a four-point scale (from 1 ‘do not use’ to 4 ‘often use’). Sample items were “I do not take the problem too seriously” and “I try to forget the whole thing”. The internal reliability of this questionnaire was sufficiently high (α = 0. 893). The Cronbach’s α for active coping and avoidant coping was 0. 871 and 0. 889, respectively.

Control variables. The moderator of gender was measured as 0 = female and 1 = male. The other demographic variables included only child (1 = yes; 2 = no), major (1 = nursing major; 2 = anesthesiology major, 3 = medical imaging major, 4 = medical laboratory science major), origin (1 = countryside; 2 = town; 3 = city), and class leader (1 = yes; 2 = no). Previous studies have shown that demographic variables, such as origin and being an only child, are likely to influence emotional intelligence and stress coping [ 57 , 58 ]; therefore, these variables were included as control variables.

In this study, the measurement scales were presented to the participants in the following order: demographic variables such as student gender, the emotional intelligence scale, and the stress coping scale.

Data analysis

The SPSS 26 statistical software package was first used for data analysis. The demographic characteristics of the sample are described as the mean (M), standard deviation (SD), number (n), and percentage (%), as appropriate. Group differences in stress coping ability were tested by t tests or one-way ANOVA. We then presented the means, standard deviations, and correlation values among the study variables. Because gender is a binary variable (female or male), we used group comparisons. We asked participants to self-identify their genders. After controlling for other demographic variables, Mplus 7.4 was used to compare the relationship between emotional intelligence and stress coping among students of different genders.

Descriptive statistics

Of all the students who participated in the survey, 81.6% were female, 73% were from the countryside, and 79.3% had brothers or sisters. The majority of the sample (60.1%) were nursing majors, and 79.2% of the students adopted active coping. The respondents’ demographic information and group differences in emotional intelligence and positive and avoidant coping are described in detail in Table  1 . Students who not-only child ( p  < 0.05), who served as class leader ( p  < 0,01) had higher level of emotional intelligence. Students from city had higher level of emotional intelligence ( p  < 0.01). Medical laboratory science major students had a higher level of active coping ( p  < . 001). Anesthesiology students ( p  < 0.01) who served as class leaders ( p  < . 001) had a greater level of avoidant coping. Furthermore, a comparison of emotional intelligence, active coping, and avoidant coping among students from three medical colleges revealed no significant differences. Table 2 details the means, standard deviations, and intervariable correlations. The results indicate a significant correlation between emotional intelligence and stress coping.

Hypothesis testing

Group comparisons were used to compare the associations between emotional intelligence dimensions and stress coping among medical students of different genders. The results are shown in Table  3 .

Figure  1 shows the results of the influence of female medical students’ emotional intelligence dimensions on stress coping. Specifically, for female medical students, self-emotional appraisal significantly negatively predicted avoidant coping (β = -0.173, CI 95% = [-0.243, -0.099], p  < 0.001). However, others’ emotional appraisal significantly positively predicted their active coping (β = 0.146, CI 95% = [0.082,0.214], p  < 0.001). Moreover, use of emotion (β = 0.235, CI 95% = [0.167,0.304], p  < 0.001) and regulation of emotion (β = 0.165, CI 95% = [0.084,0.247], p  < 0.001) significantly predicted active coping.

Female medical students’ emotional intelligence on stress coping. Note: * p  < . 05, ** p  < . 01

Furthermore, Fig.  2 shows the results of the influence of female medical students’ emotional intelligence dimensions on stress coping. For male medical students, the results showed that self-emotional appraisal significantly negatively predicted avoidant coping (β = -0.161, CI 95% = [-0.284, -0.062]; p  < 0.01). In contrast to female medical students, others’ emotional appraisal significantly positively predicted male medical students’ avoidant coping (β = 0.126, CI 95% = [0.043,0.246], p  < 0.001). The use of emotion significantly predicted active coping (β = 0.272, CI 95% = [0.182,0.382], p  < 0.001) and avoidant coping (β = 0.159, CI 95% = [0.054,0.277], p  < 0.05). Additionally, the regulation of emotion significantly negatively predicted avoidant coping (β = -0.221, CI 95% = [-0.363, -0.129], p  < 0.001).

Male medical students’ emotional intelligence on stress coping. Note: * p  < . 05, ** p  < . 01

Subsequently, we tested the moderating effects of gender on emotional intelligence dimensions and stress coping. As shown in Table  4 , we defined Diff = female‒male. None of the 95% CIs included zero, suggesting that the main effect of others’ emotional appraisal on medical students’ active coping was significant and positive (β = 0.178, CI 95% = [0.068,0.292]; p  < 0.05), indicating that others’ emotional appraisal had a greater effect on the active coping of female medical students than on that of male medical students. Additionally, the main effect of regulation of emotion on medical students’ avoidant coping was significant and positive (β = 0.169, CI 95% = [0.002,0.326]; p  < 0.05), which revealed that regulation of emotion had a greater effect on the active coping of female medical students than on that of male medical students.

Figures  3 and 4 provide graphical representations of the moderating effects of gender. The figure shows that with an increase in others' emotional appraisal score, female students engage in more active coping. Similarly, with increasing regulation of emotion, there are significant differences in avoidant coping between female students and male students.

Moderation of gender on others’ emotional appraisal-active coping correlation

Moderation of gender on regulation of emotion-avoidant coping correlation

Interpreting the findings

First, this study is the first to compare the connection between emotional intelligence and stress coping among medical students of different genders. This finding confirms that different emotional intelligence dimensions influence how medical students cope with stress. These comparisons indicate that medical students’ stress coping is complex and influenced by many individual factors. This study therefore contributes to the literature on medical students’ psychological health.

Second, the outcome of the current study confirms that self-emotional appraisal significantly negatively predicts both female and male medical students’ avoidant coping. Medical students with high self-emotional appraisal ability are more aware of changes in their emotional patterns, and they are also more likely to make plans and engage in active coping [ 59 ]. In other words, they will reduce the use of alcohol and other avoidant coping to vent their emotions. However, this finding is contrary to that presented by Jung and Yoon [ 34 ].

Additionally, the use of emotion was found to have the greatest impact on both female and male medical students’ active coping and to have positive and significant effects on male students’ avoidant coping. Students with high scores for the use of emotions will use emotions to relieve stress. There is robust evidence that positive emotions cooccur with negative emotions during intensely stressful situations [ 60 ]. Therefore, students can make full use of positive emotions and adopt positive coping styles. It is also possible to avoid coping due to the guidance of negative emotions. Compared with females, male medical students are less able to identify their negative emotions [ 61 ], resulting in their inability to use negative emotions correctly. Thus, male medical students are more likely to avoid coping under the guidance of negative emotions.

Additionally, the regulation of emotion significantly positively predicts female medical students’ active coping but significantly negatively predicts male medical students’ avoidant coping. Regulation of emotion is the ability of people to regulate their emotions. In other words, medical students with high regulation of emotion ability have greater adaptability [ 10 ]. They are more likely to face stress when they have a positive and optimistic attitude. Thus, the ability to regulate emotion helps female students cope more actively and helps male students cope less effectively. This conclusion is consistent with the literature, which indicates that an increase in the regulation of emotion increases the use of active coping [ 15 , 24 , 34 ]. However, in contrast to Eschenbeck’s results, no gender differences occurred for stress coping related to emotion regulation [ 62 ].

Fourth, others’ emotional appraisal significantly positively predicts female medical students’ active coping. Females pay more attention to participating in social activities [ 63 ], and females are more likely to seek social support to reduce stress [ 64 ]. Thus, students with greater emotional appraisal can better ‘read’ the environment and others’ emotions and respond accordingly to obtain more social support when faced with stress. Videlicet, they will cope more actively. This finding is consistent with previous research findings showing that females cope more actively to relieve stress [ 49 , 65 ].

However, for male medical students, others’ emotional appraisal has statistically positive and significant effects on avoidant coping. Male students who score higher in others’ emotional appraisal are more sensitive to others’ emotions, which leads them to bear more pressure [ 66 ]. Males are more independent and rarely seek help in the face of pressure [ 67 ]. This leads them to engage in more avoidance coping.

Finally, when comparing the influence of the emotional intelligence dimensions of students of different genders on their stress coping, our research indicates that female medical students’ others’ emotional appraisal has a much greater effect on active coping. This may be because under the influence of traditional Chinese culture, the expectations of males and females are different, males are more independent and more responsible, and females are more sensitive and more careful [ 68 ]. Thus, compared with male medical students, female medical students are more sensitive and concerned about the emotions of others. In other words, female medical students are more careful than male medical students in interpersonal relationships. This makes female medical students’ friendships more active, intimate, and emotionally supportive [ 69 ]. Thus, high others’ emotional appraisal helps female medical students maintain a better interpersonal circle and obtain more social support. When female medical students face stress, they are more likely than male medical students to use help-seeking behaviors to actively cope [ 39 ].

Furthermore, male medical students’ regulation of emotion had a stronger effect on the reduction of avoidant coping. This may be because tobacco use and alcohol consumption are greater in males than in females in China [ 70 ]. In other words, when facing stress, males are prone to think of using avoidant coping, such as smoking and drinking, to relieve stress, while females usually do not. Therefore, because females use less avoidant coping, better regulation of emotion has less of an effect on avoidant coping. In contrast, for male medical students, the ability to regulate emotion helps them to better restrain negative feelings and, in its place, promote positive feelings such as confidence, empathy and friendliness [ 71 ]. This helps male medical students face stress with optimism, so they will take the initiative to find a solution and take less avoidant coping.

In general, although female medical students suffer more stressors and are more likely to be affected by stressors [ 72 ], we have found that emotional intelligence can better help female medical students relieve stress than can male medical students.

Contributions to the literature

This research contributes to the empirical investigation of stress coping in several ways. First, we confirmed the moderating effect of gender. Previous studies have reached different conclusions about gender differences in stress coping [ 18 , 20 ]. Moreover, few studies have focused on gender differences in stress coping in the Chinese context. In China, medical students are under great pressure. We examined gender differences in stress coping and identified inconsistencies in previous studies. This study fills the gap in the literature on gender differences in the stress coping of medical students in the Chinese context and helps Chinese medical students better relieve stress.

Second, previous studies have shown that there are gender differences in emotional intelligence and stress coping. However, few studies have tested gender differences in the effect of emotional intelligence on stress coping, which represents a serious gap in the literature. Thus, we have comprehensively promoted the research progress on gender differences in these two fields rather than studying gender differences in emotional intelligence or stress coping in isolation. This can better guide medical students to relieve stress.

Furthermore, in previous research, stress coping strategies have been divided into two categories: problem-focused coping and emotion-focused coping. We divided stress coping behavior into two categories: active coping and avoidant coping. This division is more concise and easier to understand and analyze, so our results can better guide practice.

Implications for Management

The results of this study have many important implications for college education, particularly for medical majors. First, the results of this paper shed light on the complex ways in which emotional intelligence is relevant to Chinese medical students’ active stress coping. Colleges should offer mental health courses so that medical students can maintain a positive and optimistic attitude and can adopt more effective active coping in the face of pressure.

Second, given the larger proportion of female medical students, the results showing that gender differences moderate the effect of emotional intelligence on stress coping could provide an effective solution for college students. Colleges can increase medical students’ emotional intelligence skills through courses and practice, particularly for female students. This can improve students’ emotional intelligence and help them actively cope with stress to relieve their stress and anxiety. A healthy psychological state has a crucial impact on future doctors and nurses.

Finally, according to Damla, seeking social support is the most common stress coping style among doctors and nurses [ 73 ]. Social support is provided by networks comprising family, relatives, and friends. Thus, colleges should encourage students to socialize and make friends. At the same time, colleges should regularly communicate with parents to provide necessary support for students.

Limitations

There are some limitations of this study that may affect the results. One potential limitation is that all variables were measured by self-reports, which may have led to response bias. To overcome this weakness, multiple indices (e.g., physiological and physiological indices) should be used to obtain more reliable information about the emotional intelligence levels of participants in the future.

Second, all the participants in the study were from 3 regions in Hebei Province and from 3 medical colleges. Medical colleges in other provinces were not investigated. The sample data we used may not be sufficiently comprehensive. Future research should attempt to select more colleges by expanding the geographical scope and especially focusing on colleges in first-tier cities to compare the effect of different levels of economic development on students’ emotional intelligence and stress coping. In addition, there are still some important sociocultural factors that we do not take into account. Thus, attention to other variables, such as Chinese culture, is also one of the future research directions.

Finally, we use a cross-sectional study, and only preliminary inferences are made on the relationships between variables. It is impossible to clarify the causal relationships between variables. Tracking research design or experimental research is still needed to further improve the paper.

The results show that the different dimensions of emotional intelligence have different effects on the active/avoidant coping of medical students of different genders. In addition, there are gender differences in the impact of others’ emotional appraisal on active coping and the impact of the regulation of emotion on avoidant coping. This study provides compelling evidence that focusing on gender is useful for improving medical students’ stress management skills. Therefore, different interventions for medical students of different genders are beneficial for increasing the impact of emotional intelligence on stress coping and can be used to help medical students relieve severe stress.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.

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The authors thank all the participating medical teachers and students. We would like to express our gratitude to them for their assistance.

This work was funded by the National Natural Science Foundation of China 71901031.

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Zhang, N., Ren, X., Xu, Z. et al. Gender differences in the relationship between medical students’ emotional intelligence and stress coping: a cross-sectional study. BMC Med Educ 24 , 810 (2024). https://doi.org/10.1186/s12909-024-05781-9

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Systematic Review of the Literature About the Effects of the COVID-19 Pandemic on the Lives of School Children

Background: The year 2020 has been marked by the emergence of coronavirus disease 2019 (COVID-19). This virus has reached many countries and has paralyzed the lives of many people who have been forced to stay at home in confinement. There have been many studies that have sought to analyze the impact of this pandemic from different perspectives; however, this study will pay attention to how it has affected and how it may affect children between 0 and 12 years in the future after the closure of schools for months.

Objective: The objective of this article is to learn about the research carried out on the child population in times of confinement, especially those dealing with the psychological and motor aspects of minors.

Methods: To carry out this systematic review, the PRISMA statement has been followed to achieve an adequate and organized structure of the manuscript. The bibliography has been searched in the Web of Science (WOS), Scopus, and Dialnet databases, using as keywords: “COVID-19” and “Children.” The criteria that were established for the selection of the articles were (1) articles focusing on an age of up to 12 years, (2) papers relating COVID-19 to children, and (3) studies analyzing the psychological and motor characteristics of children during confinement.

Results: A total of nine manuscripts related to the psychological and motor factors in children under 12 have been found. The table presenting the results includes the authors, title, place of publication, and key ideas of the selected manuscripts.

Conclusion: After concluding the systematic review, it has been detected that there are few studies that have focused their attention on the psychological, motor, or academic problems that can occur to minors after a situation of these characteristics. Similarly, a small number of studies have been found that promote actions at the family and school level to reverse this situation when life returns to normal. These results may be useful for future studies that seek to expand the information according to the evolution of the pandemic.

Introduction

When news of an epidemic began to spread in a Chinese city in early 2020, no one anticipated the scope of the epidemic for the entire world in a very short period. From Wuhan (China) to New York (USA) through Africa, South America, Asia, and Europe, the new coronavirus, coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has paralyzed, to a greater or lesser extent, the life in many countries, causing thousands of deaths and about 6 million infections. For these reasons, the scientific community is on the alert by conducting studies on the virus, the disease it produces, the situation it creates, and the population it attacks, from different perspectives, including systematic reviews of the literature, such as the one presented in this paper.

However, researchers on this topic are not only biologists or physicians. It is worth noting the contribution of Maestre Maestre ( 2020 ), President of the Society for Latin Studies, in an article on the virus that has caused the pandemic, in which, playing with different related terms, he explains that the neutral noun “virus” means “poison” in Latin, so most current research is trying to find a medicine that will kill the virus. Likewise, the Greek term ϕάρμακoν (in Latin pharmacum) also means poison. The relationship between the two terms is that pharmacies are looking for poisons that will kill the “poisons” that undermine people's health or their desire to be safe. Remember the symbol of the pharmacies, the “Bowl of Hygieia” with the snake that pours a “poison” into it that stops being a poison to become an antidote. The name “coronavirus” is given to it because, through the microscope, the “virus-poison” is shaped like a “crown” that makes it king of poisons.

However, in addition to scientists who study the pandemic, biologists, doctors, and humanists, educators are obliged to care for the psychological and emotional health, as well as cultivate the minds, of children. The consequences of the containment measures of COVID-19 are being detrimental to the mental health of people around the world. It is logical that the most vulnerable are children who do not understand what is happening and who, along with the concern and frustration of their elders, may present risk factors, such as anxiety and affective and post-traumatic stress disorders (Giallonardo et al., 2020 ). However, not only minors are affected. According to Roy et al. ( 2020 ), more than 80% of people over 18 have shown the need for attention to their mental health as a result of the anxiety and stress experienced during the pandemic. Forte et al. ( 2020 ) agree with this idea, stating that the pandemic has caused stress, psychological discomfort, sleep disorders, and instability, among others, in a large part of the population.

In this sense, many questionnaires have been applied to obtain information in the educational context or related to it from research groups at different universities, including the one from the IDIBAPS research group at the Hospital Universitario de Barcelona, concerning behaviors to reduce emotional distress during the pandemic and confinement by COVID-19, https://enquesta.clinic.cat/index.php/268395?lang=es ; Universidad de las Palmas de Gran Canaria on family relationships during confinement: Study of the effect of COVID-19 in the family context, https://forms.gle/2xpmqRtQ8mtBMAz77 ; Universidad de Oviedo, as a longitudinal study on how isolation and the practice of physical activity (PA) during confinement is affecting to offer effective strategies that it called “pills”: EDAFIDES Questionnaire COVID-19, https://docs.google.com/forms/d/e/1FAIpQLSfyID6X7YgUejwXNv2YyOQ1YU2LrFsPkkvHzux_TD_BjPIGNw/viewform?usp=sf_link ; Euskal Herriko Unibertsitatea, to find out about the situation of university students in confinement and to propose improvements: https://forms.gle/jDkFgW7xeKfSFNHB6 ; Universidad da Coruña y Universidad de Jaén, on the activities of children in Spanish homes in times of confinement. This last questionnaire was applied in Spain and in South America: https://docs.google.com/forms/d/e/1FAIpQLSeyBBkMEmPxj-AoPQG98QorsaLyNex9wlI2FJ2Ku2q8nbsdNQ/viewform .

Based on the above-mentioned questionnaires, there is a concern to analyze how confinement has affected children under 12 at the motor and psychological levels. This literature review is carried out and explained in detail in the procedure and search strategy of the methodology. The impact of the pandemic is such that many national and international journals are offering special issues on COVID-19, including Frontiers, which, being digital, contains 229 articles signed by many authors from various countries, which look at the subject from different perspectives: there are eight that refer to age and especially to children in some way, including: who cares about the elderly (Fischer et al., 2020 ), physical inactivity (Ricci et al., 2020 ), age distribution (Cortis, 2020 ), and newborns (Ovali, 2020 ), but none discusses parents' views on the period of confinement from the psychological, educational, academic, physical, and emotional points of view of their children. Neither do they inquire into the opinion of the children themselves, understanding by these those who are in infant and primary education, that is, up to the age of 12.

Education must seek to provide the child with a comprehensive education, trying to help his or her physical, emotional, intellectual, family, social, and moral development. Active methods are crucial for early childhood education, and teachers are needed to apply them in schools (Salvador, 2008 ), now in the homes of their students, which they access through the Internet. The role of parents is also to educate, but from different perspectives, complementing those of teachers in the acquisition of children's learning. For these reasons, many families say that they do not know how to undertake these activities with their children for so long.

Likewise, the lack of other family members, such as grandparents, who had been playing a role in accompanying, especially with children in preschool, complicates the state of confinement and the lack of school attendance that is taking place, initially planned for 6 months in a row. The study by Clemente-González ( 2016 ) of the University of Murcia highlights the relevance of grandparent–grandchild relationships and the role of the former in the social and emotional development of the child, which gives great significance to their grandparents for the appreciation observed in them, recognizing their importance in the family structure. At this point, it is also necessary to point out the lack of relationships between equals, which is so important for the correct emotional development of children.

Another important aspect that has been affected by the coronavirus pandemic is the practice of PA. Many schoolchildren practice physical exercise based solely on the subject of Physical Education. This subject is not only based on motor skills but is a practice that affects schoolchildren in a global way, influences many aspects of their daily lives, and helps teachers to better understand students in their different dimensions (Founaud and González-Audicana, 2020 ). Lack of PA is associated with obesity, as indicated by different studies that relate the regular practice of physical exercise with the reduction of health problems (Castañeda-Vázquez et al., 2020 ).

The opinion article written by the Spanish secondary school teacher, Fandino-Pérez ( 2020 ), is significant in which he reflects on the virtuality of education and his position regarding personalized education, so demanded in times of normality, where teachers and students know each other, interact, and socialize, precisely the attitude that has taken away the virus. Fandino-Pérez says that the pandemic has put us in front of the mirror to see a distorted and absurd image of the work of teachers as producers of programming and good results, which turns them and their students into a kind of machine. We have forgotten the main thing: to be human beings capable of creating a better world and of overcoming ignorance, fear, and demagogy.

As a background to this study, we refer to March 11, 2020 when the World Health Organization (World Health Organization, 2020a ) declared this disease produced by the coronavirus (COVID-19) to be a pandemic. It was first reported in Wuhan (China) on December 31, 2019. According to World Health Organization ( 2009 ), the global public health community recognized the need for standardized research and data collection after the 2009 flu epidemics, so the WHO Expert Working Group on Special Research and Studies has developed several standard protocols for pandemic flu. This has led World Health Organization ( 2019a , 2020b ) to develop similar protocols for the Middle East respiratory syndrome coronavirus (MERS-CoV) and, with the support of expert advisors, has adapted the protocols for influenza and MERS-CoV to help better understand the clinical, epidemiological, and virological characteristics of COVID-19.

Some months have passed, and most of the inhabitants of planet Earth, more or less surprised, have been confined to their homes for about 60 days, where they have carried out their work online and have had to attend to their younger children, also confined without attending school and without being able to go out into the street or use the recreational facilities that some residential areas have.

When we find ourselves at the moment of reincorporation into the daily life known before the appearance of the pandemic (May 2020), other illnesses arise as a consequence of the involuntary confinement to which the population has been subjected; this is the cave syndrome or agoraphobia (fear of open spaces), and it is possible that with the passage of time, other psychological and affective disorders will arise in the adults who will be those who have suffered this confinement and this disaster as children.

The disease mainly attacks people over 70 years old and only 0.3% of children in countries where there have been more deaths (for example, Spain). According to the Instituto de Salud Carlos, this may be the reason why medical research does not deal with children, but these subjects have special psychological, academic, and emotional characteristics at a stage of their lives when they are in full development, so from the educational point of view, it is necessary to find out how children have developed in their homes, what their parents think, and what future expectations experts, teachers, and psychologists have for them.

For all these reasons, the aim of this work is to find out about the research carried out on the child population in times of confinement, especially those that deal with the psychological and motor aspects of minors.

Considering this objective and following the Population, Intervention, Comparison, and Outcome (PICO) strategy, the following research question arises: what do the studies already published determine about how confinement has affected children under the age of 12 on a psychological and motor level?

Methodology

For the elaboration of this systematic review, we have followed the items to publish systematic reviews and meta-analyses of the PRISMA statement (Sotos-Prieto et al., 2014 ; Hutton et al., 2015 ), in order to achieve an adequate and organized structure of the manuscript. The guidelines of Cochrane Training (Higgins and Green, 2011 ) have also been used.

Procedure and Search Strategy

The literature review took place during the last weeks of May 2020 and focused mainly on the Web of Science (WOS) database, using Scopus and Dialnet as support. The topic considered for the selection of articles was the one related to the global pandemic caused by COVID-19 and how it has affected psychologically and motorically children up to 12 years old. The following keywords were used: “COVID-19” and “children” and the Boolean operator “and.” After this first search and taking into account only the works published in 2020 (since that is when the pandemic occurred), 837 scientific documents were obtained. By restricting the search to only journal articles, the documents were reduced to 576 articles, after which the language filter was applied, selecting only those papers published in English and Spanish, leaving a total of 537. Since the pandemic started in China, the initial search was also done in that language, not finding any related articles. The articles signed by researchers of Chinese nationality are written in English. Finally, the following areas of research were chosen: “Psychology,” “Sociology,” and “Education Educational Research,” finally limiting the search to 48 scientific articles, which make up the sample of this study.

Inclusion and Exclusion Criteria

The criteria that were established for the selection of the articles were (1) articles focusing on an age of up to 12 years, (2) papers relating COVID-19 to children, and (3) studies analyzing the psychological and motor characteristics of children during confinement.

In order to apply these criteria, a first preliminary reading of the title and summary of each article was carried out, which made it possible to rule out papers that did not meet the above-mentioned criteria. A more exhaustive reading of the selected articles was then carried out, leaving a final sample of nine scientific papers ( Figure 1 ).

PRISMA flowchart.

Article Coding

To extract the data from the articles, the following coding process was followed: (1) author/authors and year of publication, (2) title of the research, (3) place/country of publication, and (4) key ideas of the research.

The research included in this systematic review was coded by four of the authors, in order to check the reliability of the coding and the degree of agreement among the researchers in relation to the selection and extraction of the data (González-Valero et al., 2019 ). The degree of agreement on the rating of the articles was 93%. This was obtained by dividing the number of coincidences by the total number of categories defined for each study and multiplying it by 100.

In order to establish the methodological quality of the present study, reliability was determined according to the detection and selection of the Fleiss' Kappa (Fk) statistical index for more than two evaluators (Fleiss, 1971 ). A value of Fk = 0.780 was obtained for data extraction and selection, which indicates that there is substantial agreement (0.61–0.80).

Table 1 presents the main results of different studies following the codification indicated in the previous section: (1) author/authors and year of publication, (2) title of the research, (3) place/country of publication, and (4) key ideas of the research.

Basis of the study.

Of the nine articles analyzed because they met the characteristics of the search, three have been published in The Lancet , which began as an independent international weekly medical journal, founded in 1823 by Thomas Wakley. Since its first issue, it has strived to make science widely available so that medicine can serve, transform society, and positively impact people's lives. It has evolved into a family of journals including The Lancet Child & Adolescent Health , in which one of the three articles cited appears. These three articles, and most of those analyzed, relate to the classical medicine that should serve society to help improve life.

Most of the references in this article (84.22%) are from the year 2020, a sign of the interest in the subject and the dedication of scientists and teachers. Only three are earlier, the one by Hutton et al. ( 2015 ) that deals with a more technical content, the extension of PRISMA for network meta-analysis, and the ones by Salvador ( 2008 ) and Clemente-González ( 2016 ) that highlight the role of grandparents in children's lives.

Of the two articles by Spanish teachers, the one by Álvarez-Zarzuelo ( 2020 ) is a personal opinion of a social educator who is ahead of other research. It only provides the experts' ideas on the possible repercussions of confinement. For his part, Gómez-Gerdel ( 2020 ) writes an opinion article that, exceptionally, is being published by the International Journal of Education for Social Justice in its special issue 9(e) on “Consequences of the Closure of Schools by COVID-19 on Educational Inequalities.” The author, from the perspective of the departments of Educational Guidance that deal with inclusive education, raises the chaos that it has meant for the Spanish Educational System to apply teaching only on line, which means for the most vulnerable families: difficulties in accessing technologies and delays in education. On the other hand, it raises what could be a return to the family whose members had been living together for a long time, something absolutely necessary for the correct development of the minors who spend too much time away from home.

The teaching–learning system, which should seek the comprehensive training of the child, in which parents and teachers should participate, has been drastically modified, trying not to abandon the active methods used in schools (Salvador, 2008 ), with the difficulties that this entails for families, which in many cases have no training in this area.

Of the three articles by Chinese authors, Liu et al. ( 2020 ) analyze the situation of children whose parents have been infected with the virus or have died; Zhang et al. ( 2020 ) observe the behavior of children with attention-deficit/hyperactive disorder (ADHD) during this period; and finally, Guan et al. ( 2020 ) deal with the practice of childhood PA during confinement. Therefore, only one of them studies a type of activity in this period, the one dealing with PA coinciding with what is written by the Italians Ricci et al. ( 2020 ); in the same line, we find the Turks Yarimkaya and Esentürk ( 2020 ) who deal with the importance of PA in confinement for children with autism spectrum disorder (ASD). It is important to remember that World Health Organization ( 2010 , 2019b ) recommends a minimum of 1 h/day of moderate–vigorous PA in children, but that only one-third of children exceed these recommendations (Salas-Sánchez et al., 2020 ).

The American and British authors analyze the role of parents in the confinement of their children and provide some advice on this subject. They also look at the future psychological problems that may arise as a result of over-information, change of routines, and manifestation of feelings of distress and guilt, as well as the need to see peers and other carers (teachers, grandparents). They coincide with Clemente-González ( 2016 ) project based on the grandparent–grandchild relationship and the promotion of identity, which seemed to be a premonition of what would happen with the arrival of the COVID-19 pandemic that would force the disappearance of these relationships for a long time.

It is important to note that, according to the review carried out, there are authors who analyze the pandemic from different perspectives with which we agree: cultural aspects (Maestre Maestre, 2020 ); actions of biologists and doctors, more distant from our intentions; humanists (Fandino-Pérez, 2020 ), and especially for this study, of educators who are aware that the essence of being in the classroom and the immediate feedback that students offer in this situation has been lost. To this must be added the role of the WHO, overwhelmed by the health events that have occurred so quickly, as described in these lines.

We believe that the application of many questionnaires during the confinement and currently post-COVID-19 pandemic has saturated the patience of the respondents, although most have helped scientists and educators to obtain information that will facilitate a smooth exit from this disaster.

Conclusions

The above leads us to the general conclusion that there are very few studies on how confinement has affected children under 12 years old psychologically and motorly. These articles agree on the consequences that confinement can have on minors and on the importance of psychological support from the family, and the establishment of routines can be effective. The manuscripts that deal with PA remind us of the importance of it and indicate that the rates of sedentarism have increased during these months.

It is necessary to insist on the search for and analysis of other activities, as well as the behavior of parents and children in these circumstances, in order to prevent possible psychological and academic problems and because if the online teaching situation is prolonged, it is very important to know how to act from the educational and family environment.

The main limitation the authors have faced has been the small number of scientific articles related to the area of study. This scarcity of published works makes it necessary to continue researching this. This is the reason why our study can serve as a starting point or theoretical foundation for further studies.

Author Contributions

JC-Z, MS-Z, DS-M, GG-V, AL-S, and MZ-S contributed to the conception and design of the revision. All authors wrote some part of the manuscript and all reviewed the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

* References marked with an asterisk are those articles analyzed in the systematic review.

Funding. This article has been financed by the Ministry of Science, Innovation and Universities through two grants for university teacher training (FPU) with references FPU17/00803 and FPU18/02567. This article has counted with the collaboration of the group HUM-653 of the University of Jaén.

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