a case study about covid 19

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Novel coronavirus 2019 (COVID-19)

A case report and review of treatments.

Editor(s): Saranathan., Maya

a Department of Medicine, Hackensack Meridian Jersey Shore University Medical Center Neptune

b Department of Medicine, Hackensack Meridian School of Medicine at Seton Hall University Nutley

c Department of Pulmonology and Critical Care, Hackensack Meridian Jersey Shore University Medical Center Neptune, NJ, USA.

∗Correspondence: Steven Douedi, Jersey Shore University Medical Center, Neptune, NJ 07753 (e-mail: [email protected] ).

Abbreviations: ARDS = acute respiratory distress syndrome, CoV = coronavirus, COVID-19 = novel coronavirus 2019, CVVHD = continuous veno-venous hemodialysis, ED = emergency department, FiO2 = fraction of inspired oxygen, ICU = intensive care unit, MERS-CoV = Middle East respiratory syndrome coronavirus, PCR = polymerase chain reaction, PEEP = positive end-expiratory pressure, RSV = Respiratory syncytial virus, SARS-CoV = severe acute respiratory syndrome coronavirus, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

How to cite this article: Douedi S, Miskoff J. Novel coronavirus 2019 (COVID-19): a case report and review of treatments. Medicine . 2020;99:19(e20207).

The authors have no conflicts of interests to disclose.

This manuscript is a unique submission and is not being considered for publication by any other source in any medium. Further, the manuscript has not been published, in part or in full, in any form.

The patient's next of kin provided consent for this manuscript to be published.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Rationale: 

Novel coronavirus 2019 (COVID-19) also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, non-segmented positive-sense RNA virus belonging to the beta-coronaviridae family. This virus is known to cause severe bilateral pneumonia and acute respiratory distress syndrome (ARDS) which can lead to difficulty breathing requiring mechanical ventilation and intensive care unit management.

Patient concerns: 

A 77-year-old female with a history of hypertension and hyperlipidemia who presented as a transfer to our hospital facility with worsening fevers, cough, and respiratory distress.

Diagnosis: 

Chest X-rays revealed bilateral infiltrates worse at the lung bases and CT scan of the chest showed bilateral ground-glass opacities consistent with COVID-19. While our testing revealed a negative COVID-19 result at our institution, the result at a previous hospital returned a positive result.

Interventions: 

She was being treated aggressively in the intensive care unit with high dose intravenous ascorbic acid, hydroxychloroquine, and anti-interleukin-6 monoclonal antibody. She also received a loading dose of remdesivir however was unable to complete the course due to organ failure and requirement of vasopressors for hemodynamic stability.

Outcomes: 

She remained critically ill and was eventually placed on comfort care as per the family's wishes and passed away.

Lessons: 

With a rapidly growing death rate and more than 200,000 confirmed cases worldwide, COVID-19 has become a global pandemic and major hit to our healthcare systems. While several companies have already begun vaccine trials and healthcare facilities have been using a wide-range of medications to treat the virus and symptoms, there is not yet an approved medication regimen for COVID-19 infections. The alarming increase in cases per day adds additional pressure to find a cure and decrease the global health burden and mortality rate.

1 Introduction

The novel coronavirus 2019 (COVID-19) also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, non-segmented positive-sense RNA virus belonging to the beta-coronaviridae family. [1] COVID-19 has been found to be the cause of severe pneumonia and acute respiratory distress syndrome (ARDS) with a significantly high mortality rate. [2] According to the World Health Organization, there are 207,855 confirmed cases and 8648 deaths from COVID-19 as of March 19, 2020 and rapidly increasing. [3] Originating from bats like other virulent coronavirus (CoV) strains such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), COVID-19 has become the focus of the medical world and the pandemic of 2020. [1,4] We present a case of elderly female presenting with fever, cough, and shortness of breath found to be positive for COVID-19 and started on high-dose IV ascorbic acid, anti-interleukin-6, hydroxychloroquine, and remdesivir requiring high ventilator settings and eventually requiring vasopressors and continuous veno-venous hemodialysis (CVVHD).

2 Case presentation

A 77-year-old Middle-Eastern female with a medical history of hypertension and hyperlipidemia presented to the emergency department (ED) from a day care facility apartment where 2 people at the facility have tested positive for COVID-19 but she did not have any direct contact with these individuals. About 5 days before admission the patient developed a fever with a temperature of 102°F at home, and went to her primary medical doctor who sent her to the ED. In the ED she was found to have bilateral opacities on chest X-ray and had continued intermittent fevers with generalized weakness, cough, lethargy, and dyspnea and was sent for testing for COVID-19 then transferred to our facility for further management. In our facility, her temperature was 101.7°F, blood pressure 148/76 mm Hg, heart rate of 99 beats per minute, respiratory rate of 18 per minute, and oxygen saturation of 93% on room air. Physical exam was significant for a dry cough and bilateral rales on auscultation of the lung fields bilaterally but was unremarkable otherwise. A chest X-ray ( Fig. 1 ) was performed showing bilateral opacities throughout the lung fields with predominance of the lower lung lobes she was admitted for possible pneumonia with isolation precautions for suspected COVID-19 and was started on oxygen via nasal cannula and on 1-gram ceftazidime intravenously every 8 hours and 500 mg azithromycin orally daily. CT scan of the chest ( Fig. 2 ) was performed showing bilateral ground glass appearance throughout the lung with predominance in the peripheral lower lobes. Respiratory viral panel was sent including a repeat COVID-19 test ( Table 1 ). All results came back negative however the patient's condition deteriorated 2 days after admission to our facility, and she became hypoxic to 85% oxygen saturation while on nasal cannula and remained spiking fevers up to 103.4°F. She was intubated and transferred to the intensive care unit (ICU) for further management and was switched to ceftriaxone 1 g intravenously daily and azithromycin 500 mg via orogastric tube daily and was started on hydroxychloroquine 400 mg loading dose followed by 200 mg twice daily for a 7-day course. She required 100% fraction of inspired oxygen (FiO2) and a positive end-expiratory pressure (PEEP) of 12 to maintain an oxygen saturation of >90%. 12 hours later, the COVID-19 test from the initial facility returned positive results. On day 3 of hospitalization she was started on 6 g of IV ascorbic acid twice daily and given one dose of 8 mg per kg (567 mg) of tocilizumab, an anti-interleukin-6 monoclonal antibody. Due to a shortage of vitamin C in the hospital, her dose was decreased to 1 g IV daily on the 6th day of hospitalization and she was given another dose of tocilizumab. On day 7, her PEEP increased from 12 to 16 due to worsening oxygen saturation and increased requirement despite 100% FiO2. Due to severe ARDS, the decision was made to prone the patient for 18 hours a day. She completed her course of antibiotics and hydroxychloroquine but remained on vitamin C and zinc. Approval for remdesivir was obtained from Gilead Sciences Inc and she was given a loading dose of 200 mg on day 10 and due to worsening oxygen saturation her PEEP was again increased to 18. On day 11, the patient was unable to tolerate being prone due to significant desaturation to 65% on pulse oximetry and remained supine. She eventually required levophed for maintenance of hemodynamic stability and her creatinine increased from her baseline of 0.5-0.6 since admission until day 10 to 2.65 on day 12. For this reason, remdesivir was discontinued and nephrology was consulted and recommended CVVHD on day 13. On day 14 her PEEP requirement again increased to 20 while on 100% FiO2 to maintain an oxygen saturation >90%. Her condition remained critical while being aggressively managed in the ICU and ultimately the patient's family decision was to pursue comfort measures and the patient passed away.

3 Discussion

COVID-19 is the cause of severe viral pneumonia rapidly leading to ARDS. In a case series of 135 patients, Wan et al reported 88.9% of patients presented with a fever and 76.5% had a cough. [5] Fatigue and myalgias (32.5%), headache (17.7%), and dyspnea (13.3%) were less commonly reported. [5] These symptoms were also found on presentation with our patient. While the COVID-19 tests were pending, the CT scan of the chest provided valuable information as it met the trend of findings in infected patients. Wan et al obtained CT scans on all patients in their study and found bilateral involvement and multiple patchy or ground glass appearance to be the primary finding. [5] Huang et al found similar findings where 98% of CT scans obtained had bilateral involvement and multilobular consolidations. [6] These findings on CT scans are not unusual for a viral pneumonia. Influenza A (H1N1) was first found to cause a pandemic in 2009, a retrospective review of 92 patients by Çörtük et al found 69.6% of patients with H1N1 had bilateral patchy pneumonic infiltrates and 41.3% had bilateral ground glass opacities. [7] While the lack of rapid testing for COVID-19 has caused a delay in diagnosis, perhaps the use of CT scans could provide an increased suspicion of COVID-19 infection leading to earlier treatment and management.

Our patient presented in this case received treatment with vitamin C and zinc, both of which are known to improve the human immune system and aid in shortening the duration of and improving outcomes in respiratory infections including pneumonia. [8,9] In addition to vitamin and mineral supplements, hydroxychloroquine and azithromycin have obtained a large amount of attention for the treatment of COVID-19. Hydroxychloroquine, a well-known anti-malarial and auto-immune medication, is relatively inexpensive and has been extensively studied in the treatment for COVID-19. Studies have suggested hydroxychloroquine can interfere with glycosylation of the coronavirus receptors and increase endosomal pH thus inhibiting viral fusion and decreasing viral load. [10,11] Gautret et al reported a synergistic effect using hydroxychloroquine and azithromycin in viral elimination and decreasing viral load. [12] Despite this evidence, the use of hydroxychloroquine for viral infections has been questioned. Roques et al reported a study using chloroquine in Chikungunya virus reporting cytokines were reduced causing the adaptive immune response to be delayed, exacerbating fever, and unchanged suppression of viral load. [13] While further studies are in need to provide concrete evidence on the use of hydroxychloroquine, clinical trials from China have already shown promising results for COVID-19 and several countries around the world have begun using these medications. Tocilizumab, a recombinant humanized anti-interleukin-6 receptor monoclonal antibody, has been extensively used in auto-immune conditions such as rheumatoid arthritis. [14] With this monoclonal antibody, interleukin-6 function is blocked and hence the differentiation of T helper cells and B cells into immunoglobulin-secreting cells are inhibited. [14] The cytokine storm observed in patients with COVID-19 has been difficult to control and manage leading to increased mortality, tocilizumab therefore helps decrease the immune response and the resulting damage caused by cytokines. [6,15] While still not approved in the United States, tocilizumab has thus far shown promising results in clinical trials. [15]

Other treatments for COVID-19 have also emerged and have thus far shown promising results in ongoing clinical trials. Of these, remdesivir (GS-5734) and favipiravir (T-705) have become the center of attention. Remdesivir is an adenosine analog that incorporates into viral RNA causing premature termination. [10,14] It has been found effective at inhibiting viral replication in Ebola, SARS-CoV, and MERS-CoV infections. [10,16,17] Favipiravir, an RNA-dependent RNA polymerase inhibitor, has already obtained approval for the treatment of COVID-19 in China on February 15th, 2020. [18] Studies have shown favipiravir inhibited RNA polymerase activity and thus prevented replication of RNA viruses like COVID-19 with minimal side effects. [18] Remdesivir (GS-5734, Gilead Sciences Inc.) is currently under several clinical trials and all of its side effects have not yet been defined. In our patient, within 2 days of starting remdesivir our patient had worsening renal function eventually requiring CVVHD and vasopressors thus preventing further treatment with the medication. While our patient was critically ill in the ICU, it is not known if this medication was the cause for further decompensation due to kidney injury. Further studies and clinical trials are required to fully understand the role of remdesivir and other medications in COVID-19 infected patients.

4 Conclusion

COVID-19 is a serious infection that has led to thousands of cases of severe pneumonia, ARDS, and even deaths across the globe. As of now there are no approved treatments for this viral pandemic. While several medications have shown to be effective in clinical trials, further studies are needed to establish dosing, treatment course, and side effects of these medications. As the number of cases and deaths continue to increase in the world, the race to develop faster testing modalities to rapidly diagnose and manage these patients earlier continues to be the focus of the global healthcare system.

Author contributions

Conceptualization: Steven Douedi, Jeffery Miskoff.

Writing – original draft: Steven Douedi.

Writing – review & editing: Steven Douedi, Jeffery Miskoff.

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acute respiratory distress syndrome; coronavirus; novel coronavirus 2019; infection; respiratory; severe acute respiratory syndrome coronavirus 2

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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.

This research received no external funding.

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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

School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany

Thilo Caspar von Groote

Department of Sport and Health Science, Technische Universität München, Munich, Germany

Hebatullah Mohamed Abdulazeem

School of Health Sciences, Faculty of Health and Medicine, The University of Newcastle, Callaghan, Australia

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Livia Puljak

Cochrane Brazil, Evidence-Based Health Program, Universidade Federal de São Paulo, São Paulo, Brazil

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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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Accepted : 19 May 2021

Published : 04 June 2021

DOI : https://doi.org/10.1186/s12879-021-06214-4

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• Coronavirus
• Evidence-based medicine
• Infectious diseases

BMC Infectious Diseases

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“Syndrome-negative” participants were persons hospitalized without signs or symptoms consistent with acute COVID-19 and who tested negative for SARS-CoV-2 by molecular testing. They were included as a secondary control group because of the theoretical risk of case misclassification in test-negative controls.

An adjusted odds ratio (aOR) less than 1.0 indicated that COVID-19 hospitalization was associated with being unvaccinated compared with being fully vaccinated. Vaccine effectiveness for prevention of COVID-19 hospitalization can be estimated from the aORs presented here with the following equation: vaccine effectiveness = (1 − aOR) × 100%. BNT162b2 is the vaccine produced by Pfizer-BioNTech and mRNA-1273 is the vaccine produced by Moderna. mRNA indicates messenger RNA.

a Models were mixed-effects logistic regression models with vaccination status (fully vaccinated vs unvaccinated) as the primary independent variable, case-control status (hospitalized with COVID-19 vs hospitalized without it) as the dependent variable, enrolling site as a random effect, and the following covariables: admission date (biweekly intervals), age group (18-49, 50-64, and ≥65 years), sex, and self-reported race and ethnicity. Models stratified by age group were adjusted for continuous age in years.

b Immunocompromising conditions are defined in the Table.

c Alpha estimates restricted to March to June illness-onset dates (Alpha period); Delta estimates restricted to July to August illness-onset dates (Delta period).

An adjusted odds ratio (aOR) less than 1.0 indicated that progression to death or invasive mechanical ventilation after hospital admission for COVID-19 was associated with being unvaccinated compared with being vaccinated.

a Models were adjusted for age group (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and number of chronic medical comorbidities (0, 1, 2, 3, and ≥4). Models stratified by age group were adjusted for continuous age in years.

c Analysis restricted to COVID-19 case patients with hypoxemia within 24 hours of admission, defined as receiving supplemental oxygen or having an oxygen saturation less than 92% as measured by pulse oximetry.

Cumulative incidence of hospital discharge by vaccination status (fully vaccinated with a 2-dose series of mRNA vaccine vs unvaccinated) is shown for patients not immunocompromised (A), those immunocompromised (B), those aged 18 to 64 years (C), and those aged 65 years or older (D). The event of interest was discharge from the hospital before day 28 in the presence of the competing event of death. Patients who remained hospitalized more than 28 days were censored at 28 days. Competing risk models were adjusted for age group (18-49, 50-64, and ≥65 years), sex, self-reported race and ethnicity, and number of medical comorbidities (0, 1, 2, 3, and ≥4). Models by age group were adjusted for continuous age in years. mRNA indicates messenger RNA; and SHR, subdistribution hazard ratio.

eAppendix 1. Investigators and Collaborators

eAppendix 2. Supplementary Tables and Figures

eTable 1. Modified WHO COVID-19 Clinical Progression Scale Used in This Analysis to Assess Disease Severity Among Adults Hospitalized With COVID-19

eTable 2. Underlying Medical Conditions Obtained Through Medical Record Review

eTable 3. Association Between Hospitalization for COVID-19 and Prior Receipt of Full Vaccination With a Two-Dose Series of a mRNA Vaccine, Restricted to Patients Without Immunocompromising Conditions

eTable 4. Association Between Hospitalization for COVID-19 and Prior Receipt of Full Vaccination With a Two-Dose Series of a mRNA Vaccine, Restricted to Patients Without Immunocompromising Conditions and Aged 18-64 Years

eTable 5. Association Between Hospitalization for COVID-19 and Prior Receipt of Full Vaccination With a Two-Dose Series of a mRNA Vaccine, Restricted to Patients Without Immunocompromising Conditions and Aged ≥65 Years

eTable 6. Treatments, Outcomes, and Severity of Illness Among Hospitalized COVID-19 Cases by Vaccination Status

eTable 7. Odds Prior mRNA COVID-19 Vaccination Among COVID-19 Cases Who Received In-Hospital COVID-19 Therapeutics and Those Who Did Not

eFigure 1. Whole Genome Sequencing SARS-CoV-2 Lineage Determination Among COVID-19 Cases by Admission Week

eFigure 2. Highest Severity Level Experienced on the WHO COVID-19 Clinical Progression Scale During the First 28 Days of Hospitalization Among Vaccine Breakthrough COVID-19 Cases and Unvaccinated COVID-19 Cases

• Association of Prior SARS-CoV-2 Infection With Risk of Breakthrough Infection Following mRNA Vaccination in Qatar JAMA Original Investigation November 16, 2021 This cohort study assesses protection from SARS-CoV-2 breakthrough infection after mRNA vaccination among persons with vs without prior SARS-CoV-2 infection. Laith J. Abu-Raddad, PhD; Hiam Chemaitelly, MSc; Houssein H. Ayoub, PhD; Hadi M. Yassine, PhD; Fatiha M. Benslimane, PhD; Hebah A. Al Khatib, PhD; Patrick Tang, MD, PhD; Mohammad R. Hasan, PhD; Peter Coyle, MD; Zaina Al Kanaani, PhD; Einas Al Kuwari, MD; Andrew Jeremijenko, MD; Anvar Hassan Kaleeckal, MSc; Ali Nizar Latif, MD; Riyazuddin Mohammad Shaik, MSc; Hanan F. Abdul Rahim, PhD; Gheyath K. Nasrallah, PhD; Mohamed Ghaith Al Kuwari, MD; Adeel A. Butt, MBBS, MS; Hamad Eid Al Romaihi, MD; Mohamed H. Al-Thani, MD; Abdullatif Al Khal, MD; Roberto Bertollini, MD, MPH
• Understanding Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination JAMA Editorial November 23, 2021 Michael Klompas, MD, MPH
• Durability of Antibody Levels After SARS-CoV-2 Vaccine in Individuals With or Without Prior Infection JAMA Research Letter December 28, 2021 This study examines antibody durability in individuals who received an mRNA SARS-CoV-2 vaccine with prior SARS-CoV-2 infection vs those without infection. Diana Zhong, MD; Shaoming Xiao, MSPH; Amanda K. Debes, PhD, MS; Emily R. Egbert, MPH, MAT; Patrizio Caturegli, MD, MPH; Elizabeth Colantuoni, PhD, ScMs; Aaron M. Milstone, MD, MHS

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Tenforde MW , Self WH , Adams K, et al. Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity. JAMA. 2021;326(20):2043–2054. doi:10.1001/jama.2021.19499

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Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity

• 1 CDC COVID-19 Response Team, Atlanta, Georgia
• 2 Vanderbilt Institute for Clinical and Translational Research, Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
• 3 Baylor Scott & White Health, Texas A&M University College of Medicine, Temple
• 4 Department of Emergency Medicine, University of Colorado School of Medicine, Aurora
• 5 Department of Anesthesiology, University of Colorado School of Medicine, Aurora
• 6 Departments of Medicine and Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee
• 7 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
• 8 Department of Emergency Medicine, University of Iowa, Iowa City
• 9 Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
• 10 Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
• 11 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
• 12 Departments of Emergency Medicine and Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
• 13 Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
• 14 Department of Medicine, The Ohio State University, Columbus
• 15 Department of Medicine, Montefiore Health System, Albert Einstein College of Medicine, Bronx, New York
• 16 Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
• 17 Department of Emergency Medicine, University of Washington, Seattle
• 18 Department of Medicine, Baystate Medical Center, Springfield, Massachusetts
• 19 Department of Medicine, Intermountain Medical Center, Murray, Utah; and University of Utah, Salt Lake City
• 20 School of Public Health, University of Michigan, Ann Arbor
• 21 Department of Medicine, Oregon Health & Science University, Portland
• 22 Department of Medicine, Emory University, Atlanta, Georgia
• 23 Emory Critical Care Center, Emory Healthcare, Atlanta, Georgia
• 24 Department of Medicine, Cleveland Clinic, Cleveland, Ohio
• 25 Department of Emergency Medicine, Stanford University School of Medicine, Stanford, California
• 26 Department of Medicine, University of California–Los Angeles, Los Angeles
• 27 Department of Medicine, University of Miami, Miami, Florida
• 28 Department of Medicine, Washington University, St Louis, Missouri
• 29 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
• 30 Departments of Internal Medicine and Microbiology and Immunology, University of Michigan, Ann Arbor
• 31 Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee
• 32 Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
• 33 Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee
• 34 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
• Editorial Understanding Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination Michael Klompas, MD, MPH JAMA
• Original Investigation Association of Prior SARS-CoV-2 Infection With Risk of Breakthrough Infection Following mRNA Vaccination in Qatar Laith J. Abu-Raddad, PhD; Hiam Chemaitelly, MSc; Houssein H. Ayoub, PhD; Hadi M. Yassine, PhD; Fatiha M. Benslimane, PhD; Hebah A. Al Khatib, PhD; Patrick Tang, MD, PhD; Mohammad R. Hasan, PhD; Peter Coyle, MD; Zaina Al Kanaani, PhD; Einas Al Kuwari, MD; Andrew Jeremijenko, MD; Anvar Hassan Kaleeckal, MSc; Ali Nizar Latif, MD; Riyazuddin Mohammad Shaik, MSc; Hanan F. Abdul Rahim, PhD; Gheyath K. Nasrallah, PhD; Mohamed Ghaith Al Kuwari, MD; Adeel A. Butt, MBBS, MS; Hamad Eid Al Romaihi, MD; Mohamed H. Al-Thani, MD; Abdullatif Al Khal, MD; Roberto Bertollini, MD, MPH JAMA
• Research Letter Durability of Antibody Levels After SARS-CoV-2 Vaccine in Individuals With or Without Prior Infection Diana Zhong, MD; Shaoming Xiao, MSPH; Amanda K. Debes, PhD, MS; Emily R. Egbert, MPH, MAT; Patrizio Caturegli, MD, MPH; Elizabeth Colantuoni, PhD, ScMs; Aaron M. Milstone, MD, MHS JAMA

Question   Does prior COVID-19 vaccination reduce hospitalizations for COVID-19, and among patients hospitalized for COVID-19, does prior vaccination reduce disease severity?

Findings   In a case-control study that included 4513 hospitalized adults in 18 US states, hospitalization for a COVID-19 diagnosis compared with an alternative diagnosis was associated with an adjusted odds ratio (aOR) of 0.15 for full vaccination with an authorized or approved mRNA COVID-19 vaccine. Among adults hospitalized for COVID-19, progression to death or invasive mechanical ventilation was associated with an aOR of 0.33 for full vaccination; both ORs were statistically significant.

Meaning   Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and with disease progression, consistent with risk reduction among vaccine breakthrough infections.

Importance   A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people.

Objective   To evaluate the association between vaccination with mRNA COVID-19 vaccines—mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)—and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease.

Design, Setting, and Participants   A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021.

Exposures   COVID-19 vaccination.

Main Outcomes and Measures   Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression.

Results   Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) ( P  < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) ( P  < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58).

Conclusions and Relevance   Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.

The COVID-19 pandemic, caused by SARS-CoV-2, continues to be a global public health crisis. 1 The messenger RNA (mRNA) COVID-19 vaccines, including mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech), are highly effective for preventing SARS-CoV-2 infections and COVID-19 hospitalizations. 2 - 5 However, vaccine breakthrough COVID-19 (defined as development of COVID-19 despite prior full vaccination) is now being reported throughout the world. 6 Because vaccine effectiveness is less than 100%, breakthrough cases are expected, and as vaccine coverage increases in the population, the ratio of vaccinated to unvaccinated cases will increase.

A full interpretation of the protective benefits of COVID-19 vaccines must account for protection against SARS-CoV-2 infection, as well as against progression of disease severity after breakthrough infection. 7 , 8 To date, evaluations of COVID-19 vaccines have primarily focused on prevention of symptomatic infection and hospitalizations. 2 , 3 , 9 - 11 Once hospitalized, patients with COVID-19 can progress to more severe disease, including respiratory failure and death. SARS-CoV-2 infection in vaccinated persons is expected to trigger memory antibody and cellular responses owing to prior vaccination; these immune responses could mitigate disease progression, possibly preventing life-threatening organ failure and death. 12 , 13 However, the association between prior vaccination and disease progression to the most severe forms of COVID-19 is not well understood.

To estimate the benefits of mRNA vaccination against severe COVID-19, this study examined the association between prior vaccination and hospitalization for COVID-19, as well as the association between prior vaccination and progression to death or invasive mechanical ventilation among patients hospitalized for COVID-19.

This program was conducted by the Influenza and Other Viruses in the Acutely Ill (IVY) Network, a collaboration among 21 US hospitals in 18 states and the Centers for Disease Control and Prevention (investigators and collaborators are listed in eAppendix 1 in the Supplement ). 4 , 14 A total of 4513 patients hospitalized at the network hospitals between March 11, 2021, and August 15, 2021, were included. Data on hospitalizations were included for patients enrolled through August 15, 2021, and data on 28-day outcomes after hospitalization were included for patients enrolled through July 14, 2021. This analysis was an update to information previously published using earlier versions of the program’s data. 4 , 15 , 16 STROBE guidelines for reporting were followed. This case-control study was determined to be a public health surveillance program, with waiver of participant informed consent by all participating institutions and the Centers for Disease Control and Prevention (CDC).

We used a test-negative case-control design to assess the association between hospitalization for COVID-19 and prior vaccination with an mRNA COVID-19 vaccine. In this analysis, case patients were those hospitalized with COVID-19 and control patients were those hospitalized for other reasons. 17 - 19 In a second analysis among only patients hospitalized with COVID-19, we assessed the association between COVID-19 disease progression and prior vaccination with an mRNA vaccine. In the second analysis, cases and controls were patients hospitalized with COVID-19 with and without progression to death or invasive mechanical ventilation, respectively.

Sites screened hospitalized adults aged 18 years and older for potential eligibility through daily review of hospital admission logs and electronic medical records (eAppendix 2 in the Supplement ). COVID-19 cases included patients hospitalized with a clinical syndrome consistent with acute COVID-19 and a positive molecular or antigen test result for SARS-CoV-2 within 10 days after symptom onset. 20 We included 2 control groups: “test-negative” controls were persons hospitalized with signs or symptoms consistent with acute COVID-19 but who tested negative for SARS-CoV-2 by molecular testing; and “syndrome-negative” controls were persons hospitalized without signs or symptoms consistent with acute COVID-19 and who tested negative for SARS-CoV-2 by molecular testing and were included as a secondary control group because of the theoretic risk of case misclassification in test-negative controls. 21 Sites attempted to capture all cases admitted to the hospital during the surveillance period and targeted a case-control ratio of approximately 1:1 for each group of controls. Controls were selected from lists of eligible participants hospitalized within 2 weeks of enrollment of cases. Information on vaccination status was not collected until after patients were enrolled.

Demographic, clinical, and laboratory data were collected by trained personnel through standardized participant (or proxy) interviews and medical record reviews. Data on race and ethnicity were collected because the association between vaccination and COVID-19 may vary by race or ethnicity. Information on race and ethnicity was reported by participants during interviews conducted by research personnel using fixed categories.

Details of COVID-19 vaccination, including dates and location, vaccine product, and lot number, were ascertained through a systematic process including patient or proxy interview and source verification. Sources of documentation included vaccination cards, hospital records, state vaccine registries, and vaccine records requested from clinics and pharmacies. Vaccine doses were classified as administered if source documentation was identified or if the patient or proxy reported a vaccine dose with a plausible date and location of vaccination.

Upper respiratory specimens were collected from enrolled patients, frozen, and shipped to a central laboratory at Vanderbilt University Medical Center (Nashville, Tennessee). Specimens underwent reverse transcriptase–polymerase chain reaction testing for SARS-CoV-2 nucleocapsid gene targets with standardized methods and interpretive criteria. 22 Specimens positive for SARS-CoV-2 with a cycle threshold less than 32 were shipped to the University of Michigan (Ann Arbor, Michigan) for viral whole-genome sequencing using the ARTIC Network version 3 protocol on an Oxford Nanopore Technologies instrument (GridION). 23 SARS-CoV-2 lineages were assigned with greater than 80% coverage with Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN). 24

During this study period, the mRNA COVID-19 vaccines were administered as a series of at least 2 doses; participants were considered fully vaccinated 14 days after receipt of the second dose. 25 Vaccination status was classified according to vaccine receipt before a reference date, which was the date of symptom onset for cases and test-negative controls and 4 days before hospital admission for syndrome-negative controls. Participants were classified as unvaccinated if they had received no vaccine doses before the reference date and fully vaccinated if they had received 2 or more mRNA vaccine doses at least 14 days before the reference date. Patients were excluded if they had previously received at least 1 dose of an mRNA vaccine but were not fully vaccinated, if they received a different type of COVID-19 vaccine, such as AD26.COV2.S (Janssen/Johnson & Johnson), or if they were vaccinated with a mixed vaccine schedule (ie, BNT1262b2 vaccine for 1 dose and mRNA-1273 vaccine for 1 dose).

We collected data on severity for patients hospitalized with COVID-19. These outcome data were collected until the earlier of hospital discharge or 28 days after hospital admission. The primary classification of disease severity was a binary measure that divided patients into those who experienced death or invasive mechanical ventilation (progression to high disease severity) and those who did not (no progression to high disease severity).

As a secondary assessment, we classified COVID-19 severity using a modified version of the World Health Organization COVID-19 Clinical Progression Scale, a commonly used ordinal scale for assessing COVID-19 severity that ranges from uninfected (level 0) and infected but asymptomatic (level 1) to death (level 9) (eAppendix 2 [eTable 1] in the Supplement ). We classified severity according to the highest ordinal level that the patient experienced during the first 28 days of hospitalization. In this analysis of hospitalized patients, the highest severity level experienced could range from level 4 to 9, including hospitalized without supplemental oxygen (level 4), with standard supplemental oxygen (level 5), with high-flow nasal cannula or noninvasive ventilation (level 6), with invasive mechanical ventilation (level 7), or with mechanical ventilation and additional organ support (extracorporeal membrane oxygenation, vasopressors, or new kidney replacement therapy; level 8); and in-hospital death (level 9).

We also evaluated in-hospital receipt of treatments used for severe COVID-19 (corticosteroids, remdesivir, COVID-19 convalescent plasma, tocilizumab, or baricitinib) according to a binary category of no COVID-19 treatments vs 1 or more.

We also characterized COVID-19 severity by hospital length of stay while accounting for the competing risk of death.

For the association between COVID-19 hospitalization and prior vaccination, we compared the odds of being fully vaccinated with an mRNA vaccine (exposed) vs being unvaccinated (unexposed) in cases hospitalized with COVID-19 vs controls hospitalized with other conditions. Patients from the test-negative and syndrome-negative control groups were pooled for this analysis in accordance with a prior analysis showing similar results with each control group individually. 4 , 15 A mixed-effects logistic regression model was generated, treating enrolling site as a random effect and with the following covariables: admission date (biweekly intervals), age, sex, and race and ethnicity. In this model, an adjusted odds ratio (aOR) less than 1.0 indicated that COVID-19 hospitalization was associated with reduced likelihood of vaccination. The aOR was used to estimate vaccine effectiveness for the prevention of COVID-19 hospitalizations via the following equation: vaccine effectiveness = (1 − aOR) × 100%. 4 , 26

The association between COVID-19 hospitalization and prior vaccination was also evaluated in stratified secondary analyses, including by immunocompetent vs immunocompromised, age group (18-49, 50-64, or ≥65 years), vaccine type (mRNA-1273 or BNT162b2 vaccine), and time between second vaccine dose and illness onset (14-120 days; >120 days). Additional models were constructed to evaluate interactions between vaccination and exposure variable group. For immunocompetent vs immunocompromised status and age groups, we added interaction terms between vaccination and the stratifying variable to the regression model. For vaccine type and time since vaccination, the vaccination exposure variable was replaced with a product variable (unvaccinated, vaccinated with mRNA-1273, and vaccinated with BNT162b2) or time variable (unvaccinated, vaccinated 14-120 days before illness onset, and vaccinated >120 days before illness onset). P values for comparisons across subgroups were calculated for the interaction term between the exposure variable and vaccination status (immunocompetent vs immunocompromised; age group) or with the pwcompare Stata function for pairwise comparisons (vaccine product; time between second vaccine dose and illness onset). In addition, separate assessments were conducted evaluating the association between hospitalization with SARS-CoV-2 variants (B.1.1.7 [Alpha]; B.1617.2 or AY [Delta]) and period of illness onset (March to June 2021, which had predominant Alpha variant circulation; July to August 2021, which had predominant Delta variant circulation). 27

Among patients hospitalized with COVID-19 through July 14, 2021, the association between progression to death or invasive mechanical ventilation and prior mRNA vaccination was calculated with multivariable logistic regression adjusted for the following covariables: age, sex, race and ethnicity, and number of medical comorbidities by category (eTable 2 in the Supplement ). The association between death alone and prior vaccination was similarly calculated with multivariable logistic regression evaluating the odds of vaccination among patients with COVID-19 who died vs survived.

In a subgroup analysis to assess disease progression among COVID-19 patients admitted with hypoxemia, the association between death or invasive mechanical ventilation and prior vaccination was calculated among the subgroup of patients who received oxygen therapy or had oxygen saturation less than 92% as measured by pulse oximetry within 24 hours of hospital admission.

A multivariable proportional odds model was used to compare the highest severity level experienced on the World Health Organization COVID-19 Clinical Progression Scale between patients with vaccine breakthrough COVID-19 and unvaccinated patients with COVID-19, using the same covariables described earlier. An aOR less than 1.0 for this model indicated lower odds of vaccinated patients’ experiencing higher severity levels on the ordinal scale compared with unvaccinated patients.

For receipt of in-hospital COVID-19 treatments, a multivariable logistic regression model was constructed to calculate the aOR of vaccination among patients who did vs did not receive at least 1 COVID-19 treatment.

To assess hospital length of stay, we calculated the probability of hospital discharge within 28 days after admission in vaccinated vs unvaccinated patients with COVID-19, using a Fine-Gray time-to-event analysis. We developed cumulative incidence function curves, with discharge from the hospital as the event of interest, death as the competing event, and patients who remained hospitalized censored at 28 days. 28 Point estimates of subdistribution adjusted hazard ratios were reported.

Missing data for illness onset was imputed according to the median number of days between illness onset and hospital admission for study patients within the same participant group. Imputation was not used for other variables; the number of patients with missing data was reported. Because of the potential for type I error owing to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Statistical significance was indicated by 95% CIs not containing the null or a 2-sided P  < .05. Stata version 16 was used for statistical analysis.

During March 11, 2021, to August 15, 2021, 5479 patients were enrolled from 21 hospitals; 966 patients were excluded from this analysis, with the most common reasons for exclusion being receipt of at least 1 mRNA vaccine but not being fully vaccinated (n = 547) and receipt of a COVID-19 vaccine other than an mRNA vaccine (n = 194) ( Figure 1 ). The analytic population included 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), including 1983 cases with COVID-19 and 2530 controls without it (1359 test-negative controls and 1171 syndrome-negative controls).

Among 1983 COVID-19 case patients, vaccine breakthrough patients compared with unvaccinated patients tended to be older (median age 67 vs 53 years), were more likely to be White non-Hispanic (64.0% vs 43.0%), and were more likely to be immunocompromised (40.8% vs 11.5%) ( Table ). Among 1700 fully vaccinated patients (including both COVID-19 cases and controls), 1036 (60.9%) received the BNT162b2 vaccine and 664 (39.1%) received the mRNA-1273 vaccine; 1666 (98.0%) vaccinated patients had source documentation of vaccine doses and 34 (2.0%) had plausible self-report only. Full vaccination was less common in COVID-19 case patients (15.8%) than controls without COVID-19 (54.8%) (absolute difference, −39.0%; 95% CI, −41.5% to −36.4%).

Among 730 COVID-19 case patient specimens that had SARS-CoV-2 lineage determined, 245 (33.6%) were identified as B.1.1.7 (Alpha) variant, 335 (45.9%) as B.1.617.2 or AY group (Delta) variant, and 150 (20.5%) as other variants. The predominant variant shifted from Alpha to Delta in mid-June 2021 (eFigure 1 in the Supplement ), and in this analysis the period between July 1, 2021, and August 15, 2021, was considered dominated by Delta variant circulation.

Overall, COVID-19 hospitalization was strongly associated with a lower likelihood of vaccination, with an aOR of 0.15 (95% CI, 0.13-0.18) ( Figure 2 ). Effect modification was observed by immunocompromised status, with a greater magnitude of association for patients without immunocompromising conditions (aOR, 0.10; 95% CI, 0.09-0.13) than with immunocompromising conditions (aOR, 0.49; 95% CI, 0.35-0.69) ( P  < .001) ( Figure 2 ; eTable 3 in the Supplement ). The magnitude of association was higher for the mRNA-1273 vaccine (aOR, 0.11; 95% CI, 0.08-0.14) than the BNT162b2 vaccine (aOR, 0.19; 95% CI, 0.16-0.23) ( P  < .001), with this difference largely because of a lower aOR for patients at more than 120 days since vaccination with the mRNA-1273 vaccine (aOR, 0.15; 95% CI, 0.09-0.23; median 141 days from vaccine dose 2 to illness onset) than with the BNT162b2 vaccine (aOR, 0.36; 95% CI, 0.27-0.49; median 143 days from vaccine dose 2 to illness onset) ( P  < .001). A lower aOR for the mRNA-1273 vaccine compared with the BNT162b2 vaccine for patients with illness onset greater than 120 days after vaccination was observed after restricting to patients without immunocompromising conditions and further stratifying these patients into younger (18-64 years) and older (≥65 years) groups (eTables 3-5 in the Supplement ). By SARS-CoV-2 variants sequenced, COVID-19 hospitalization was strongly associated with lower likelihood of vaccination for both the B.1.1.7 (Alpha) variant (aOR, 0.10; 95% CI, 0.06-0.16) and B.1.617.2 or AY (Delta) variant (aOR, 0.14; 95% CI, 0.10-0.21).

Among 1197 patients hospitalized with COVID-19 between March 11, 2021, and July 14, 2021, 142 (11.9%) were vaccinated breakthrough cases and 1055 (88.1%) were unvaccinated. Compared with unvaccinated cases, vaccine breakthrough cases were older and had more chronic medical conditions ( Table ). Compared with unvaccinated cases, vaccine breakthrough cases less commonly received ICU-level care (24.6% vs 40.1%; absolute difference, −15.5%; 95% CI, −23.1% to −7.8%; P  < .001) and invasive mechanical ventilation (7.7% vs 23.0%; absolute difference, −15.3%; 95% CI, −20.4% to −10.2%; P  < .001) (eTable 6 in the Supplement ).

Unvaccinated patients accounted for 93.9% (261/278) of cases with disease progression to death or invasive mechanical ventilation. The composite of death or mechanical ventilation was experienced by 17 of 142 (12.0%) vaccine breakthrough cases and 261 of 1055 (24.7%) unvaccinated cases. Among patients hospitalized with COVID-19, death or invasive mechanical ventilation was associated with a lower likelihood of vaccination (aOR, 0.33; 95% CI, 0.19-0.58) ( Figure 3 ). Restricting to cases admitted with hypoxemia (n = 902, 75.4% of cases), death or mechanical ventilation was also associated with a lower likelihood of vaccination (aOR, 0.30; 95% CI, 0.16-0.58). Receipt of 1 or more COVID-19–related therapeutics during hospitalization was also associated with a lower likelihood of vaccination (aOR, 0.32; 95% CI, 0.20-0.52) (eTable 7 in the Supplement ).

Unvaccinated patients accounted for 91.0% (91/100) of deaths among patients with COVID-19 in this study. Death occurred in 9 of 142 (6.3%) vaccine breakthrough cases and 91 of 1055 (8.6%) unvaccinated patients with COVID-19. Progression to death after COVID-19 hospitalization was associated with a lower likelihood of vaccination (aOR, 0.41; 95% CI, 0.19-0.88).

According to the World Health Organization COVID-19 Clinical Progression Scale, the highest level of disease severity experienced was significantly lower among vaccine breakthrough cases than unvaccinated cases (aOR, 0.36; 95% CI, 0.25-0.51) (eFigure 2 in the Supplement ). Hospital discharge alive within 28 days of hospital admission was experienced by 125 of 142 (88.0%) vaccine breakthrough cases and 814 of 1055 (77.2%) unvaccinated cases ( P  = .003). In the competing risk model evaluating time to hospital discharge with a competing risk of death, vaccine breakthrough cases had a higher rate of hospital discharge (ie, shorter length of stay) than unvaccinated cases (subdistribution adjusted hazard ratio, 1.73; 95% CI, 1.42-2.10). These findings remained consistent when stratified by age and immunocompromised status ( Figure 4 ).

In this analysis of adults hospitalized in 21 US hospitals between mid-March and mid-August 2021, vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 than other conditions and among those with COVID-19 who progressed to death or mechanical ventilation than those with COVID-19 who did not have disease progression. These findings are consistent with risk reduction of developing severe COVID-19 among patients with vaccine breakthrough infections compared with absence of vaccination.

The aOR in this analysis corresponds to an estimated overall vaccine effectiveness of 85% for mRNA vaccines to prevent COVID-19 hospitalizations. The findings also correspond to an estimated vaccine effectiveness of 90% for the immunocompetent population and 86% for COVID-19 hospitalizations caused by the Delta variant. When the mRNA-1273 and BNT162b2 vaccines were compared, estimated vaccine effectiveness was similar within 120 days of vaccination. In contrast, beyond 120 days, the results corresponded to an estimated effectiveness of 85% for the mRNA-1273 and 64% for the BNT162b2 vaccine to prevent COVID-19 hospitalizations.

Among patients hospitalized with COVID-19, the outcome of death or invasive mechanical ventilation was associated with a lower likelihood of vaccination. These data suggest that the COVID-19 mRNA vaccines may attenuate disease severity among patients who develop COVID-19 despite vaccination, and the total benefits of vaccination exceed those estimated from the prevention of hospitalization alone.

These data complement vaccine trials and emerging postmarketing data that suggest receipt of mRNA vaccination is associated with risk reduction of severe COVID-19. The mRNA vaccine clinical trials were not powered to address severe disease, including complications after hospitalization. 29 , 30 Observational postmarketing studies, including this analysis, have consistently demonstrated a strong association between vaccination and risk reductions in COVID-19 hospitalization in immunocompetent individuals, suggesting that the high efficacy observed in mRNA clinical trials translates into beneficial effects in the community setting. 2 , 3 , 10 As vaccine coverage increases, breakthrough cases are also expected to increase. Concerns about vaccine failure against severe disease are especially likely among patients with complicated comorbidities who are overrepresented in inpatient settings compared with the general population. This analysis demonstrated a strong association between hospitalization for COVID-19 and lower likelihood of vaccination. Moreover, disease progression to critical illness after hospital admission was associated with a lower likelihood of vaccination among a population representing typical hospitalized patients in the US, which included high prevalence of medical comorbidities and multimorbidity.

Recent surges of COVID-19 cases from the SARS-CoV-2 Delta variant and signs of potential waning protection over time from a 2-dose mRNA vaccine series have prompted policy discussions about additional vaccine doses. 16 , 31 , 32 Several findings from this study could help inform ongoing policy discussions on implementing booster vaccination and guiding future research. First, the association between mRNA vaccination and reduced risk of COVID-19 hospitalization was substantially weaker in the immunocompromised population than the immunocompetent one, supporting recent recommendations for additional vaccine doses among immunocompromised persons. 33 Second, vaccine breakthrough COVID-19 hospitalization appeared to be more common with the BNT162b2 than the mRNA-1273 mRNA vaccine in this analysis. Third, the association between vaccination with the BNT162b2 vaccine and reduced risk of COVID-19 hospitalization declined after 4 months from vaccination, potentially indicating clinically important waning of protection over time, including for severe COVID-19.

Similar product-specific differences between the mRNA-1273 and BNT162b2 vaccines have also been reported in other recent observational studies in inpatient and outpatient settings. 34 Furthermore, recent immunologic studies have shown higher antibody responses after vaccination with mRNA-1273 compared with BNT162b2. 16 , 35 These differences may be related to higher antigen content in the mRNA-1273 vaccine, a longer recommended interval between vaccine doses (4 weeks for mRNA-1273 and 3 weeks for BNT162b2), or both. However, differences in the population vaccinated with the mRNA-1273 and BNT162b2 vaccines could also contribute to observed differences in vaccine breakthrough. Differences in memory B- and T-cell responses between COVID-19 vaccines have not been assessed and may be robust and similar for both mRNA vaccine products. 36

An unresolved question is whether observed differences by product and time since vaccination are due to declining immunity, evasion of immunity by the Delta variant, or a combination of the 2. Disentangling the mechanism of decline in protection could inform decisions on whether improving protection would be better achieved through booster vaccine dosing of the same products or administration of new vaccine formulations with a strain change, as is done with seasonal influenza vaccines. 37 These issues are epidemiologically challenging to disentangle with certainty because the Alpha variant preceded Delta circulation, and thus patients infected with the Delta variant also were more likely to have been vaccinated longer ago. The association between prior vaccination and COVID-19 hospitalization was strong for sequenced Alpha and Delta variants. Because the numbers sequenced were smaller than the full cohort numbers, the report also evaluated the magnitude of association by time since vaccination between March and June when the Alpha variant circulated vs July and August when the Delta variant predominated. The association between mRNA vaccination and reduced risk for COVID-19 hospitalization observed during the Delta variant circulation was high for participants with illness onset within 120 days of vaccination and lower for participants with illness onset after that period. This suggests that waning immunity rather than primary evasion by the Delta variant may be a driving mechanism of reduced vaccine protection observed. Whether this decline is restricted to specific high-risk subpopulations or vaccine types or is due to unmeasured confounding warrants further investigation.

This study has several limitations. First, although several relevant confounders were controlled for, unmeasured confounding in this observational case-control study could have occurred. Second, progression of COVID-19 to high severity was measured with multiple outcomes that considered death, organ failures, oxygen use, and duration of hospitalization. Although these measures do not comprehensively characterize disease severity, they capture life-threatening complications of COVID-19. Third, this analysis included only hospitalized patients and cannot inform whether vaccination attenuates COVID-19 severity among outpatients. Fourth, if vaccine breakthrough cases were systematically more likely to be hospitalized for COVID-19 of lesser severity than unvaccinated patients, our analyses of the association between vaccination and severe disease could be confounded by an admission bias. However, lower risk of progression to severe disease among vaccine breakthrough cases was sustained after the population was limited to patients who were admitted with hypoxemia. Fifth, sample size limitations prevented assessments of disease attenuation stratified by vaccine type, SARS-CoV-2 variant, and time since vaccination.

Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and with disease progression to death or invasive mechanical ventilation. These findings are consistent with risk reduction of developing severe COVID-19 among vaccine breakthrough infections compared with absence of vaccination.

Corresponding Author: Mark W. Tenforde, MD, PhD, Centers for Disease Control and Prevention, 1600 Clifton Rd, Mailstop 24/7, Atlanta, GA 30329 ( [email protected] ).

Accepted for Publication: October 13, 2021.

Published Online: November 4, 2021. doi:10.1001/jama.2021.19499

Author Contributions: Dr Tenforde had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Tenforde and Self and Ms Adams contributed equally to this work as lead authors.

Concept and design : Tenforde, Self, Adams, Ginde, Talbot, Hager, Exline, Gong, Peltan, Brown, Busse, Qadir, Grijalva, Rice, Kobayashi, Verani, Patel.

Acquisition, analysis, or interpretation of data : Tenforde, Self, Adams, Gaglani, Ginde, McNeal, Ghamande, Douin, Talbot, Casey, Mohr, Zepeski, Shapiro, Gibbs, Files, Hager, Shehu, Prekker, Erickson, Exline, Gong, Mohamed, Henning, Steingrub, Peltan, Brown, Martin, Monto, Khan, Hough, Busse, ten Lohuis, Duggal, Wilson, Gordon, Qadir, Chang, Mallow, Rivas, Babcock, Kwon, Halasa, Chappell, Lauring, Grijalva, Rice, Jones, Stubblefield, Baughman, Womack, Rhoads, Lindsell, Hart, Zhu, Olson, Patel.

Drafting of the manuscript : Tenforde, Self, Adams, Mohamed, Khan, Mallow, Patel.

Critical revision of the manuscript for important intellectual content : Tenforde, Self, Adams, Gaglani, Ginde, McNeal, Ghamande, Douin, Talbot, Casey, Mohr, Zepeski, Shapiro, Gibbs, Files, Hager, Shehu, Prekker, Erickson, Exline, Gong, Henning, Steingrub, Peltan, Brown, Martin, Monto, Khan, Hough, Busse, ten Lohuis, Duggal, Wilson, Gordon, Qadir, Chang, Mallow, Rivas, Babcock, Kwon, Halasa, Chappell, Lauring, Grijalva, Rice, Jones, Stubblefield, Baughman, Womack, Rhoads, Lindsell, Hart, Zhu, Olson, Kobayashi, Verani, Patel.

Statistical analysis : Tenforde, Adams, Talbot, Casey, Monto, Grijalva, Lindsell, Zhu, Olson.

Obtained funding : Self, Steingrub, Verani, Patel.

Administrative, technical, or material support : Self, Mohr, Files, Hager, Exline, Gong, Khan, ten Lohuis, Duggal, Wilson, Gordon, Qadir, Mallow, Babcock, Jones, Baughman, Womack, Rhoads, Lindsell, Hart, Kobayashi, Verani, Patel.

Supervision : Self, Mohr, Shapiro, Exline, Henning, Martin, Monto, Khan, ten Lohuis, Wilson, Gordon, Halasa, Chappell, Grijalva, Hart, Patel.

Operational support for enrollment : McNeal.

Data cleaning, data management : Olson.

Supervision of staff at study site : Kwon.

Conflict of Interest Disclosures: Dr Self reported receiving grants from the Centers for Disease Control and Prevention (CDC) (principal investigator of the primary funding contract from CDC for this work) during the conduct of the study. Dr Gaglani reported receiving grants from CDC, Vanderbilt University Medical Center, Baylor Scott & White Health (BSWH), and the IVY study during the conduct of the study; grants from CDC–BSWH HAIVEN influenza/COVID-19 vaccine effectiveness study, CDC–BSWH ambulatory US influenza/COVID-19 vaccine effectiveness study, CDC–Abt Associates BSWH RECOVER COVID-19/influenza study, and CDC–Westat BSWH VISION COVID-19/influenza study outside the submitted work; and Pfizer BSWH Independent Grants for Learning & Change for meningococcal vaccination of adolescents and an institutional contract with Janssen (BSWH Observational RSV Study in infants). Dr Ginde reported receiving grants from CDC during the conduct of the study; and grants from the National Institutes of Health (NIH), Department of Defense, and AbbVie outside the submitted work. Dr McNeal reported receiving grants from the CDC HAIVEN study group that become the IVY-3 study group during the conduct of the study. Dr Talbot reported receiving grants from CDC during the conduct of the study. Dr Casey reported receiving grants from NIH K23HL153584 outside the submitted work. Dr Mohr reported receiving grants from CDC during the conduct of the study. Dr Shapiro reported receiving grants from CDC during the conduct of the study. Dr Files reported receiving grants from CDC during the conduct of the study and personal fees from Cytovale and Medpace outside the submitted work. Dr Prekker reported receiving grants from CDC during the conduct of the study. Dr Exline reported receiving a speaking honorarium from Abbott Laboratories outside the submitted work. Dr Gong reported receiving grants from CDC during the conduct of the study; grants from NIH to conduct clinical trials on COVID-19 and non–COVID-19 outside the submitted work; and data and safety monitoring board fees for participating in Regeneron trials outside the submitted work. Dr Henning reported receiving grants from CDC during the conduct of the study. Dr Peltan reported receiving grants from CDC during the conduct of the study; grants from NIH, Intermountain Research and Medical Foundation, and Janssen Pharmaceuticals outside the submitted work; and payment to Intermountain Medical Center for subject enrollment from Regeneron and Asahi Kasei Pharma outside the submitted work. Dr Brown reported receiving grants from CDC during the conduct of the study. Dr Martin reported receiving grants from CDC during the conduct of the study and personal fees from Pfizer outside the submitted work. Dr Khan reported receiving grants from United Therapeutics, Actelion Pharmaceuticals, Eli Lilly, Johnson & Johnson, Regeneron Pharmaceuticals, and Gilead Sciences outside the submitted work. Dr Hough reported receiving grants from CDC during the conduct of the study and grants from NIH outside the submitted work. Dr Wilson reported receiving grants from CDC/Vanderbilt during the conduct of the study. Dr Chang reported receiving personal fees from La Jolla Pharmaceuticals and PureTech Health outside the submitted work. Dr Babcock reported receiving grants from CDC during the conduct of the study. Dr Kwon reported receiving grants from NIH National Institute of Allergy and Infectious Diseases (award 1K23 AI137321-01A1) outside the submitted work. Dr Halasa reported receiving grants from CDC during the conduct of the study; grants from Sanofi outside the submitted work; and hemagglutination inhibition and microneutralization testing, vaccine donation, and grants from Quidel outside the submitted work. Dr Chappell reported receiving grants from CDC during the conduct of the study. Dr Lauring reported receiving consulting fees from Sanofi for an influenza antiviral and fees from Roche as a member of an influenza antiviral trial steering committee outside the submitted work. Dr Grijalva reported receiving a contract from CDC during the conduct of the study; consulting fees from Pfizer, Merck, and Sanofi; a contract from CDC, Campbell Alliance, and the Food and Drug Administration outside the submitted work; and grants from NIH and the Agency for Healthcare Research and Quality outside the submitted work. Dr Rice reported receiving grants from CDC during the conduct of the study and personal fees from Cumberland Pharmaceuticals, Sanofi, and Cytovale outside the submitted work. Dr Lindsell reported receiving grants from CDC to Vanderbilt University during the conduct of the study; grants from NIH to institution, grants from Department of Defense to institution, contracts to Vanderbilt University for research services from bioMérieux, Endpoint Health, and Entegrion. In addition, he had a patent for risk stratification in sepsis and septic shock, issued to Cincinnati Children's Hospital Medical Center. Dr Zhu reported receiving grants from CDC during the conduct of the study. No other disclosures were reported.

Funding/Support: Primary funding for this study was provided by the CDC (75D30121F00002).

Role of the Funder/Sponsor: Investigators from CDC were involved in all aspects of the study, including the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The CDC had the right to control decisions about publication via the CDC publication clearance process.

Group Information: A full list of investigators and collaborators in the Influenza and Other Viruses in the Acutely Ill (IVY) Network is available in eAppendix 1 in the Supplement .

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

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Home » COVID-19 Research at Cambridge Biomedical Research Centre » COVID-19 case studies

• COVID-19 case studies

Read about some of the COVID-19 studies the NIHR Cambridge BRC supported.

Speeding up the diagnosis of COVID-19 in a hospital setting using a SAMBA II

COVIDx, a study supported by the NIHR Cambridge BRC and NIHR Cambridge CRF, aims to investigate the impact of two new tests for COVID-19 on delivering faster diagnoses and understanding the development of immunity following infection.

The first part of the study will evaluate the accuracy of the new SAMBA II-based test and whether it speeds up the diagnosis of COVID-19 in a ‘real-time’ hospital setting at the point of care.

The second part will investigate a point of care finger prick ‘antibody’ test of the blood, to determine how quickly markers of immunity appear following infection and a positive SAMBA test. These antibody tests will be important for understanding which patients and staff have already had the infection, and may be safe to return to work following recovery.

Research nurses from the NIHR Cambridge CRF are collecting samples from patients with suspected COVID-19 to support the COVIDx study, using the SAMBA II machine to test nasal and throat swabs to determine if a patient has COVID-19 and if the new device is an improved source of testing.

The SAMBA II test can provide extremely reliable results in less than two hours, meaning decisions about clinical care or self-isolation can be made much more rapidly. The antibody tests require serum from blood samples, which will be tested in specialised facilities at the  Cambridge Institute for Therapeutic Immunology and Infectious Diseases  (CITIID).

Once the two diagnostic tests have been validated in patients with confirmed COVID-19, the study will enrol a second group of participants – healthcare workers. The SAMBA II test will be able to quickly identify staff who are positive for COVID-19, even if they have no symptoms, allowing them to self-isolate or access treatment if required.

This is an abridged version of the news item  posted on our website  on April 17, 2020.

Cambridge trial targets immune response to treat COVID-19 patients

A new national study, supported by the NIHR Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit, will test whether two drugs that are already in use to treat other immune-related conditions can prevent the development of severe COVID-19 infection.

The TACTIC-R trial will target patients as they are admitted to hospital, and test whether drugs that suppress the immune system can prevent the body from ‘over-reacting’ to infection and destroy healthy tissues as well as virus-infected ones, leading to severe COVID-19 disease.

For the majority of people who have COVID-19, the infection causes only mild symptoms including a fever and cough. However, around 15% of patients develop severe disease, which includes serious damage to the lungs and multiple organ failure. This lung and organ damage appears to be mostly caused by the body’s own immune system responding to the presence of infected cells. Researchers hope that preventing the immune ‘over-reaction’ using drugs that stop or ‘suppress’ the immune response will stop patients developing the severest form of COVID-19, preventing the need for intensive care.

TACTIC will initially test two drugs – Ravulizumab and Baricitinib – that used to treat other conditions caused by an overactive immune system.

Ravulizumab is usually used to treat autoimmune conditions where the body destroys red blood cells.

Baricitinib is used to treat people with rheumatoid arthritis.

Both these drugs have been carefully selected by a consortium of doctors and scientists with expertise in treating immune-mediated diseases, and are thought to have a high chance of reducing the immune ‘over-reactions’ seen in very sick patients with COVID-19.

This is an abridged version of the news story that was first  published on our website  on 16 May 2020.

Single dose of Pfizer BioNTech vaccine reduces asymptomatic infections and potential for SARS-CoV-2 transmission

New data from Addenbrooke’s Hospital suggests that a single dose of the Pfizer BioNTech vaccine can reduce by 75% the number of asymptomatic SARS-CoV-2 infections.

This implies that the vaccine could significantly reduce the risk of transmission of the virus from people who are asymptomatic, as well as protecting others from getting ill.

The study analysed results from thousands of COVID-19 tests carried out each week as part its screening programmes on hospital staff who showed no signs of infection.

The results were then separated out to identify unvaccinated staff, and staff who had been vaccinated more than 12 days prior to testing (when protection against symptomatic infection is thought to occur). The study found that 0·8% of tests from unvaccinated healthcare workers were positive, compared with 0.37% of tests from healthcare workers less than 12 days post-vaccination and 0·2% from healthcare workers at 12 days or more post-vaccination.

This suggests a four-fold decrease in the risk of asymptomatic COVID-19 infection amongst healthcare workers who have been vaccinated for more than 12 days (75 percent protection). The level of asymptomatic infection was also halved in those vaccinated for less than 12 days.

When the team included symptomatic healthcare workers, their analyses showed similar reductions. 1·71% unvaccinated healthcare workers tested positive, compared with 0·4% healthcare workers at 12 or more days post-vaccination.

This is an abridged version of the press release which was first  published on our website  on March 2, 2021.

Pfizer BioNTech vaccine likely to be effective against B1.1.7 strain of SARS-CoV-2

The Pfizer BioNTech vaccine BNT162b2 is likely to be effective against the B1.1.7 variant of SARS-CoV-2, say scientists at the University of Cambridge.

However, when the E484K mutation – first seen in the South African variant – is added, it substantially increases the amount of antibody required to prevent infection.

The preliminary data also suggest that a significant proportion of over-eighty olds may not be sufficiently protected against infection until they have received their second dose of the vaccine.

As the SARS-CoV-2 virus replicates and spreads, errors in its genetic code can lead to changes in the virus.

Towards the end of 2020, the Cambridge-led COVID-19 Genomics UK (COG-UK) Consortium identified a variant of the virus (now known as B1.1.7) and its emergence led to strict lockdown measures in the UK because of concerns over its transmissibility. There is particular concern that these changes might enable the virus to ‘escape’ the newly-developed vaccines.

The UK has begun rolling out two vaccines – the Pfizer BioNTech vaccine and the Oxford AstraZeneca vaccine. The efficacy of the vaccines can be boosted by a second dose; however, in order to reach as large a number of people as possible in a short amount of time, the government has concentrated on delivering a first dose to as many individuals as possible by giving the second dose at 12 weeks, rather than three.

Researchers at the  Cambridge Institute of Therapeutic Immunology & Infectious Disease  (CITIID) created a synthetic version of the SARS-CoV-2 virus, known as a pseudovirus. They found that the Pfizer BioNTech vaccine is likely to offer similar protection against B1.1.7 as it does against the previous strain of SARS-CoV-2, however it may be less effective when dealing with E484K mutation, which so far has only been seen in a relatively small number of individuals.

This is an abridged version of the press release which was first  published on our website  on February 2, 2021.

A DNA test that can identify secondary infections in COVID-19 patients.

Researchers have been able to develop a DNA test to quickly identify secondary infections in COVID-19 patients,

Patients who are diagnosed with severe COVID-19 may need mechanical ventilation in order for clinicians to help treat the virus. However, some may be susceptible to secondary bacterial infections.

COVID-19 patients are thought to be more at risk of a secondary infection because of the amount of lung damage from the virus and will spend more time on a ventilator than those without COVID-19. Many of these patients also have a poorly-regulated immune system, where the immune cells damage the organs and also have impaired anti-microbial functions, so trying to diagnose these patients early is vital.

Cambridge researchers have developed a DNA test to identify those who may have developed the secondary infection a lot sooner.

The test uses multiple polymerase chain reaction (PCR) to help detect the DNA of the bacteria within a few hours rather than waiting for it to grow in the lab. The test runs multiple PCR reactions and can simultaneously pick up 52 different pathogens (organism that causes disease), which often infect the lungs of patients in intensive care. At the same time, it can also test for the bacteria which may be resistant to antibiotics.

Often patients have already started to receive antobiotics before the bacteria has had time to grow meaning cultures are often negative. However, the PCR test doesn’t need to viable bacteria to be able to detect it, not only making it a more accurate test and are able to speed up the diagnosis.

This is one of the first times that this technology has been used in routine clinical practice and was approved by Addenbrooke’s hospital in Cambridge.

Read the full story from January 2021

Can a tapeworm drug boost protection from COVID-19 for high-risk kidney patients?

UK researchers are launching a clinical trial to investigate if the drug niclosamide, usually used to treat tapeworms, can prevent Covid-19 infection in vulnerable, high-risk kidney patients and reduce the number of people who become seriously ill or die from it.

If the charity and industry-funded trial is successful, it may pave the way for a new treatment to prevent or alleviate the impact of Covid-19 in people on dialysis, people who have had a kidney transplant, and people with auto-immune diseases affecting the kidneys such as vasculitis who require treatment to suppress their immune system. The treatment will last up to nine months.

Patients on the trial will receive either a placebo (or dummy) drug, or UNI911 (niclosamide) as a nasal spray, both provided by the manufacturer UNION therapeutics, in addition to all their usual treatments. The trial plans to expand to other UK healthcare centres and aims to recruit at least 1,500 kidney patients.

Niclosamide has shown real promise in the lab, with early tests showing it could stop SARS-CoV-2 multiplying and entering cells of the upper airways.

Niclosamide has been re-formulated into a nasal spray and participants will take one puff up each nostril twice a day.

The trial will identify whether niclosamide can protect people from the virus either on its own, or in combination with any of the vaccines currently available.

If successful, this trial could mean that the treatment becomes available to kidney patients more widely within months.

This is an abridged version of the press release which was first  published on our website  on February 22, 2021.

Genomics study identifies routes of transmission of coronavirus in care homes

Genomic surveillance – using information about genetic differences between virus samples – can help identify how SARS-CoV-2 spreads in care home settings, whose residents are at particular risk.

Care homes are at high risk of experiencing outbreaks of COVID-19, the disease caused by SARS-CoV-2. Older people and those affected by heart disease, respiratory disease and type 2 diabetes are at greatest risk of severe disease and even death, making the care home population especially vulnerable.

Care homes are known to be high-risk settings for infectious diseases, owing to a combination of the underlying vulnerability of residents who are often frail and elderly, the shared living environment with multiple communal spaces, and the high number of contacts between residents, staff and visitors in an enclosed space.

In research published in eLife, a team led by scientists at the University of Cambridge and Wellcome Sanger Institute used a combination of genome sequencing and detailed epidemiological information to examine the impact of COVID-19 on care homes and to look at how the virus spreads in these settings.

In this study, researchers analysed samples collected from 6,600 patients between 26 February and 10 May 2020 and tested at the Public Health England (PHE) Laboratory in Cambridge. Out of all the cases, 1,167 (18%) were care home residents from 337 care homes, 193 of which were residential homes and 144 nursing homes, the majority in the East of England. The median age of care home residents was 86 years.

Compared with non-care home residents admitted to hospital with COVID-19, hospitalised care home residents were less likely to be admitted to intensive care units (less than 7% versus 21%) and more likely to die (47% versus 20%).

“Using this technique of ‘genomic surveillance’ can help institutions such as care homes and hospitals better understand the transmission networks that allow the spread of COVID-19,” said Dr William Hamilton from the University of Cambridge and CUH. “This can then inform infection control measures, helping ensure that these places are as safe as possible for residents, patients, staff and visitors.”

This is an abridged version of the press release which was first  published on our website  on March 3, 2021.

Differing immune responses discovered in asymptomatic cases and those with severe COVID-19

A UK-wide study part-funded by the NIHR has identified differences in people’s immune responses to COVID-19, depending on whether they have no symptoms or more serious reactions to the virus.

In the study, researchers and their collaborators in the Human Cell Atlas initiative analysed blood from 130 people with COVID-19. These patients came from three different UK centres in Newcastle, Cambridge and London and ranged from asymptomatic to critically severe.

The researchers found raised levels of specific immune cells in asymptomatic people to help fight infection – but patients with more serious symptoms had lost these protective cell types and instead gained inflammatory cells. In severe cases this led to lung inflammation, blood clotting difficulties and hospitalisation.

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator.

This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease.

In the future, research may identify those who are more likely to experience moderate to severe disease by looking at levels of these immune cells in their blood.

This is an abridged version of the press release which was first  published on our website  on April 22, 2021.

Cambridge hosts world-first COVID-19 vaccine booster study

The Cov-Boost study offered individuals a chance to have a third dose of COVID-19 vaccine to see whether such a booster dose can better protect against the virus.

In this Government-funded trial, Cambridge were one of the sites to host the ‘booster’ COVID-19 vaccine trial at the NIHR Cambridge Clinical Research Facility.

With thousands of volunteers taking part in the UK, the study would provide researchers vital data on the impact of a third dose on patients’ immune responses.

The trial looked at seven different COVID-19 vaccines (including the Pfizer/BioNTech, and Valneva vaccines) as potential boosters, given at least 10 to 12 weeks after a second dose as part of the ongoing vaccination programme. One booster will be provided to each participant and could be a different brand to the one they were originally vaccinated with.

All the data was then analysed to help inform decisions by the Joint Committee on Vaccination and Immunisation (JCVI) on any potential booster programme for autumn of 2021.

Researchers in Cambridge saw more than 180 participants from the Cambridgeshire area. Professor Krishna Chatterjee, Director of the NIHR Clinical Research Facility in Cambridge, who led the trial in Cambridge said in June: “We are delighted to support this study here in Cambridge. We have conducted trials of several COVID-19 vaccine studies over the last year. It’s an exciting opportunity to now work on a study to determine the effects of a third ‘booster’ dose of vaccines and I want to thank both the trial participants and our staff who are helping with this important research.”

Read the full story from  June 2021 .

Key mutations in Alpha variant enable SARS-CoV-2 to overcome evolutionary weak points

One of the key mutations seen in the ‘Alpha variant’ of SARS-CoV-2 – the deletion of two amino acids, H69/V70 – enables the virus to overcome chinks in its armour as it evolves, say an international team of scientists.

SARS-CoV-2 is a coronavirus, so named because spike proteins on its surface give it the appearance of a crown (‘corona’). The spike proteins bind to cells in our body, where the virus then replicates and spreads.

But as it divides and replicates, it also mutates. Some mutations make the virus more infectious, some help it evade the immune response, potentially making vaccines less effective, while others have little effect.

Towards the end of 2020, Cambridge scientists observed SARS-CoV-2 mutating in the case of an immuno-compromised patient treated with convalescent plasma (where the patient received blood plasma which already had antibodies). In particular, they saw the emergence of a key mutation – the deletion of two amino acids, H69/V70.

This deletion has since been seen across much of Europe, Africa and Asia – the so-called ‘Alpha’ variant – and appears to have spread multiple times independently.

Working under secure conditions, Professor Gupta and colleagues used a ‘pseudotype virus’ to understand how the spike protein interacts with host cells and what makes this mutation so important.

They found that the deletion makes the virus twice as infectiv – that is, the variants were both better at escaping immunity and more infectious.

This is an abridged version of the press release which was first  published on our website  on June 29, 2021.

‘Biological fingerprint’ in blood could help identify COVID patients with no symptoms

Cambridge researchers have discovered a biomarker – a biological fingerprint – in the blood of patients who previously had COVID-19.

This means they can identify people who have had COVID-19 even if they displayed no symptoms – and the biomarkers last several months after infection.

Current practice requires people to take a PCR test at the time of infection or an antibody test, to see if they had the virus but were asymptomatic.

As a result of the research the team has received £370,000 from the National Institute for Health Research (NIHR) to develop a COVID-19 diagnostic test that will complement existing antibody tests, as well as develop a test that could diagnose and monitor long Covid.

The research builds on a pilot project supported by the Addenbrooke’s Charitable Trust which has been recruiting patients from the Long COVID Clinic established in May 2020 at Addenbrooke’s Hospital.

During the pilot, the team recruited 85 patients to the Cambridge-led NIHR COVID BioResource, which collects blood samples from patients when they are first diagnosed and then at follow-up intervals over several months.

In their initial findings, they identified a molecule known as a cytokine produced by T cells in response to infection – which persists in the blood for a long time after infection.

By following patients for up to 18 months post-infection, the team hopes to address several questions, including whether immunity wanes over time. This will be an important part of helping understand whether people who have been vaccinated will need to receive boosters to keep them protected.

As part of their pilot study, the team also identified a biomarker found in patients with long COVID. Their work suggests these patients produce a second type of cytokine, which persists in patients with long COVID and might be useful for diagnosing long COVID and help in the development of new treatments against COVID.

This is an abridged version of the press release which was first  published on our website  on July 19, 2021.

World first for AI and machine learning to treat Covid patients worldwide

In a ground-breaking study supported by the NIHR Cambridge BRC, Addenbrooke’s Hospital, healthcare technology firm NVIDIA and 20 other hospitals worldwide have used artificial intelligence (AI) to predict Covid patients’ oxygen needs.

In what’s known as federated learning, the research applied an algorithm to analyse anonymised electronic patient health data and chest x-rays from 10,000 Covid patients worldwide, including 250 at Addenbrooke’s Hospital.

The study – dubbed EXAM – took just two weeks of AI ‘learning’ to achieve high-quality predictions on how much extra oxygen a patient would need in the first days of hospital care.

To maintain strict patient confidentiality, the patient data was fully anonymised and an algorithm was sent to each hospital so no data was shared or left its location.

Once the algorithm had ‘learned’ from the data, the analysis was brought together to build an AI tool which could predict the oxygen needs of hospital Covid patients anywhere in the world.

This model can be used to help frontline physicians worldwide.

This is an abridged version of the article first  published on our website  on 15 September 2021.

Positive phase 3 results reported in trial for new COVID-19 vaccine supported by Cambridge

A clinical trial supported by the NIHR Cambridge BRC and NIHR Cambridge CRF for a new vaccine against COVID-19 has received positive Phase 3 results.

The trial has been taking place at 22 locations across the UK and recruited a total of 4012 participants aged 18 years and over, and 660 adolescents.

Results showed in October 2021, that the vaccine was successful in producing high levels of neutralising antibodies against the COVID-19.

Developed by the French specialty vaccine company Valneva and manufactured in Scotland, the vaccine is the only inactivated, adjuvanted COVID-19 vaccine in clinical development in Europe. This means, that like flu and polio vaccines, it contains dead versions of the virus that cannot cause disease. Valneva hopes to initially get the jab approved for those aged between 18 and 55.

This national trial was supported at the Cambridge site by the NIHR  Cambridge Clinical Research Facility  and NIHR Cambridge BRC.

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Wednesday, August 21, 2024

NIH-funded study finds long COVID affects adolescents differently than younger children

Adolescents were most likely to experience low energy/tiredness while children were most likely to report headache.

Scientists investigating long COVID in youth found similar but distinguishable patterns between school-age children (ages 6-11 years) and adolescents (ages 12-17 years) and identified their most common symptoms. The study, supported by the National Institutes of Health (NIH) and published in JAMA , comes from research conducted through the NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative , a wide-reaching effort to understand, diagnose, treat, and prevent long COVID, a condition marked by symptoms and health problems that linger after an infection with SARS-CoV-2, the virus that causes COVID-19.

Children and adolescents were found to experience prolonged symptoms after SARS-CoV-2 infection in almost every organ system with most having symptoms affecting more than one system.

“Most research characterizing long COVID symptoms is focused on adults, which can lead to the misperception that long COVID in children is rare or that their symptoms are like those of adults,” said David Goff, M.D., Ph.D., division director for the Division of Cardiovascular Sciences at the NIH’s National Heart, Lung, and Blood Institute. “Because the symptoms can vary from child to child or present in different patterns, without a proper characterization of symptoms across the life span, it’s difficult to know how to optimize care for affected children and adolescents.”

The observational study included 3,860 children and adolescents with a SARS-CoV-2 infection history at more than 60 sites across the United States between March 2022 and December 2023. A comparison group of 1,516 children and adolescents with no history of a SARS-CoV-2 infection were also included to disentangle whether prolonged symptoms of those who had experienced COVID-19 were related to SARS-CoV-2 itself or more broadly related to the effects of the pandemic.

Caregivers completed a comprehensive symptom survey that asked about 75 prolonged symptoms in all major body systems that occurred at least 90 days after an initial SARS-CoV-2 infection and lasted for at least a month. They also completed a survey asking for their perception of the child’s overall health, physical health, and quality of life. The researchers then employed a commonly used statistical technique to identify which symptoms were best at differentiating participants who did and did not have history of SARS-CoV-2 infection. They identified combinations of symptoms distinct for each age group that together generated a long COVID research index, which indicates the likely condition of long COVID.

Researchers identified 18 prolonged symptoms that were more common in school-age children, including headache (57%), followed by trouble with memory or focusing (44%), trouble sleeping (44%), and stomach pain (43%). Other common symptoms in school-age children not included in the research index included body, muscle, and joint pain; daytime tiredness/sleepiness or low energy; and feeling anxious.

In adolescents, 17 symptoms were more common, including daytime tiredness/sleepiness or low energy (80%); body, muscle, or joint pain (60%); headaches (55%); and trouble with memory or focusing (47%). Feeling anxious and trouble sleeping were other commonly reported symptoms that were not included in the research index.

“The symptoms that make up the research index are not the only symptoms a child may have and they’re not the most severe, but they are most predictive in determining who may have long COVID,” said Rachel Gross, M.D., associate professor in the departments of pediatrics and population health at New York University Grossman School of Medicine and lead author on the study.

Fourteen symptoms overlapped between the age groups. Comparing previous research on long COVID in adults, the new study found that adults and adolescents had a greater overlap in symptoms, such as loss of or change in smell or taste. Researchers found less overlap between adults and school-age children, underscoring the importance of age-based long COVID research.

The study identified separate research indexes for school-age children and adolescents along with overlapping, but distinguishable symptom patterns in each group. Of the 751 school-age children that had COVID-19, 20% met the long COVID research index threshold. Of the 3,109 adolescent children with a history of SARS-CoV-2 infection, 14% met the research index threshold, though researchers noted that these numbers should not be used as measures of incidence in the general population, since their study may have included more children with long COVID than the overall population.

Scientists note that the research index provides a framework for looking at common symptoms for research purposes – not necessarily as a guide for clinical care – and will likely be refined as researchers study more children with and without long COVID.

“Our next step is to study children ages 5 years and younger so we can better understand long COVID in the very young,” said Gross.

In compliance with NIH’s Data Sharing and Management Policy, a dataset containing RECOVER Pediatric Observational Cohort Study data collected through June 15, 2024 – which includes data used for this publication – will be released on NHLBI BioData Catalyst® this fall.

Research reported in this press release was supported by NIH under award numbers OT2HL161841, OT2HL161847, and OT2HL156812. Additional support came from grant R01 HL162373. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. For more information on RECOVER, visit https://recovercovid.org .              

HHS Long COVID Coordination:  This work is a part of the  National Research Action Plan  (PDF, 1.3 MB), a broader government-wide effort in response to the  Presidential Memorandum  directing the Secretary for the Department of Health and Human Services to mount a full and effective response to Long COVID. Led by Assistant Secretary for Health Admiral Rachel Levine, the Plan and its companion  Services and Supports for Longer-term Impacts of COVID-19 report  (PDF, 1.6 MB) lay the groundwork to advance progress in the prevention, diagnosis, treatment, and provision of services for individuals experiencing Long COVID.

About RECOVER:  The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative brings together clinicians, scientists, caregivers, patients, and community members to understand, diagnose, and treat long COVID. RECOVER has created one of the largest and most diverse groups of Long COVID study participants in the world. In addition, RECOVER clinical trials are testing potential interventions across five symptom focus areas. For more information, please visit  recoverCOVID.org .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Gross RS, Thaweethai T, Kleinman LC, et al. Characterizing Long COVID in Children and Adolescents: RECOVER Pediatric Study . Journal of the American Medical Association. 2024. doi: 10.1001/jama.2024.12747

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Impact of COVID-19 on Life of Students: Case Study in Hong Kong

1 Centre for Health Education and Health Promotion, The Chinese University of Hong Kong, 4/Floor, Lek Yuen Health Centre, Shatin, Hong Kong, China; kh.ude.khuc@gnuekarev (V.M.W.K.); kh.ude.khuc@ualtnecniv (V.T.C.L.); kh.ude.khuc@gnuehcnivlac (C.K.M.C.); kh.ude.khuc@olailema (A.S.C.L.)

2 School of Public Health, Prince of Wales Hospital, Shatin, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, 4/Floor, School of Public Health, Prince of Wales Hospital, Shatin, Hong Kong, China

Vera M. W. Keung

Vincent t. c. lau, calvin k. m. cheung, amelia s. c. lo, associated data.

Not applicable.

COVID-19 has an impact on the day-to-day life of students, with school closure and detrimental effects on health and well-being that cannot be underestimated. A study collected data reflecting the health and well-being of secondary school students entering a programme entitled “Healthy Life Planning: Assist Students to Acquire and Practice Health Knowledge and Skills” (ASAP study) in September and October 2019 before the outbreak of COVID-19. Follow-up data were collected in June and July 2020, over half a year since the spread of COVID-19, which facilitated analyses of its impact on the health behaviours and well-being of young people. Comparative analyses between baseline and the follow-up period were conducted on weight status, sleep pattern and quality, pattern of sedentary lifestyle, pattern of physical activity, attitudes and perceived barriers for exercise, and hand hygiene. Attitudes toward precautionary measures and influenza vaccination, self-reported changes in hygiene practices, exercise habits and eating habits were analysed. Although hygiene habits and risk perceptions among young people have improved in many aspects, the level of physical activity has declined as well as the beliefs and attitudes on increasing time on electronic media and change in sleep hygiene. Attitudes and beliefs towards influenza vaccination have declined, which would reflect the slow increase in the uptake rate of COVID-19 vaccination. Health education should equip students with the knowledge and skills to cultivate beliefs and attitudes to face health challenges.

1. Background and Introduction

Since the COVID-19 pandemic was declared, lockdown measures have been implemented in many parts of the world. Implementation of physical measures to interrupt or reduce the spread of respiratory viruses based on sustained physical distancing, restriction of social gathering, and “shut-down” measures has a strong potential to reduce the magnitude of the peak of the COVID-19 pandemic [ 1 ].

However, impacts on other aspects of health must not be underestimated. A study during the semi-lockdown period has shown males with BMI 24 or above had lost weight, but all other subjects had gained weight as a result of a significant decline in the amount of moderate or vigorous exercise [ 2 ]. Obesity has been shown to increase the risk of mortality of COVID-19 after adjusting for confounding factors such as age in different parts of the world [ 3 ].

A study by Fong et al. in 2020 found that 65.3% of participants experienced increased stress due to staying at home and 29.7% experienced moderate to severe levels of depressive symptoms; increases in the use of electronic devices and decreases in outside activities were positively associated with a higher level of depression severity [ 4 ]. Studies have also found increasing prevalence of obesity [ 5 ] and myopia [ 6 ] among school children due to longer screen times, lack of physical activity, and living in small, crowded living and learning spaces at home. Increasing physical activity and maintaining a healthy diet, leading to positive changes to their physical health, have also been shown to be associated with better mental health [ 7 , 8 ]. Non-communicable diseases such as cardiovascular diseases, chronic lung diseases, cancer and diabetes are still constituting the main health burdens of society [ 9 ]. The main drivers for an unhealthy diet and lack of physical activity would be a lack of places and opportunities to be physically active and industries’ opposition to public health interventions [ 10 ]. Behavioural, environmental and occupational, and metabolic risks can explain half of the global mortality and more than one-third of global disability-adjusted life year (DALY) [ 11 ]. A substantial burden of global cardiovascular disease morbidity and mortality is attributable to a sedentary lifestyle, and the attributable burden of high BMI has increased in the past 23 years; physical inactivity and unhealthy eating are the key underlying causes [ 11 ].

COVID-19 also has an impact on the day-to-day life of students with school closures [ 12 ]. Results of one study have shown a dramatic decline in assessment during COVID-19 in schools, suggesting lower performance when students start school in 2020 [ 13 ]. Schools may need to leverage decision-making frameworks, such as the Multi-Tiered Systems of Support/Response-to-Intervention (MTSS/RTI) framework [ 14 ] to identify needs and target instruction where it matters most when school begins in late 2020. During the first half of the academic year in 2020 in Hong Kong, schools were closed during the spring term with online learning, with half-day sessions in the summer term before closure again due to a third wave in July 2020 in Hong Kong. Schools reopened after the summer break in September 2020, with half-day sessions, and closed again in early December 2020 due to the fourth wave. Schools reopened in February 2021 with half-day sessions. The government has imposed restrictions on social gathering including numbers of people grouped together and the operation of restaurants and recreation facilities. Many recreation facilities including public utilities were closed or operated under strict control of people flow periodically in 2020. There is a need to study the impact of COVID-19 on student life with disruption of usual school life and social interaction during that period.

The Centre for Health Education and Health Promotion of the Chinese University of Hong Kong (CHEHP) has pioneered the Healthy School/Health Promoting School (HPS) movement in Hong Kong and neighbouring countries over the last two decades [ 15 , 16 ]. It has developed many initiatives, making use of the HPS framework to improve the health literacy of students [ 15 ]. Recently, it launched the ASAP study (Healthy Life Planning: Assist Students to Acquire and Practice Health Knowledge and Skills) to enrich the knowledge and skills of students on a variety of health-related matters. The ASAP Project provided health educational materials covering nine teaching units designed for junior secondary schools. Topics covered sleep hygiene, infectious disease control, travellers’ health, physical activity, body image, stress management, etc. From these, teachers chose one or more units for school-based curriculum enrichment. They were also required to develop experiential learning activities for students based on the topics they have taught. Students might conduct project learning on them as well.

The impact of COVID-19 on the lives of students who received the ASAP program is being studied. The aim of this study is to investigate the impact of COVID-19 on student health and well-being by collecting data reflecting the health and well-being of students at the entry of ASAP (before COVID-19 outbreak), then at a yearly interval (after the outbreak), to analyse any changes.

2. Materials and Methods

2.1. study design.

For this case study, comparative analyses between baseline and follow-up periods were conducted to identify potential changes in students’ weight status, sleep pattern and quality, pattern of sedentary lifestyle, pattern of physical activity, attitudes and perceived barriers for exercise, and hand hygiene. The attitudes toward precautionary measures to COVID-19 and influenza vaccination, self-reported changes in daily living habits, exercise habits, eating habits and hygiene practices were analysed.

The study has been approved by the Survey and Behaviour Research Ethics Committee (SBRE-19-104). The surveys were anonymous. The participating schools have obtained consent from parents and students and students’ participation was entirely voluntarily with no adverse repercussions.

2.2. Study Population

The study targeted students studying in grades between Secondary 1 (S1) and Secondary 3 (S3), aged about 11–15 years.

2.3. Sample Population

Eleven secondary schools in Hong Kong that participated in the ASAP study were invited to the pre-and-post questionnaire survey. School teachers were allowed to use the teaching materials provided by the programme to enrich their health-related curricula such as Physical Education, Technology and Living, Biology, and the school-based health curriculum. The teaching materials covered various health contents such as physical activities, sleep hygiene, stress management, body image, infectious disease control, dental health, the prevention of prolonged use of electronic devices, etc. At least one grade between S1 and S3 of the participating schools was beneficial to the study and eligible for the survey. A total of 1355 students studying in the selected grades were invited, and 1102 completed two administrations of the questionnaire, giving a response rate of 81.3%. The survey was anonymous and used the class number of each responding student to match the questionnaires completed in two administrations in September and October 2019 (baseline) and June and July 2020 (follow-up), respectively.

2.4. Measuring Tools

The Hong Kong Student Health Survey Questionnaire (HKSHQ) was used to collect data reflecting lifestyles, including hygiene practice and general health status. HKSHQ adopts a system of surveillance of student health status, taking reference from the US Centres for Disease Control and Prevention (CDC) Youth Risk Behavioural Surveillance (YRBS) [ 17 , 18 ] and Wessex Healthy School Award [ 19 ], which has been used by CHEHP [ 20 , 21 , 22 ] with continuous refinement as a tool for assessing student health status and health-related outcomes [ 16 ].

The parameters on demography include date of birth, gender, and self-rated health status (3 questions). The survey also uses the Family Affluence Scale (FAS), which was utilised to reflect the economic status of the respondents’ family from the following criteria (4 questions): the number of vehicles owned by the respondent’s family; whether the respondent has a separate bedroom; the number of family trips; and the number of computers owned by the family [ 23 , 24 ]. The Pittsburgh Sleep Quality Index was utilised to measure sleep quality [ 25 ].

Self-reported body weight of students was classified into wasting, desirable, and obese according to the weight-for-height charts in a local guide to childhood growth and nutrition assessment by Leung [ 26 ]. The charts are gender-specific, in which obesity is defined as body weight values above 120% of the median weight-for-height, while wasting is defined as body weight values below 80% of the median weight-for-height. When the body height value of a subject exceeds the data available in the charts, Body Mass Index (BMI) cut-offs for Asian adult populations are used to interpret the subject’s body weight, where a value between 18.5 kg/m 2 and 22.9 kg/m 2 is considered normal [ 27 ].

The Theory of Planned Behaviour by Ajzen [ 28 ] was applied in this survey to assess the attitudes and perceived behavioural control on physical activity ( Appendix A ). Similarly, the study also assessed the attitudes and perceived behavioural control on the uptake of influenza vaccination. COVID-19 vaccination was not available at the time of data collection, so their attitudes towards influenza vaccination would help us understand their perspectives on vaccination. Since follow-up data were collected during the COVID-19 pandemic, questions reflecting the respondents’ risk perception (such as the wearing of face masks, hand hygiene, social distancing, actions taken with suspected symptoms) were added to the questionnaire.

The Rosenberg Self-esteem Scale (RSE) by Morris Rosenberg was adopted in this survey to evaluate self-esteem in teenagers at the baseline of the study [ 29 , 30 ]. Leung and Wong [ 31 ] studied the validity and reliability of the Chinese translation of the RSE and gave recommendations on the Chinese wordings in some of the items. The current study adopted the Chinese translations recommended by Leung and Wong for item 3 (“I feel like a person who has a number of good qualities”), 7 (“I feel that I am a person of worth, at least on an equal plane with others”) and 8 (“I wish that I could have more respect for myself”) to optimise the reliability. The RSE and the Theory of Planned Behaviours [ 28 ] give a complete description of the non-cognitive development of the participants and a clear indication of the effects of the interventions in developing the habit of doing exercise and receiving a flu vaccine to prevent them from being infected.

The Mental Toughness Scale for Adolescents (MTS-A) by McGeown, St. Clair-Thompson and Putwain [ 32 ] was adopted in this survey to examine the mental toughness of teenagers before and after the interventions. The scale is an 18-item Likert scale with items answered on a four-point scale from “strongly disagree” to “strongly agree”. The concept of mental toughness in adolescents includes six domains: challenge, interpersonal confidence, confidence in abilities, emotion control, control of life, and commitment. Three statements describe each of the above domains in the teenager context, and respondents have to indicate how strongly they agree or disagree with each sentence. The author of MTS-A has granted the research team permission to use the scale supplemented with the Chinese translation.

2.5. Data Collection

The study collected data reflecting the health and well-being of students at the beginning and then at a yearly interval to monitor any changes. The baseline data were collected in September and October 2019 at the beginning of the academic year before the outbreak of COVID-19, and follow up data were collected in June and July 2020, half a year after its outbreak.

2.6. Data Analysis

The McNemar test was used to determine if there were differences among dichotomous dependent variables (such as whether the subjects had played ball games over the last seven days) between pre and post groups. Paired t-test was used for similar purposes but for comparing the means of continuous dependent variables (such as the subjects’ attitude score toward physical activities). A difference was considered statistically significant if the p -value was <0.05. Data were analysed by SPSS Statistics, version 25.0.

3. Findings

Table 1 describes the background demographic characteristics of the subjects, including socioeconomic status. The subjects had an average age of 13.28 years at baseline and 13.99 years at follow-up (standard deviation: 1.07 year). Sixty percent (60.2%) of them were female because two participating schools were girls’ schools, while the other nine were co-education. The subjects came from schools in urban settings, semi-urban settings and satellited towns.

Demographic characteristics of the subjects (N = 1102).

a Semi-urban setting b Urban setting. c Satellite towns (evolved from rural areas to urban setting).

About 50% of students came from the middle affluence group and about one-quarter from either high or low affluence groups. Most of the schools in this study are located in districts with monthly median domestic household incomes below the overall median level in Hong Kong. The sample is not skewed towards higher socioeconomic groups.

Results of the current study show that the proportion of students classified as obese decreased from 23.0% to 20.5% and 13.3% to 12.0% among male and female students, respectively. The changes were not statistically significant.

The percentage of students engaged in 60 min of moderate to vigorous exercise decreased with statistical significance from 40.8% to 30.1%, particularly those rigorous activities taking place in groups or in public, or vigorous activities such as running and jogging, ball games, swimming, playground activities, skating, and martial arts ( Table 2 ). The item “stretching” was added to the post-test questionnaire. Over one-fourth of students (26.6%) reported that they had done some stretching during the seven days before the post-survey, but no baseline data were available for direct comparison.

Level of physical activity.

Footnote . The item “stretching” was added to the post-test questionnaire. Over one-fourth of students (26.6%) reported that they had done some stretching during the seven days before the post-survey, but no baseline data were available. McNemar Test was performed. Arrows indicate the direction of significant changes. NS: non-significant.

Higher proportion of students spent more than two hours on an average school day watchng video programmes as well as internet surfing (not for academic purpose) on both ordinary school days and during holiday with statistical significance ( Table 3 ). The percentage of students who perceived no influence on the prolonged use of electronic media increased, and those who perceived eye fatigue and shoulder discomfort reduced ( Table 3 ). However, an increased impact on their concentration and study was reported with statistical significance ( Table 3 ). The proportion of students going to bed after 11:00 pm increased from 43.5% to 66.1%, and that of students getting up after 8:00 am increased from 10.0% to 32.9% with statistical significance, though sleep quality was not affected significantly ( Table 3 ). Self-reported handwashing behaviours improved, with a higher proportion of students washing hands thoroughly and a smaller proportion not taking handwashing seriously with statistical significance ( Table 4 ).

Time spent on electronic media (non-academic purpose) and sleep time.

Footnote . McNemar Test was performed except for comparing the average sleep hours and the scores of Pittsburgh Sleep Quality Index (PSQI). A PSQI score above 5 indicates poor sleep quality in the respondent. Paired t-test was performed to compare means. Arrows indicate the direction of significant changes. NS: non-significant.

Self-reported handwashing behaviours (number of valid cases = 971).

Footnote . McNemar Test performed. Arrows indicate the direction of significant changes.

Table 5 shows the changes in attitudes and beliefs towards physical activities from baseline to follow-up. The decline is observed in the goal of action, attitudes, subjective norm, perceived behavioural control, behavioural beliefs and norm beliefs with statistical significance. The behavioural intention and control beliefs also declined, although statistical significance was not detected.

Attitudes and beliefs toward physical activities.

Footnote . Paired t-test was performed to compare means. NS: non-significant.

Regarding the changes in attitudes and beliefs towards influenza vaccination from baseline to follow-up, Table 6 shows a decline in all domains with statistical significance, particularly behavioural intention and subjective norm and perceived behavioural control. Students are a target group for influenza vaccination in Hong Kong. Table 7 shows that a high proportion of students would continue wearing face masks and handwashing, but there was a lower proportion for other hygiene measures. This is reflected by just over half of students (54.9%) reporting a significant change in hygiene habits. More than half of students (52.8%) reported a decrease in physical activities such as running and walking, and 41.2% reported fewer ball games, and only a low proportion of students reported having participated in other physical activities such as outdoor activities ( Table 7 ). Although students tend to eat healthier at home, this proportion (55.0%) is not very high, and less than one-fifth of students (17.5%) had a significant change in eating habits ( Table 7 ).

Attitudes and beliefs toward influenza vaccination.

Footnote . Paired t-test was performed to compare means.

Change in health and hygiene behaviours during COVID-19.

Table 8 shows students’ intention to maintain precautionary measures over the next three months post-test. The majority of students would continue to wear a face mask and be meticulous about handwashing, in line with findings of current practices, shown in Table 6 . About half of the students would like to see a relaxation on physical distancing and restriction of gathering to allow more interaction. Students have a higher risk perception of respiratory symptoms; they would not go to school or activities and would only continue if no fever and reporting symptoms ( Table 8 ).

Intention to maintain precautionary measures over next three months post-test.

4. Discussion

The decline in the level of physical activity and the prolonged use of electronic media, with increasing effects on students’ learning, concentration, and sleep pattern (going to bed late and getting up late), are worrying ( Table 2 and Table 3 ). Socioecological models state that a person’s health status is not only influenced by individual behaviours, but also by factors situated in a person’s environment [ 33 , 34 ]. The concept of “environment” captures multiple dimensions, and a Built Environment (BE) can be defined broadly as “the human-made space in which people live, work and recreate on a day-to-day basis” [ 35 ]. During the COVID-19 pandemic, the BE has been altered due to various preventive and lockdown measures. It not only encompasses green spaces and parks, but also includes the internal environment and social capital (defined as social networks and interactions that inspire trust and reciprocity among citizens) [ 36 ]. The social environment, part of the BE, refers to factors such as social support and social networks, social deprivation, and social cohesion and systems [ 37 ]. BE shapes individual health behaviour through diverse mechanisms and can be adverse or beneficial for health [ 38 ]. Neighbourhoods that are more walkable, either leisure-oriented or destination-driven, are associated with increased physical activity, increased social capital, lower overweight rates, lower reports of depression, and less reported alcohol use [ 39 ]. Better street connectivity or walkability tended to be positively related to increased physical activity and walking [ 40 ].

One study has found that adolescents undertook more physical activity during lockdown if they had stronger prior physical activity habits, but some were unsure of what to do when they did not have instruction from a coach. Some adolescents reported that physical activity became a method of entertainment during lockdown, and this mindset change increased the level of physical activity [ 41 ]. Living space is very limited in Hong Kong, making physical activity at home not feasible for many young people. Online coach-led physical activity sessions have helped encourage and support adolescents to follow online exercise routines [ 41 ]. The implementation of lockdown measures and school closures has a significant impact on the BE, not only in terms of walkability and connectivity but also in terms of social connectivity and support. Apart from the effect on physical activities, we must not underestimate its negative effect on other aspects of health, such as psycho-social well-being, as a result of the impact of COVID on the BE diminishing social capital. This might be reflected by less positive beliefs and attitudes towards physical activities ( Table 5 ). Around half of the students reported a decreased frequency of walking or running and ball games without much increase in other types of indoor physical activities ( Table 7 ).

Although staying at home should enable students to eat healthier, this proportion is not high and less than 20% of students had a significant change in eating habits ( Table 7 ). Previous studies have revealed a low level of physical activities and healthy eating among secondary students [ 42 , 43 ]. COVID-19 might have worsened these conditions.

Some previous studies stated that lockdown and school closures might exacerbate childhood obesity [ 44 ] and cause unhealthy changes to the diet of students [ 45 , 46 ]. Past studies also support the claim that when students are not in school, they tend to have less healthy diets [ 47 ]. The findings of our survey showed similar results, with 29.2% students consuming unhealthy takeaway food, and one-fifth of students having increased consumption of soft drinks (20.2%), desserts (19.8%) and crispy food (19.7%). However, over half of the students (55.0%) indicated that they had healthier meals at home, and 38.6% of them consumed more fresh fruits, implying that the COVID-19 pandemic might have brought not only negative impacts but also some positive changes to the diet of students. Such positive changes may partly be explained by the fact that before the pandemic, most secondary students in Hong Kong consumed their lunch at nearby restaurants or fast food shops when they had whole-day classes on average school days [ 14 ]. School suspension as well as the fear of infection drove students to stay home for food, while lockdown and work-from-home arrangements also allowed more parents to prepare meals for their children. Further studies are required to investigate whether such changes will lead to any changes in childhood obesity in Hong Kong.

The percentage of students who perceived no influence on the prolonged use of electronic media increased, but those who perceived eye fatigue and shoulder discomfort reduced ( Table 3 ). This may be due to adaptation. However, prolonged use had an impact on their studies and concentration as well as sleep pattern ( Table 3 ).

It is encouraging to observe the improvement in hand hygiene reflected by more serious handwashing ( Table 4 ). However, it is disappointing and alarming to find the decline in beliefs and attitudes, including motivation and perceived control, towards influenza vaccination with statistical significance (most showing p-value lower than 0.001) ( Table 6 ). This could be due to school suspension during the pandemic, and so, they perceived having a lower risk of being infected. However, the scores at baseline were already low, which makes it difficult to identify a further significant decline. This might reflect the weak perception of the beneficial effect of influenza vaccination. It might also account for the slow increase in the uptake of COVID-19 vaccination in Hong Kong [ 48 ], which is also observed in other parts of the world [ 49 ]. Previous studies on predictive factors of influenza vaccination suggested that factors related to health belief models such as perceived adverse effects and efficacy and advice given by health care professionals are determinant factors for the uptake of vaccination [ 50 , 51 ].

The uptake rate of COVID-19 vaccines in Hong Kong is still unsatisfactory, despite the availability and accessibility of the vaccine. There is room for improvement to enhance the health beliefs and attitudes towards vaccines for preventing the disease. A study on the acceptance of the COVID-19 vaccine found that people who perceived the seriousness of the infection, vaccine conferring benefits, and received calls to action were significantly more likely to accept the vaccine [ 52 ]. Conversely, perception of barriers to accessibility and potential harm of the vaccine were found negatively to be associated with their acceptance. Recommendation by the government stood out as the most important cue. Public health intervention programmes focusing on increasing the perception of the benefits of vaccination and perceived susceptibility to infection while reducing the identified barriers should be warranted [ 53 ]. The study also revealed that the public values efficacy and safety more than the cost of vaccines. Another study in the US found that a greater likelihood of COVID-19 vaccine acceptance was associated with more knowledge about vaccines, less acceptance of vaccine conspiracies, elevated COVID-19 threat appraisals, and being up to date with influenza immunisation [ 49 ]. The other demographic predictors of a likelihood of being vaccinated against COVID-19 were higher income group (income of USD 120,000 or higher) and being a Democrat (in comparison to the reference category Republican), and respondents relying on social media for information about COVID-19 anticipated a lower likelihood of COVID-19 vaccine acceptance. More public health interventions targeting those factors facilitating and hindering uptake should be put in place.

The closure of schools during COVID-19 could result in the loss of opportunity to foster positive beliefs and attitudes in students towards influenza vaccination. It could also have an impact on the low uptake rate of COVID-19 vaccination. From the findings of this study, there is room to enhance the perception of the benefits of vaccination against infectious disease in students, particularly before pandemics and the potential consequences if not vaccinated. Health education should cultivate a positive and supportive culture to support family members and friends to receive the vaccination. Health literacy includes access and analysing health information and problem solving such as breaking the barriers to access these services. This would help to improve the acceptance and uptake rate. A recent study in Hong Kong has found a higher level of vaccine acceptance among the youngest adult group (age 18 to 24), which would be due to better exposure to vaccine education and receiving the free vaccine at birth [ 52 ]. Findings from this study have shown that students perceived the importance of wearing face masks in public places, were meticulous about handwashing and highly vigilant with regard to respiratory symptoms ( Table 8 ). Risk perceptions are a critical determinant of health behaviour, and the profile of risk perceptions and accuracy of perception would affect the association between risk perceptions and health behaviours [ 54 ]. Although a high level compliance of facemask wearing was observed and more people maintained social distancing and used alcohol hand rub during the pandemic, decreasing willingness to accept the COVID-19 vaccines was also observed. This might be associated with increasing concerns about vaccine safety and growing compliance of personal protection behaviours [ 55 ]. Therefore, the concept of “ASAP” should be adopted for school curriculum development to assist students in acquiring and practicing health knowledge and skills, including health risk perception and preventive measures for infectious diseases from a broader perspective that includes vaccination.

A substantial proportion of students expressed their wishes to relax social distancing and restriction of gathering ( Table 8 ). Although measures such as closing and restricting most places where people gather in smaller or larger numbers for extended periods (businesses, bars, schools and so on) are most effective, they can cause substantial collateral damage to society, the economy, trade and human rights [ 56 ]. This study has shown the collateral damage to students’ health and well-being and their health beliefs and attitudes. The COVID-19 pandemic has also been found to lead to an increase in myopia among young children in Hong Kong; the prevalence of myopia among school-age children during the pandemic has increased significantly compared to a study conducted before the outbreak [ 57 ]. Prolonged exposure to screens and less time spent outdoors were linked to faster progress in myopia, according to researchers. One study found several highly effective measures that are less intrusive, including land border restrictions, governmental support to vulnerable populations and risk-communication strategies [ 58 ]. Therefore, governments and other stakeholders should consider adopting non-pharmaceutical interventions tailored to the local context when infection numbers surge (or surge a second time) before choosing those intrusive options. Less drastic measures may also foster better compliance from the population [ 52 ].

There are limitations to this study. The subjects are participants of the ASAP study, not a random sample of secondary students. The demography of the students is not markedly different from the demography of students in Hong Kong. They do not skew towards particular demographic characteristics except for the subjects’ gender as two schools are girls’ schools while the others are co-education.

There is a potential bias that they are more health-conscious and have better knowledge and more positive attitudes towards health. Most of the schools are located in districts with median monthly household income below the median in Hong Kong. The sample is not skewed towards higher socioeconomic groups. The students should be more resilient towards the impact of COVID-19 on healthy living. The findings of the study that reflect the beliefs, attitudes, perceived control, and behaviours of students under the pandemic have significant implications. There is an assumed hypothesis that students with better health literacy will maintain positive health beliefs and positive attitudes and behaviours towards healthy living. The findings will help to test this assumption and shed light on which aspects of their beliefs, attitudes and behaviours can be sustained under adverse conditions (such as COVID-19) and how young people should be supported further, notwithstanding that they might have enriched knowledge and skills in health.

Another limitation is the lack of a control group. It is technically difficult to engage more students and schools to participate in the survey under the COVID-19 situation. Moreover, there will not be a perfect control group as schools and students cannot be controlled to receive information and skills enhancement to fight against COVID-19. However, the study has included studies on belief, perceived barriers of control, and attitudes. The findings would partially explain why students behave in a particular way during the COVID-19 period. The global impact of the COVID-19 pandemic has not been experienced for nearly a century. Data reflecting the impact on students’ life would provide useful insights for combating similar challenges in the near future.

5. Conclusions

The current study reveals the changes in physical activities, hygiene and dietary behaviours in Hong Kong adolescents between September 2019 and July 2020, when the novel coronavirus disease (COVID-19) started to hit many parts of the world, resulting in the pandemic. These changes include less moderate and rigorous physical activities, and the attitudes and beliefs of students towards physical activities have become less positive and less persistent. Although hygiene habits and risk perceptions among young people have improved in many aspects, attitudes and beliefs towards influenza vaccination have declined, which would reflect the slow increase in the uptake rate of COVID-19 vaccination. This study has shown the changes in students’ health behaviours, beliefs and attitudes. Health education targeting young people and the public should equip them with the knowledge and skills to cultivate beliefs and attitudes and this would have impact on risk perceptions and behaviours to face health challenges.

Acknowledgments

We would also like to thank the school teachers for using the teaching materials provided by the ASAP study and facilitating students to complete the survey.

• Attitude (4 items): “My taking regular physical activity over the next six months would be…” (harmful to beneficial; unpleasant to pleasant; unenjoyable to enjoyable) and “My attitude towards doing physical activity is…” (from very negative to very positive)
• Perceived Barrier Control (2 items): “For me to exercise for at least 60 minutes every day for the next fortnight will be…” (from very easy to very difficult) and “I am confident that I can accumulate 60 minutes of physical activity every day in the next two weeks.” (from strongly disagree to strongly agree)

Author Contributions

Conceptualization, A.L. and V.M.W.K.; methodology and analysis, V.M.W.K. and V.T.C.L.; writing—original draft preparation, A.L.; writing—reviewing and editing, V.M.W.K., C.K.M.C. and A.S.C.L. All authors have read and agreed to the published version of the manuscript.

Keung M.W., Cheung K.M. and Lau T.C. were supported by a grant from the Quality Education Fund (QEF 2017/1070) awarded to Lee A. QEF was established in 1998 by the Government of the Hong Kong Special Administrative Region for educational initiatives and projects within the ambit of school education of Hong Kong, including kindergarten, primary, secondary and special education.

Institutional Review Board Statement

The survey was approved by the Survey and Behavioural Research Ethics Committee of the Chinese University of Hong Kong (SBRE-19-104).

Informed Consent Statement

School consent was obtained from each participating school.

Data Availability Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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• Published: 06 August 2024

Asymptomatic infection and disappearance of clinical symptoms of COVID-19 infectors in China 2022–2023: a cross-sectional study

• Kaige Zhang 1 ,
• Xiaoying Zhong 2 ,
• Xiaodan Fan 1 ,
• Dongdong Yu 3 ,
• Zhuo Chen 1 ,
• Chen Zhao 4 ,
• Xiaoyu Zhang 4 ,
• Zhiyue Guan 1 ,
• Xuxu Wei 1 ,
• Siqi Wan 1 ,
• Xuecheng Zhang 1 ,
• Mengzhu Zhao 1 ,
• Qianqian Dai 1 ,
• Wenjing Liu 1 ,
• Qianqian Xu 1 ,
• Yifan Kong 1 ,
• Songjie Han 1 ,
• Hongyuan Lin 5 ,
• Wenhui Wang 5 ,
• Huiru Jiang 1 ,
• Chunling Gu 1 ,
• Xiaowei Zhang 5 ,
• Tong Jiang 6 ,
• Shuling Liu 1 ,
• Herong Cui 1 ,
• Xinyu Yang 7 ,
• Yin Jiang 4 ,
• Zhao Chen 4 ,
• Yang Sun 1 ,
• Liyuan Tao 1 , 8 ,
• Rui Zheng 1 , 9 ,
• Ruijin Qiu 1 , 10 ,
• Liangzhen You 1 &
• Hongcai Shang 1  

Scientific Reports volume  14 , Article number:  18232 ( 2024 ) Cite this article

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• Epidemiology
• Infectious diseases
• Risk factors
• Signs and symptoms

To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

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Introduction.

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 , has spread widely in more than 200 countries and regions worldwide at present. As of January 31, 2023, there were 753,479,439 confirmed cases worldwide, including 6,812,798 deaths, have been reported to WHO 2 . COVID-19 has caused significant and far-reaching impact on the global economy, society, public health, and has become a catastrophic public health crisis worldwide. Since the outbreak of COVID-19 in China in December 2019, its high pathogenicity and high infectivity have seriously affected our daily life. Meanwhile, on November 9, 2021, the SARS-CoV-2 B.1.1.529 variant named Omicron was detected for the first time in South Africa, which has become the main circulating strain worldwide. The Omicron variant is characterized by rapid transmission, strong concealability, significant immune escape, besides, most infection were asymptomatic or mild cases 3 , 4 . Obvious study has shown that vaccine effectiveness against symptomatic disease caused by the Omicron variant is substantially lower than with the delta variant 5 . However, Emerging clinical data have demonstrated that vaccine protection is more preserved against severe outcomes than against infection in the Omicron era 6 .

SARS-CoV-2 became widespread in China from November to December, 2022 7 , and we have made major adjustments to the prevention and control strategy since December 7, 2022 8 . The new measures allow at-home quarantine of asymptomatic and mild cases, reduce the frequency and scale of mass testing. Since the policy adjustment, as of 24:00 on December 23, 2022, the cumulative number of reported confirmed cases has increased from 354,017 9 to 393,067 10 . Due to the residents with suspected SARS-CoV-2 infections gradually adopted the use of RAT (rapid antigen test) for health surveillance at home and without reporting to community health departments and medical institutions, it is difficult to fully understand the clinical characteristics of SARS-CoV-2 patients at present. Therefore, we conducted this online questionnaire to record the sociodemographic characteristics, clinical symptoms, adopted prevention and treatment, prognosis and outcome of patients infected with SARS-CoV-2 in China at present, which is conducive to providing high-quality evidence for further optimization of epidemic prevention and control measures.

This study involving human participants were reviewed and approved by the Dongzhimen Hospital, Beijing University of Chinese Medicine (No. 2023DZMEC-009). Informed consent was obtained from participants before the study. All research was performed in accordance with the Declaration of Helsinki 11 .

Study design

We included data through professional questionnaire survey platform ( www.wenjuan.com ) online in China from December 24, 2022 to January 16, 2023. The participants were required positive test result of COVID-19, no matter NAT (nucleic acid test) or RAT, with or without clinical symptoms related to COVID-19. We adopted the snowball sampling method. The links or QR codes of online questionnaire were sent by researchers to their personal WeChat contacts, groups and moments for dissemination. Participants were also encouraged to forward the questionnaire links. WeChat is the most widely used social media platform in China, with more than 1 billion users. The dissemination of questionnaires through WeChat platform can effectively guarantee the spread range of questionnaires. All participants were anonymous and filled out voluntarily and information in the questionnaire that may reveal personal identity was hidden when reporting the results. Besides, all survey data was collected and managed by researchers familiar with the use, confidentiality, and data management of online questionnaires. Each questionnaire has unique ID number.

The orientation of the questionnaire and the classification of questions were discussed at the panel. Experts involved in respiratory, emergency, infection, psychology, and statistics were invited to demonstrate the rationality of the questionnaire. Before the distribution of questionnaire, we carried out a preliminary survey, finally determined and completed the online distribution of the questionnaire. The problems mainly include 4 categories: (1) Sociodemographic characteristics and general characteristics (age, sex, career, etc.). (2) Infection-related characteristics (time of contact, time of attack, time of diagnosis, method of diagnosis, symptomatic or not, symptom characteristics and duration, etc.). (3) Adopted prevention and intervention measures (situation of vaccination, situation of the use of Chinese herbal medicine, Chinese patent medicine, western drug and other non-drug therapies, etc.). (4) Final outcome (whether all clinical symptoms disappeared and their duration). All the information above were described clearly and normatively, which ensure consistent understanding and reporting. The questionnaire takes about 5–10 min to complete.

Data cleaning process

After the recruitment, we exported the data into Excel file format. Before analysis, we checked the overall quality of data, carried out data cleaning, which aimed to summarize problems such as filling errors, omissions and misfilling. If the filling time is less than 1 min, or there are major logic mistakes, doubtful authenticity that cannot confirmed from the respondents, we will eliminate all these questionnaires. As for the omissions and misfilling of part questions, if there was no serious logic error and we cannot confirm from respondents, we would eliminate the data with problems and retain the rest of the data.

Statistical analysis

Data analysis was completed by SPSS 24.0, all categorical variables were presented by absolute value and percentage. Besides, binary Logistics regression model would be used to analyze the correlation between each factor and the appearance of asymptomatic infection. We defined asymptomatic infection as laboratory-confirmed COVID-19 cases that did not exhibit any clinical symptoms, including fever, upper respiratory symptoms, pneumonia, fatigue, headache, myalgia, dehydration, or gastrointestinal dysfunction, at the time of testing, besides, those continued to exhibit no clinical symptoms during at least 7 days of follow-up after testing would also be considered as asymptomatic infection 12 . Meanwhile, in the symptomatic participants, whether all clinical symptoms disappeared would be taken as outcome, and the record time was 14 days. If the symptoms had not been cured at the moment of filling out questionnaire and the duration was less than 14 days, this data would be considered as censored data. Relevant factors affecting the duration of clinical symptom remission were sorted out as covariates, including age, gender, reinfection, vaccination conditions and the presence of pre-existing conditions. Cox proportional-hazards regression model would be used to analyze the correlation between each factor and the outcome, besides, we fully considered the mutual influence of each factor, and conducted adjustment analysis of each covariate. As for the self-assessed mental conditions, Mann–Whitney U test was used to evaluate the differences in mental conditions of participants in each period. All P values were from 2-sided tests and results were deemed statistically significant at p  < 0.05.

Ethics approval and consent to participate

This study involving human participants were reviewed and approved by the Dongzhimen Hospital, Beijing University of Chinese Medicine (No. 2023DZMEC-009).

A total of 66,448 patients with confirmed SARS-CoV-2 infection participated in the online questionnaire survey, of which 1933 (2.91%) participants were excluded after discussion due to less than 1 min to fill in questionnaire, major logical mistakes, and lack of confirmation from the respondents. Among the remaining 64,515 participants, 66 (0.10%) had unclear career information, 564 (0.87%) did not clearly fill in infection-related conditions and treatment, which were partially eliminated.

In this study, majority of participants were 18 to 60 years old (90.17%; 63,865/64,515), with slightly more male participants (59.71%; 38,520/64,515), and a small group of female participants were pregnancy during infection (6.67%; 1735/25,995). Most participants were first infected (98.89%; 47,512/64,515), and few reinfections (1.01%; 650/64,515). All participants were confirmed through RAT (67.94%; 43,830/64,515) or NAT (40.20%; 25,935/64,515). The largest group of participants were student (18.34%; 11,817/64,449). In terms of reporting pre-existing conditions, part of participants reported a history of healthy conditions (32.91%; 21,233/64,515), most of which are cardiovascular and cerebrovascular disease (16.87%; 10,884/64,515), respiratory disease (8.59%; 5542/64,515) and endocrine system disease (6.21%; 4005/64,515). In terms of prevention, majority of participants had completed three doses of COVID-19 vaccine (85.83%; 55,370/64,515). In term of the treatment, part of participants had adopted Chinese herbal medicine (37.52%; 23,994/63,951), majority of participants had adopted Chinese patent medicine (79.34%; 50.740/63,951) and western drugs (83.43%;53,353/63,951), but a small group of participants only took regular rest without intervention (9.95%; 6552/63,951). Most treatment recommendations were derived from medical orders (34.21%; 21,877/63,951), personal experience (34.15%; 21,840/63,591) and consulting health care provider (33.21%; 21,241/63,951) (Table 1 ).

Characteristics of clinical symptom evolution

Asymptomatic infection accounted for a small proportion of the participants in this study (9.33%; 5969/63,951). The majority of participants still had clinical symptoms at the moment of filling in the questionnaire (55.99%; 35,809/63,951). Among the participants who had been cured, most of which achieved complete cured within 7 days (69.82%; 17,793/22,173), and a few patients achieved complete cured more than 14 days (1.38%; 306/22,173). There were 4 symptoms that were reported more than 50% in this study, including dry and itchy throat (64.16%; 37,203/57,982), sore throat (59.95%; 34,762/57,982), hoarseness (57.90%; 33,574/57,982), nasal obstruction (53.39%; 30,954/57,982) (Table 2 ). The dynamic changes of clinical symptoms recorded in this study over a period of 14 days are shown (Table 3 and Fig.  1 ).

Symptoms of enrolled COVID-19 patients in 14 days.

Characteristics of self-assessed mental conditions in each period of infection

In this study, we initially investigated the self-assessed mental conditions of the participants in each period of infection. Before infection (64.07%; 40,973/63,951), infection confirmed (64.07%; 40,973/63,951), and after infection, (67.76%; 43,331/63,951). The number of participants who self-reported no mental disorders increased gradually, and the difference between the period of infection was statistically significant ( p  < 0.01) (Table 4 ).

Associations between covariates and appearance of asymptomatic infection

A total of 5969 asymptomatic infections were reported. A binary Logistics regression model was used to analyze the correlation between each factor and the appearance of asymptomatic infections. Factors included age, gender, pre-existing conditions, reinfections and vaccination as covariates. We not only independently analyzed the correlation between each single factor and the appearance of asymptomatic infection, but also fully considered the mutual influence of each factor, and carried out the adjustment analysis of each covariate (Fig.  2 ).

Correlation between covariates and appearance of asymptomatic infection*. *The correlation between all covariates and appearance of asymptomatic infection was estimated with the use of a binary Logistics regression model. The higher the hazard ratio, the greater the association between the listed characteristic and appearance of asymptomatic infection. CI denotes confidence interval.

Associations between covariates and disappearance of clinical symptoms

In this study, a total of 57,982 participants reported significant clinical symptoms, and the characteristics of symptom evolution were recorded from 1 to 14 days after infection. Therefore, we defined disappearance of symptoms as the outcome and analyzed the correlation between each factor and outcome through a multivariate Cox proportional-hazards regression model. Factors included age, gender, pre-existing conditions, reinfection, vaccination and treatment as covariates. We not only independently analyzed the correlation between each single factor and the outcome, but also fully considered the mutual influence of each factor, and carried out the adjustment analysis of each covariate (Fig.  3 ).

Correlation between covariates and disappearance of clinical symptoms*. *The correlation between all covariates and amelioration of clinical symptoms was estimated with the use of a multivariate Cox proportional-hazards regression model. The higher the hazard ratio, the greater the association between the listed characteristic and amelioration of clinical symptoms. CI denotes confidence interval.

In this study, more than half of the participants were not cured at the time they filled out the questionnaire. The clinical symptoms mainly showed as upper respiratory symptoms, including dry and itchy throat, sore throat, hoarseness and nasal obstruction. Besides, other symptoms such as chills, fever, headache and fatigue were also common. One study found that comparing with patients who suffered from SARS-CoV-2 Delta variant, patents infected with Omicron variant were more likely to show sore throat and hoarseness, rather than hyposmia and eyes pain 13 . The symptoms of patients in this study are generally consistent with the common characteristics of Omicron infection reported presently. Most participants who had been cured in this study achieved amelioration in 1 week. However, we still need to pay attention to the potential risk of “long COVID”. Previous studies showed that over 30% of COVID-19 patients (including asymptomatic cases) and approximately 80% of hospitalized patients with COVID-19 may experience post-COVID symptoms 14 , 15 . What we need to focus is that most “long-COVID” symptoms would appear after cured, and these symptoms could persist for 3 months or even more 16 . The main symptoms of “long-COVID” are fatigue, headache, attention disorder, hair loss and breathing difficulty, which are different from that in acute infection period 17 , 18 , 19 , 20 , 21 . These characteristics provide essential reference for further observation in our follow-up study.

Considering the combined effects of numerous factors on the clinical characteristics of COVID-19 patients, we analyzed the correlations between age, gender, pre-existing conditions, reinfection, vaccination and the appearance of asymptomatic infections, besides, the improvement of clinical symptoms, which is one significant strength of this study. We found that asymptomatic infections were more likely to occur in those who were males, without pre-existing conditions, reinfected and fully vaccinated. Meanwhile, the factors including over 60 years, females, pre-existing conditions and no vaccination could impact the early recovery of COVID-19. Besides, these factors could also influence each other. In this study, over 30% of the participants reported pre-existing conditions, which is detrimental to early recovery. As independent factor, each pre-existing condition could impact the appearance of asymptomatic patients and the rapid amelioration of symptoms in COVID-19 patients. Considering interactions of other factors, patients who had suffered from cardio-cerebrovascular disease, respiratory disease, digestive system disease and endocrine system disease were still correlation with the adverse impact of clinical characteristics and prognosis. One study with a large sample of 61,414,470 individuals in England found that type 1 and type 2 diabetes were both independently associated with a significant increased odds of in-hospital death with COVID-19 22 . Meanwhile, COVID-19 may increase the burden of pre-existing conditions. Studies had found increasing risk of cardio-cerebrovascular disease after acute infection of COVID-19, which showed significant burden within 1 year 23 , 24 . As for reinfection, current study found that the risk of reinfection and hence hospitalization in recovered individuals remains low in 20 months, vaccination could further reduce these risks 25 . In this study, the reinfection group accounted for a very low proportion, and asymptomatic infection was more likely to occur than that in first infection group. Meanwhile, after interactive adjustment of various factors, we have found that there is no correlation between reinfection and rapid amelioration. Thus, this condition still needs to be alerted. As for gender, current evidence suggests that sexual dimorphism in COVID-19 has potential implications, the severity and mortality of COVID-19 is higher in males than that in females, whereas females might be at increased risk of reinfection and development of long COVID 26 . Combined with our study, males were more likely to occur asymptomatic infections, and females were more difficult to achieve amelioration of symptoms rapidly than males. However, whether it means more risk of “long COVID” should be confirmed in longer follow-up. As for vaccination, over 95% of the participants in this study received at least one dose vaccine of SARS-CoV-2, and over 80% of the participants completed three or more doses of vaccine. Results show clearly that vaccination is positively correlated with the appearance of asymptomatic infection and the rapid amelioration of symptoms, besides, positive effect of booster injection is also showed in this study. Sufficient evidence have shown that vaccination could significantly reduce risks of hospitalization, severity and mortality, besides, the booster vaccination could further reduce the risk of infection and the severity of COVID-19 27 , 28 , 29 . Therefore, in the following of prevention and control, vaccination is still a link that needs continuous attention.

The mental conditions of patients before and after infection are also essential in this study. The WHO has warned unequivocally that the COVID-19 pandemic is a major potential risk for a surge in mental health disorders 30 . An study demonstrates that the increasing problems of mental disorder during COVID-19 pandemic is closely related to the disease, growth of confirmed cases and severity of control measures 31 . Comparing the self-assessed mental conditions of the participants before infection, moment of confirmed and after infection, we found that the overall mental condition showed a gradual improvement trend over time. However, part of participants became severe anxiety and depression at the moment of infection confirmed, which, combined with existing research, may be related to the short-term increasing of confirmed cases and the fear that the prognosis of the disease is unknown 31 . Nevertheless, with the advance of time, people with severe anxiety and depression showed a downward trend again. These characteristics can not only reflect the influence of this disease in mental condition, but also serve as one potential reference to evaluate whether the adjustment of prevention and control policy is reasonable.

Lastly, majority of participants received treatment in this study, including Chinese herbal medicine, Chinese patent medicine, western drugs and other non-pharmaceutical therapy. Each treatment was independently conducive to the rapid amelioration of clinical symptoms. Considering the interaction of other factors, participants in this study could also profit through treatment. One meta-analysis found that Integrated Medicine showed better effects than western medicine independently and did not increase adverse drug reactions in the treatment of COVID-19 32 . What we should be focused is that in addition to medical orders, most treatment were based on “consult health care provider” and “personal experience”, which may be related to the widespread dissemination of this questionnaire in medical institutions and medical universities. However, we should still be alert to the risk of medicine abuse and repeated medication. Therapy without guidance and prescription from formal medical institution may pose more potential risks that we should pay more attention.

Limitations and strengths

Firstly, this study recruit participants through WeChat platform based on online questionnaire survey, which made it difficult for part group to participate effectively, including elderly, children, disabled. Besides, populations with severe cases, adverse events and dead population cannot participate in online questionnaire survey. Moreover, most asymptomatic patients would not conduct NAT or RAT without relative symptoms, which may lead to an underestimation of the prevalence of asymptomatic patients. Factors above could lead to the limitations of participating populations, which would influence the overall reflection of clinical characteristics. Secondly, this study lacked physicochemical indicators, besides, relied on self-reports of clinical symptoms from participants rather than assessment from clinicians, which may led to limitations in objective assessment of disease. Thirdly, the questionnaire neglected to collect the educational level and literacy of the study participants. In self-reports, this information is crucial for assessing the potential impact of participant understanding on the accuracy and completeness of the reported data. We would solve this problem through further follow-up.

Despite above limitations, we also have strengths. Firstly, this study extensively collected numerous samples of COVID-19 patients nationwide and recorded the characteristics of symptom changes of within 2 weeks in detail, which was helpful to further understand the clinical characteristics of COVID-19 presently. Secondly, we analyzed the correlation between age, gender, reinfection, pre-existing conditions, vaccination and the appearance of asymptomatic infections, besides, the amelioration of symptoms, which may help guide us to adopt more targeted prevention and control measures for corresponding populations. Lastly, we we preliminarily explored the effect of different treatment on the amelioration of symptoms in COVID-19 patients, providing a reference for the specific clinical studies of COVID-19 in the future.

In this cross-sectional study, the clinical symptoms of the participants were mainly upper respiratory symptoms, which are according with symptoms after infected with Omicron variant of SARS-CoV-2. Meanwhile, relevant factors including age, gender, pre-existing conditions, reinfection and vaccination could influence the clinical characteristics and rapid amelioration of symptoms in COVID-19 patients, which reminds us to further optimize the prevention and treatment measure of COVID-19. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19, which is conducive to the appearance of asymptomatic patients and rapid amelioration of clinical symptoms. Therefore, strategy of vaccinating everyone should still be keep focused in the subsequent policy. Lastly, the use of Chinese medicine is beneficial to the amelioration of symptoms in COVID-19 patients, however, reasonable guidance is necessary. In summary, we need to strengthen early identification of clinical symptoms, actively promote the vaccination procedure of COVID-19 vaccine, and do a good job of prognostic follow-up.

Data availability

The data and materials are available in Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine and could be obtained only with the approval of the corresponding author.

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This work was supported by the Funds Entrusted by the State Administration of Traditional Chinese Medicine (NO.GZY-KJS-2021-055) and Young backbone personnel project by Beijing University of Chinese Medicine Dongzhimen Hospital.

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Kaige Zhang, Xiaodan Fan, Zhuo Chen, Zhiyue Guan, Xuxu Wei, Siqi Wan, Xuecheng Zhang, Mengzhu Zhao, Qianqian Dai, Wenjing Liu, Qianqian Xu, Yifan Kong, Songjie Han, Huiru Jiang, Chunling Gu, Shuling Liu, Herong Cui, Yang Sun, Liyuan Tao, Rui Zheng, Ruijin Qiu, Liangzhen You & Hongcai Shang

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Dr Kaige Zhang, Xiaoying Zhong, Xiaodan Fan, Dongdong Yu and Zhuo Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Kaige Zhang, Xiaoying Zhong, Xiaodan Fan, Dongdong Yu and Zhuo Chen contributed equally as co-first authors. Kaige Zhang, Xiaoying Zhong, Xiaodan Fan, Dongdong Yu, Zhuo Chen, Liangzhen You and Hongcai Shang designed this study; Kaige Zhang, Xiaoying Zhong, Xiaodan Fan, Dongdong Yu and Zhuo Chen conducted research, analyzed the data collectively; Kaige Zhang wrote the main manuscript text; Xiaoying Zhong prepared all figures; Xiaodan Fan created the online questionnaire; Liangzhen You and Hongcai Shang were in charge of supervision; All authors reviewed and approved the final version of the paper.

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Zhang, K., Zhong, X., Fan, X. et al. Asymptomatic infection and disappearance of clinical symptoms of COVID-19 infectors in China 2022–2023: a cross-sectional study. Sci Rep 14 , 18232 (2024). https://doi.org/10.1038/s41598-024-68162-8

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Low cortisol may play a role in fueling long COVID, study suggests

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Proteins left behind by COVID-19 long after initial infection can cause cortisol levels in the brain to plummet, inflame the nervous system and prime its immune cells to hyper-react when another stressor arises, according to new animal research by CU Boulder scientists.

The study, published in the journal Brain Behavior and Immunity , sheds new light on what might underlie the neurological symptoms of long COVID, an intractable syndrome that impacts as many as 35% of those infected with the virus.

The findings come as COVID makes a striking late summer comeback, with cases rising in 84 countries .

“Our study suggests that low cortisol could be playing a key role in driving many of these physiological changes that people are experiencing with long COVID,” said lead author Matthew Frank, a senior research associate with the Department of Psychology and Neuroscience at CU Boulder.

Previous research has shown that SARS-CoV-2 antigens, immune-stimulating proteins shed by the virus that causes COVID-19, linger in the blood of long COVID patients as much as a year after infection. They’ve also been detected in the brains of COVID patients who have died.

Role of COVID spike protein subunit

To explore just how such antigens impact the brain and nervous system, the research team injected an antigen called S1 (a subunit of the “spike” protein) into the spinal fluid of rats and compared them to a control group.

After seven days, levels of the cortisol-like hormone corticosterone plummeted by 31% in the hippocampus of rats exposed to S1. That is the region of the brain associated with memory, decision making and learning. After nine days, levels were down 37%.

“Nine days is a long time in the life span of a rat,” said Frank, noting that rats live on average for two to three years.

He noted that cortisol is a critical anti-inflammatory agent, helps convert fuel into energy and is important for regulating blood pressure and the sleep-wake cycle and keeping the immune response to infection in check. One recent study showed that people with long COVID tend to have low cortisol levels—as do people with chronic fatigue syndrome, research shows.

“Cortisol has so many beneficial properties that, if it is reduced, it can have a host of negative consequences,” said Frank.

In another experiment, the researchers exposed different groups of rats to an immune stressor (a weakened bacteria) and observed their heart rate, temperature and behavior as well as the activity of glial—or immune—cells in the brain.

They found that the group of rats that had previously been exposed to the COVID protein S1 responded far more strongly to the stressor, with more pronounced changes in eating, drinking, behavior, core body temperature and heart rate, more neuroinflammation and stronger activation of glial cells.

“We show for the first time that exposure to antigens left behind by this virus can actually change the immune response in the brain so that it overreacts to subsequent stressors or infection,” said Frank.

Continuing long COVID research

He stressed that the study was in animals and that more research is necessary to determine whether and how low cortisol might lead to long COVID symptoms in people.

He theorizes that the process might go something like this: COVID antigens lower cortisol, which serves to keep inflammatory responses to stressors in check in the brain. Once a stressor arises—whether it be a bad day at work, a mild infection or a hard workout—the brain’s inflammatory response is unleashed without those limits and serious symptoms come screaming back.

Those might include fatigue, depression, brain fog, insomnia and memory problems.

Frank said he is doubtful that cortisol treatments alone could be an effective treatment for long COVID, as they would not get at the root cause and come with a host of side effects.

Instead, the findings suggest that identifying and minimizing different stressors might help manage symptoms.

Rooting out the source of antigens—including tissue reservoirs where bits of virus continue to hide out—might also be an approach worth exploring.

The study was funded by the nonprofit PolyBio Research Foundation.

“There are many individuals out there suffering from this debilitating syndrome. This research gets us closer to understanding what, neurobiologically, is going on and how cortisol may be playing a role,” said Frank.

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Ninth Circuit did not rule COVID-19 shots are not vaccines | Fact check

The claim: us court ruled covid-19 shots don't qualify as traditional vaccines.

An Instagram post ( direct link , archive link ) shows a headline from the conservative media outlet LouDobbs.com.

"BREAKING: 9th Circuit Court of Appeals Rules mRNA COVID-19 Jab is NOT a Vaccine Under Traditional Medical Definitions," reads the headline.

The June 10 post was liked more than 3,000 times in about two months. A similar post on Instagram was liked more than 5,000 times in two months. Variations also spread across social media platforms .

More from the Fact-Check Team: How we pick and research claims | Email newsletter | Facebook page

Our rating: False

The 9th U.S. Circuit Court of Appeals made no such ruling, a legal expert said. The claim misstates the appellate court's opinion in an ongoing lawsuit challenging the pandemic-era vaccination policy of a California school district.

Circuit court did not rule COVID-19 vaccines are not vaccines

The LouDobbs.com article referenced in the Instagram post is about a ruling by the 9th Circuit in June that reopened a 2021 lawsuit alleging the pandemic-era vaccination policy of the Los Angeles Unified School District violated the right of workers to refuse medical treatment. The school district was one of many that mandated the COVID-19 vaccine for employees during the pandemic.

The lawsuit – which names several school district employees as plaintiffs – claims COVID-19 vaccines are not "vaccines," as that term has traditionally been understood, because they do not "prevent the infection or transmission" of the virus. Rather, the lawsuit asserts they are "treatments" that reduce symptoms of the disease, a distinction at the heart of the plaintiffs' argument against the school district's previously imposed vaccination mandate.

A U.S. district judge dismissed the case in 2022 after concluding, in part, that the school district had a legitimate government purpose in requiring COVID-19 vaccination. The 9th Circuit's June 7 ruling overturned the dismissal and sent the case back to the district court for further proceedings. The appellate court held that the district judge misapplied an early 1900s U.S. Supreme Court decision that upheld a vaccination mandate for smallpox .

But the 9th Circuit did not rule COVID-19 shots are not vaccines, said Dorit Reiss , a law professor at the University of California College of the Law San Francisco whose research includes legal issues related to vaccines. Instead, the appeals court allowed the workers' claims that the shots are not vaccines to go on to the fact-finding stage of the case, Reiss said, citing the 9th Circuit's opinion .

The opinion says the 9th Circuit panel of judges was required to treat the school district employees' allegations about the COVID-19 vaccine as true for the purpose of analyzing whether the district court properly applied a 1905 Supreme Court case Jacobson v. Massachusetts , which held that mandatory vaccinations were rationally related to preventing the spread of smallpox. The appeal was based on use of the 1905 case, so the court essentially created a hypothetical conclusion to the still-undecided question of vaccine definitions in order to consider the question that arises once that is settled.

"At this stage, we must accept plaintiffs' allegations that the vaccine does not prevent the spread of COVID-19 as true," the 9th Circuit's opinion states.

Fact check : No, study didn't blame COVID-19 vaccines for excess pandemic deaths

It goes on to say, "We note the preliminary nature of our holding. We do not prejudge whether, on a more developed factual record, plaintiffs' allegations will prove true. ... Because we thus must accept them as true, plaintiffs have plausibly alleged that the COVID-19 vaccine does not effectively 'prevent the spread' of COVID-19. Thus, Jacobson does not apply, and so we vacate the district court's order of dismissal and remand."

Reiss, the law professor, boiled the 9th Circuit's decision down further.

"In essence, the court ruled that because it is so early in the proceeding, they are treating the plaintiffs' claims as true, and if the plaintiffs were right, the standard the district court used – Jacobson – is the wrong standard," she said.

The lawsuit is ongoing.

COVID-19 vaccines are effective at protecting people from serious illness, hospitalization and death, according to the Centers for Disease Control and Prevention .

Attorneys for the plaintiffs and defendants in this case did not respond to requests for comment. Attempts to reach LouDobbs.com for comment were not successful. The Instagram users who shared the posts did not immediately respond to requests for comments.

Science Feedback also debunked the claim.

Our fact-check sources:

• Dorit Reiss , June 24, Email exchange with USA TODAY
• 9th U.S. Circuit Court of Appeals, June 7, Opinion
• U.S. District Court for the Central District of California, March 14, 2022, Second Amended Complaint for Violation of Civil Rights and Declaratory and Injunctive Relief
• U.S. District Court for the Central District of California, Sept. 2, 2022, Order GRANTING Defendants’ Motion for Judgment on the Pleadings
• CalMatters, June 7, Trump-appointed judges revive lawsuit against L.A. schools’ COVID vaccine mandate

Thank you for supporting our journalism. You can subscribe to our print edition, ad-free app or e-newspaper here .

USA TODAY is a verified signatory of the International Fact-Checking Network, which requires a demonstrated commitment to nonpartisanship, fairness and transparency. Our fact-check work is supported in part by a grant from Meta .

A groundbreaking study aims to determine if long COVID-19 could lead to another type of dementia

A groundbreaking study aims to determine if long COVID-19 could lead to another, new type of dementia.

Dr. Marwan Sabbagh is the professor of Neurology at the Barrow Neurological Institute. He says one of the biggest complaints that people have, weeks or months after their COVID-19 symptoms have subsided, is brain fog or other issues, like memory loss.

So while the COVID-19 virus does not appear to cross the blood/brain barrier , "We initially thought so. Now we don't think so," he said. "But there is evidence of fragments or an inflammatory kind of a massive inflammatory response that occurs triggered by COVID. And those inflammatory markers we tend to notice in the brain."

And that could cause something called COVID-19 Cognitive Impairment.

"And we are going to compare people with COVID cognitive impairment. To be clear on this, I think that COVID can cause cognitive impairment and maybe even dementia, but it doesn't cause Alzheimer's."

Anyone between the ages of 50 and 90, with a documented COVID-19 infection and long-term COVID-19 effects can participate in the study.

"We are asking people to commit though. And to be clear on this, the commitment involves brain scans, PET scans, spinal tap, memory tests, twice in the span of two years," he explained. "So people who we want to sign up are people who are really committed to helping us find the answer to this problem." 

Sabbagh says there are currently no treatment guidelines for the management of the long-term effects of neurological COVID-19, which is why this study is so significant.

Members of the public interested in participating in the study should call 602-406-4280 or email [email protected] .