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

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

figure 1

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 ).

figure 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%).

figure 3

A meta-analysis of the prevalence of fever

figure 4

A meta-analysis of the prevalence of cough

figure 5

A meta-analysis of the prevalence of dyspnea

figure 6

A meta-analysis of the prevalence of fatigue or myalgia

figure 7

A meta-analysis of the prevalence of headache

figure 8

A meta-analysis of the prevalence of gastrointestinal disorders

figure 9

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgments

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

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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

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Hebatullah Mohamed Abdulazeem

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Livia Puljak

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

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Yorkville University, Fredericton, New Brunswick, Canada

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

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  • 1 Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia. Electronic address: [email protected].
  • 2 Division of Infectious Diseases, AichiCancer Center Hospital, Chikusa-ku Nagoya, Japan. Electronic address: [email protected].
  • 3 Department of Family Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia. Electronic address: [email protected].
  • 4 Department of Pulmonology and Respiratory Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia. Electronic address: [email protected].
  • 5 School of Medicine, The University of Western Australia, Perth, Australia. Electronic address: [email protected].
  • 6 Siem Reap Provincial Health Department, Ministry of Health, Siem Reap, Cambodia. Electronic address: [email protected].
  • 7 Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Denpasar, Indonesia; Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA. Electronic address: [email protected].
  • 8 Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Department of Clinical Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia. Electronic address: [email protected].
  • 9 Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, MI 48109, USA. Electronic address: [email protected].
  • 10 Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia; Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia. Electronic address: [email protected].
  • PMID: 32340833
  • PMCID: PMC7142680
  • DOI: 10.1016/j.jiph.2020.03.019

In early December 2019, an outbreak of coronavirus disease 2019 (COVID-19), caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in Wuhan City, Hubei Province, China. On January 30, 2020 the World Health Organization declared the outbreak as a Public Health Emergency of International Concern. As of February 14, 2020, 49,053 laboratory-confirmed and 1,381 deaths have been reported globally. Perceived risk of acquiring disease has led many governments to institute a variety of control measures. We conducted a literature review of publicly available information to summarize knowledge about the pathogen and the current epidemic. In this literature review, the causative agent, pathogenesis and immune responses, epidemiology, diagnosis, treatment and management of the disease, control and preventions strategies are all reviewed.

Keywords: 2019-nCoV; COVID-19; Novel coronavirus; Outbreak; SARS-CoV-2.

Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

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  • Betacoronavirus
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  • Disease Outbreaks* / prevention & control
  • Pneumonia, Viral* / epidemiology
  • Pneumonia, Viral* / immunology
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  • Pneumonia, Viral* / virology
  • Introduction
  • Conclusions
  • Article Information

eTable 1. Characteristics of Preventive Medicine Trial Cohort Participants and Reported COVID-19 Cases to Date

eTable 2. Adjusted Odds of COVID-19 by Level of Physical Activity Before the COVID-19 Pandemic, Restricting Follow-Up Through December 2020

eTable 3. Adjusted Odds of COVID-19 Hospitalization by Level of Physical Activity Before the COVID-19 Pandemic, Restricting Follow-Up Through December 2020

eTable 4. Adjusted Odds of COVID-19 by Level of Physical Activity Before the COVID-19 Pandemic, With Additional Adjustment for SARS-CoV-2 Vaccination Status

eTable 5. Adjusted Odds of COVID-19 Hospitalization by Level of Physical Activity Before the COVID-19 Pandemic, With Additional Adjustment for SARS-CoV-2 Vaccination Status

eTable 6. Adjusted Odds of COVID-19 by Level of Physical Activity Before the COVID-19 Pandemic, Combining Consistently Inactive and Insufficiently Active Participants in 1 Group vs Sufficiently Active

eTable 7. Adjusted Odds of COVID-19 Hospitalization by Level of Physical Activity Before the COVID-19 Pandemic, Combining Consistently Inactive and Insufficiently Active Participants in 1 Group vs Sufficiently Active

eFigure. Data Collection and Completeness of COVID-19 Outcomes

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Muñoz-Vergara D , Wayne PM , Kim E, et al. Prepandemic Physical Activity and Risk of COVID-19 Diagnosis and Hospitalization in Older Adults. JAMA Netw Open. 2024;7(2):e2355808. doi:10.1001/jamanetworkopen.2023.55808

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Prepandemic Physical Activity and Risk of COVID-19 Diagnosis and Hospitalization in Older Adults

  • 1 Osher Center for Integrative Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2 Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

Question   Are higher prepandemic physical activity (PA) levels associated with lower risk of developing or being hospitalized for COVID-19?

Findings   In this cohort study of 61 557 women and men aged 45 years or older who reported 5890 incident cases of COVID-19 and 626 hospitalizations, those who achieved at least 7.5 metabolic equivalent hours per week of PA before the pandemic had significantly reduced odds of COVID-19 diagnosis and hospitalization compared with the inactive group.

Meaning   Higher prepandemic PA levels were associated with lower odds of developing and being hospitalized for COVID-19.

Importance   Higher prepandemic physical activity (PA) levels have been associated with lower risk and severity of COVID-19.

Objective   To investigate the association between self-reported prepandemic PA levels and the risk and severity of COVID-19 in older US adults.

Design, Setting, and Participants   This cohort study combined cohorts from 3 ongoing prospective randomized clinical trials of US adults aged 45 years or older who provided prepandemic self-reports of baseline leisure-time PA and risk factors for COVID-19 outcomes using the most recent questionnaire completed as of December 31, 2019, as the baseline PA assessment. In multiple surveys from May 2020 through May 2022, participants indicated whether they had at least 1 positive COVID-19 test result or were diagnosed with or hospitalized for COVID-19.

Exposure   Prepandemic PA, categorized into 3 groups by metabolic equivalent hours per week: inactive (0-3.5), insufficiently active (>3.5 to <7.5), and sufficiently active (≥7.5).

Main Outcome and Measures   Primary outcomes were risk of COVID-19 and hospitalization for COVID-19. Multivariable logistic regression was used to estimate odd ratios (ORs) and 95% CIs for the association of COVID-19 diagnosis and/or hospitalization with each of the 2 upper PA categories vs the lowest PA category.

Results   The pooled cohort included 61 557 participants (mean [SD] age, 75.7 [6.4] years; 70.7% female), 20.2% of whom were inactive; 11.4%, insufficiently active; and 68.5%, sufficiently active. A total of 5890 confirmed incident cases of COVID-19 were reported through May 2022, including 626 hospitalizations. After controlling for demographics, body mass index, lifestyle factors, comorbidities, and medications used, compared with inactive individuals, those insufficiently active had no significant reduction in infection (OR, 0.96; 95% CI, 0.86-1.06) or hospitalization (OR, 0.98; 95% CI, 0.76-1.28), whereas those sufficiently active had a significant reduction in infection (OR, 0.90; 95% CI, 0.84-0.97) and hospitalization (OR, 0.73; 95% CI, 0.60-0.90). In subgroup analyses, the association between PA and SARS-CoV-2 infection differed by sex, with only sufficiently active women having decreased odds (OR, 0.87; 95% CI, 0.79-0.95; P  = .04 for interaction).

Conclusions and Relevance   In this cohort study of adults aged 45 years or older, those who adhered to PA guidelines before the pandemic had lower odds of developing or being hospitalized for COVID-19. Thus, higher prepandemic PA levels may be associated with reduced odds of SARS-CoV-2 infection and hospitalization for COVID-19.

Research supports physical activity (PA) for health and reductions in major morbidity and mortality. 1 , 2 Adherence to US guidelines of at least 150 min/wk of moderate to vigorous PA may help prevent or mitigate effects of cardiovascular disease (CVD), cancer, type 2 diabetes, and other chronic conditions. 3 - 6 Some health benefits of PA are attributable to the delay of age-related immunosenescence, reduced low-grade systemic inflammation, and boosted immunity. 7 - 10 However, significant gaps exist in the evidence that PA protects against infectious diseases.

The COVID-19 pandemic provides a unique opportunity to address the association of PA with infection. 8 , 11 - 14 A recent study found that meeting PA guidelines before COVID-19 diagnosis was associated with fewer severe outcomes, including hospitalization, admission to intensive care, and death. 15 Other studies have assessed potential for PA and other healthy lifestyle factors, such as healthy body weight, limited alcohol intake, or high-quality diet, to synergically boost the immune system to prevent or ameliorate the severity of COVID-19. 16 - 18 However, the generalizability of these findings to older adults is limited in studies published to date.

This study pooled data from 3 large, ongoing prospective trial cohorts of older adults who self-reported PA levels before the COVID-19 pandemic and were prospectively followed up for SARS-CoV-2 infection and hospitalization through 2021. We hypothesized that higher levels of prepandemic PA would be associated with reduced risk of SARS-CoV-2 infection and COVID-19 hospitalization.

This prospective cohort study combined participants from 3 large-scale randomized clinical trials (RCTs) directed by our research group: the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a double-blind, placebo-controlled, factorial RCT of a cocoa extract and multivitamin supplement in the prevention of CVD and cancer among 21 442 women aged 65 years or older and men aged 60 or older 19 , 20 ; the Vitamin D and Omega-3 Trial (VITAL), a double-blind, placebo-controlled, factorial RCT of fatty acid supplements in the prevention of CVD and cancer among 25 871 women aged 55 or older and men aged 50 or older 21 ; and the Women’s Health Study (WHS), a double-blind, placebo-controlled, factorial RCT of low-dose aspirin and vitamin E in the primary prevention of CVD and cancer among 39 876 US female health professionals aged 45 or older. 22 - 24 The institutional review board at Mass General Brigham approved all study-related activities. Written informed consent was obtained from participants in all 3 trials. We followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. 25

In May, June, and August 2020, we sent 3 separate online REDCap surveys asking about COVID-19 symptoms, testing, diagnoses, treatments, severity of illness, and risk factors to COSMOS, VITAL, and WHS participants who provided email addresses and were willing to be contacted by email to complete surveys online (eFigure in Supplement 1 ). Those who responded to at least 1 survey or study follow-up questionnaire and had PA measurements were included. In addition, we repeated questions on COVID-19 testing, diagnoses, and hospitalization from the previous year on regular annual follow-up questionnaires for each cohort in 2021 and 2022.

To assess prepandemic self-reported PA (as validated in previous studies 3 , 19 , 22 ) and other relevant risk factors, we leveraged long-term prospective questionnaire data in COSMOS, VITAL, and WHS and used the most recent annual questionnaire on or before December 31, 2019 (median year of completion, 2017; range, 2003-2019), as the baseline for the PA assessment. We asked 2 questions about typical PA habits over the past year: (1) “During the past year, what was your approximate average time (in minutes) per week spent at each of the following recreational activities (eg, walking, jogging, running, aerobic exercise, etc)?” and (2) “On average, how many flights of stairs (1 flight is typically 10 steps) do you climb daily?” Participant responses were converted into total reported PA as metabolic equivalent [MET] hours per week by assigning MET values to different activities and estimating total energy expenditure based on reported duration and frequency of those activities for a given week. 3 - 6 Based on US and World Health Organization (WHO) PA guidelines, 4 , 6 we created 3 PA categories, in MET-h/wk, for our analyses: inactive (0-3.5), insufficiently active (>3.5 to <7.5), and sufficiently active (≥7.5). Our determination for being at least sufficiently active was based on the lower bounds for recommended moderate to vigorous PA (≥3 METs for 150 minutes per week), resulting in 450 MET-min/wk, or 7.5 MET-h/wk. 6

Other self-reported covariates included those collected at the most recent annual questionnaire closest to December 31, 2019, before the start of the COVID-19 pandemic. Demographic variables included sex; age; and race and ethnicity (African American or Black; Asian or Native American; Hispanic or Latinx; non-Hispanic White; and other [ie, different from the 4 other categories], unknown, or not reported), ascertained by self-report and included to explore racial and ethnic differences in subgroup analyses. We also examined educational attainment (no high school, high school, some college, college graduate, and postcollege) and income (<$30 000, $30 000 to <$50 000, $50 000 to <$100 000, and ≥$100 000). 19 , 21 , 22 Lifestyle factors included smoking status (never, past, and current) and alcohol consumption (rarely or never, monthly, weekly, and daily). Body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) was based on self-reported height and weight. We also considered several comorbidities and medications used at the end of 2019. Comorbidities were adjudicated by a committee of physicians and investigators according to standardized procedures (cancer, myocardial infarction, and stroke) 26 or based on self-reports of medications and/or diagnoses (history of diabetes, hypertension, or statin use). Current medications used included nonsteroidal anti-inflammatory drugs and aspirin.

Based on 3 REDCap surveys in 2020 and annual follow-up questionnaires, we classified participants as having had COVID-19 if they reported a test positive for SARS-CoV-2 or its antibodies, were told by a health care professional that they were probably or definitely diagnosed with COVID-19, or reported being hospitalized for COVID-19 on any of the questionnaires. Participants also provided the month and year of a positive test result, diagnosis, and/or hospitalization for COVID-19. We used the date of questionnaire return for missing dates. We separately defined severity of COVID-19 based on whether individuals reported COVID-19 hospitalization. We used information on all reported diagnoses, test results, and hospitalizations for COVID-19 through May 10, 2022.

Our primary outcomes were risk of SARS-CoV-2 infection and hospitalization due to COVID-19. We compared demographics, lifestyle factors, comorbidities, and medications among the 3 PA groups using analysis of variance tests for continuous variables and χ 2 tests for categorical variables. Multivariable logistic regression models estimated the odd ratios (ORs) and 95% CIs for the association of each of the 2 upper PA categories (vs the lowest PA category) with SARS-CoV-2 infection and hospitalization for COVID-19 (model 1 adjusted for demographic characteristics, model 2 added lifestyle factors, and model 3 added comorbidities and medications). We also considered a priori subgroup analyses by sex, BMI, race and ethnicity, and income 27 and post hoc analyses by history of CVD and cancer. We evaluated these potential multiplicative modifications of associations using the Wald test for homogeneity. Two-sided P  < .05 was considered significant.

We conducted 3 sensitivity analyses to evaluate the stability and reliability of our results. First, we restricted analyses through December 31, 2020, before SARS-CoV-2 vaccines became widely available in the US. Second, we conducted analyses adding SARS-CoV-2 vaccination status, initially collected on annual questionnaires to all participants starting January 2021. Third, we combined the consistently inactive and insufficiently active groups vs the sufficiently active group. Analyses were performed using SAS, version 9.4 (SAS Institute Inc).

A total of 69 604 adults aged 45 years or older were invited to participate, of whom 61 557 (88.4%) responded and comprised the cohort for our analyses. eTable 1 in Supplement 1 provides the number of individuals who reported positive test results and/or hospitalizations per study, along with other demographic characteristics. As of December 31, 2019, the cohort had a mean (SD) age of 75.7 (6.4) years; 70.7% were female, and 29.3% were male ( Table 1 ). For PA, 20.2% of participants reported being inactive; 11.4%, insufficiently active; and 68.5%, sufficiently active. A total of 7.5% of participants were African American or Black; 2.1%, Asian or Native American; 2.3%, Hispanic or Latinx; 87.2%, non-Hispanic White; and 0.9%, other, unknown, or unreported race and ethnicity. Also, 24.1% of the cohort reported a BMI of 30 or greater. Participants with higher educational and income levels and those who never smoked were more likely to report sufficient PA. During follow-up, there were 5890 incident cases of COVID-19 and 626 of hospitalization due to COVID-19 (eFigure in Supplement 1 ).

In all models, sufficiently active participants had significantly lower odds of SARS-CoV-2 infection (eg, model 3: OR, 0.90; 95% CI, 0.84-0.97; P  = .01) compared with those who were inactive ( Table 2 ). In the insufficiently active group, PA was not associated with odds of SARS-CoV-2 infection compared with the inactive group in any model (eg, model 3: OR, 0.96; 95% CI, 0.86-1.06; P  = .89). Participants who were sufficiently active had consistently lower odds of hospitalization due to COVID-19 (eg, model 3: OR, 0.73; 95% CI, 0.60-0.90; P  = .001) compared with those who were inactive ( Table 3 ). In the insufficiently active group, there was no association of PA with odds of COVID-19 hospitalization (eg, model 3: OR, 0.98; 95% CI, 0.76-1.28; P  = .25).

In subgroup analyses, the association between PA and COVID-19 differed by sex. Women who were sufficiently active had decreased odds of SARS-CoV-2 infection compared with inactive women (OR, 0.87; 95% CI, 0.79-0.95; P  = .04 for interaction) ( Table 4 ). There was no association in men. No evidence of association modification was observed for BMI, race and ethnicity, income, and CVD or cancer. In sensitivity analyses restricting results to follow-up through December 2020 (before widespread vaccination programs), the number of cases was reduced by 53.5% (2739 cases). There was no association between sufficient PA and SARS-CoV-2 infection in any model (eg, model 3: OR, 0.98; 95% CI, 0.88-1.09; P  = .58). The lack of an association persisted for the insufficiently active group (eg, model 3: OR, 1.01; 95% CI, 0.88-1.17; P  = .72). However, the odds of COVID-19 hospitalization through December 2020 were significantly lower for the sufficiently active than for the inactive group (eg, model 3: OR, 0.64; 95% CI, 0.49-0.83; P  = .003) (eTables 2 and 3 in Supplement 1 ).

We also conducted a sensitivity analysis adjusting for potential confounding by SARS-CoV-2 vaccination status in model 3. The ORs for infection and hospitalization did not substantially change for the sufficiently active group (eg, infection: OR, 0.89; 95% CI, 0.82-0.96; P  = .007; hospitalization: OR, 0.74; 95% CI, 0.60-0.92; P  = .005) (eTables 4 and 5 in Supplement 1 ). SARS-CoV-2 vaccination was associated with substantially decreased odds of infection (OR, 0.55; 95% CI, 0.50-0.61; P  < .001) and hospitalization (OR, 0.37; 95% CI, 0.30-0.47; P  < .001) for all PA levels assessed before the COVID-19 pandemic. Our third sensitivity analysis combined the consistently inactive and insufficiently active groups to assess whether sufficient PA was still associated with lower odds of SARS-CoV-2 infection and COVID-19 hospitalization in model 3. The decreased ORs for infection and hospitalization did not substantially change for the sufficiently active group (eg, infection: OR, 0.92; 95% CI, 0.86-0.98, P  = .01; hospitalization: OR, 0.74; 95% CI, 0.62-0.89; P  = .001) (eTables 6 and 7 in Supplement 1 ).

In this cohort study, sufficiently active participants had significantly reduced odds of SARS-CoV-2 infection and of hospitalization due to COVID-19 compared with those who were inactive. This difference was not observed between the insufficiently active and inactive groups. Results were robust across models adjusting for multiple covariates. These findings parallel a previously reported association between high PA levels and reduced odds of infection and mortality due to viral and bacterial pneumonia. 28 Other studies have reported potential inverse associations between PA levels and risk and/or severity of COVID-19; their results included a wider age range in adult populations. 15 - 18 , 29 Our findings extend the understanding of the association between PA and vulnerability to infections, specifically with highly infectious respiratory viruses, among older adults. 10

We found reduced odds of infection across all 3 models when comparing the sufficiently active vs inactive groups. There was no apparent benefit of PA in the insufficiently active group. This suggests that the association between PA and COVID-19 may depend on the amount, intensity, and/or type of PA. 11 , 15 Cho et al 30 found equivalent ORs for COVID-19 among individuals engaging in both moderate (10 MET-h/wk) and vigorous (17.5 MET-h/wk) PA. Ahmadi et al 31 reported inverse associations between PA and COVID-19 for both insufficiently (<10 MET-h/wk) and sufficiently (≥10 MET-h/wk) active individuals. Rowlands et al 32 also described higher odds of nonsevere COVID-19 when adjusting for PA intensity (accelerometer-assessed) and self-reported PA levels (moderate to vigorous PA [MVPA]: 7.5-15 MET-h/wk). Lee et al 33 reported a consistent inverse association of PA with risk of COVID-19 among individuals practicing both aerobic and muscle strengthening exercises but not either alone and among those fulfilling the recommended range of 8.3 to 17 MET-h/wk. Regardless of differences in study designs, population characteristics, and PA or risk of SARS-CoV-2 infection and severity assessments, these studies are consistent with our findings regarding the inverse association between PA levels and risk of SARS-CoV-2 infection and COVID-19 severity. Also, our findings parallel the conclusions from 2 systematic reviews and meta-analyses characterizing the association between PA and risk of infection with other community-acquired respiratory infectious viruses, such as influenza and current variants of SARS-CoV-2. 10 , 13

For the association between PA and hospitalization due to COVID-19, our results align with those reported by English and Scottish health surveys, which also found an inverse association between MVPA (≥150-minute/wk) and COVID-19 mortality among 97 844 participants who, on average, were 56 years of age. 34 A study of comparatively younger adults also found an association between PA and hospitalization due to COVID-19 among those consistently meeting PA guidelines, even after multivariable adjustment. 15 A study characterizing associations between accelerometer-assessed PA and severe COVID-19 cases (ie, hospitalization or death) found lower odds of severe cases when adjusting for intensity and MVPA (7.5-15 MET-h/wk). 32 Other studies reported similar patterns. 18 , 30 , 33 , 35 Therefore, PA may prevent more severe cases of COVID-19 among those at greater risk of major morbidity and mortality, potentially explaining the lower odds of COVID-19 hospitalization among those meeting PA guidelines. 31

Our subgroup analyses suggest that the inverse association between PA and COVID-19 outcomes may be greater among women, potentially due to differences in respiratory system physiology. 36 As other studies indicated that older age, male sex, ethnicity status, low socioeconomic status, and having multiple morbidities were associated with higher risk of COVID-19 and more severe cases, 31 - 33 , 37 - 40 future studies should clarify whether the role of PA extends to both short- and long-term COVID-19–related outcomes in these groups.

When we restricted our follow-up through December 2020 to examine risk of infection before the introduction of COVID-19 vaccines, the inverse associations of prepandemic PA with COVID-19 were absent, possibly suggesting residual confounding; for example, behavioral and psychosocial factors may have modified the association between PA and risk of SARS-CoV-2 infection. 41 When we added vaccination status to model 3, the inverse association between meeting PA guidelines and COVID-19 was sustained. A previous study reported similar findings in a younger population. 16 Moreover, in agreement with previous studies, 29 , 42 , 43 the association of the COVID-19 vaccine with reduced risk of infection and hospitalization were evident regardless of PA status. Likewise, when we compared the combined inactive and insufficiently active groups with the sufficiently active group, the inverse associations remained. Previous studies also indicated the relevance of PA parameters in meeting PA guidelines (eg, ≥7.5 MET-h/wk). 4 , 32

Increased PA may protect against COVID-19 and other infectious diseases through various mechanisms. It enhances immune surveillance mechanisms by increasing the activity of natural killer cells and neutrophils and the number of circulating monocytes and lymphocytes and by modulating inflammatory processes through different mediators, such as cytokines, myokines, immunoglobulins (Igs), cortisol, and oxylipins. 7 - 9 , 31 , 33 Moreover, the increment of blood flow during PA biomechanically augments the lamina shear stress over endothelial cells, which triggers the production and bioavailability of nitric oxide, counteracting the oxidative and proinflammatory effect of SARS-CoV-2 infection. 44 , 45 Physical activity also improves neurocognitive functioning and well-being, slows neurodegeneration, and optimizes stress response. 46 In the myofascial system, the immunological and neurological pathways interplay by promoting muscle-derived anti-inflammatory interleukin 6 (ie, myokine production), long-term reduction of proinflammatory mediators, and release of endocannabinoids. 46 - 48 Physical activity increases levels of salivary IgA, an antibody known to protect against respiratory viruses. 10 , 49 , 50 Still, the exact mechanisms by which PA and more specific components of PA (eg, frequency, duration, intensity, and type) affect these physiological pathways warrant further investigation. 8 , 11 , 12 , 14

This study has strengths. The prospective design allowed us to define PA using validated questionnaires before the COVID-19 pandemic for the subsequent risk of COVID-19 and hospitalization due to COVID-19 as collected during the pandemic via multiple longitudinal surveys. Furthermore, we adjusted for a range of demographic, lifestyle, and clinical factors defined just before the COVID-19 pandemic.

Several limitations should be considered. First, the comparatively higher prevalence of sufficiently active participants in the combined cohort may reflect inherent volunteer bias for initially healthier individuals originally recruited and randomized into long-term clinical trials with continued follow-up. 19 , 22 , 51 Second, because PA levels were self-reported, information inaccuracies (eg, random misclassification) could have penalized the insufficiently active group. 2 Third, we likely underestimated COVID-19 cases due to missed asymptomatic cases without available serologic data and to underreporting typically seen in prospective studies. Longer follow-up for COVID-19 outcomes would have increased case counts, but the wider-spread integration of vaccines would have made it more difficult to isolate the role of PA. Furthermore, we did not account for changes in PA before and during the pandemic. Fourth, our definition of COVID-19 severity relied on hospitalization alone; however, some individuals with moderate or severe cases may not have been hospitalized. Fifth, we could not rule out the possibility of unmeasured confounders associated with high PA, including wearing masks, social distancing, and other protective behaviors, 52 - 54 despite extensive control for known confounders. 55 Sixth, although some participants were enrolled in more than 1 of the included studies, our main findings for risk of COVID-19 and hospitalization were unchanged in sensitivity analyses limited to those in 1 study only. Seventh, the cohort corresponded to a subset of participants from 3 parent RCTs and was largely a non-Hispanic White population (ie, sampling bias) recruited for specific purposes (eg, the WHS recruited only females); the generalizability of our findings to groups with different genders, ages, races and ethnicities, and comorbidities (ie, healthy volunteer bias) warrants further study. 56

In this cohort study of adults aged 45 years or older, meeting PA guidelines was associated with significantly lower odds of developing and being hospitalized for COVID-19. Future studies including quantitative control of PA parameters, broader racial and ethnic diversity, and information from other potential confounders (eg, sleep quality, dietary patterns, access to health care, and preventive behaviors) are warranted.

Accepted for Publication: December 19, 2023.

Published: February 13, 2024. doi:10.1001/jamanetworkopen.2023.55808

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Muñoz-Vergara D et al. JAMA Network Open .

Corresponding Author: Dennis Muñoz-Vergara, DVM, MPH, Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Commonwealth Ave East, Boston, MA 02215 ( [email protected] ).

Author Contributions: Drs Kim and Sesso 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. Drs Muñoz-Vergara and Wayne contributed equally to this work.

Concept and design: Wayne, Manson, Sesso.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Muñoz-Vergara, Wayne, Sesso.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Muñoz-Vergara, Kim.

Obtained funding: Wayne, Lee, Sesso.

Administrative, technical, or material support: Muñoz-Vergara, Lee, Manson, Sesso.

Supervision: Wayne, Manson, Sesso.

Conflict of Interest Disclosures: Dr Lee reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Buring reported receiving grants from the NIH during the conduct of the study. Dr Manson reported receiving grants from the NIH during the conduct of the study and from Mars Edge outside the submitted work. Dr Sesso reported receiving grants from the NIH during the conduct of the study and from Mars Edge outside the submitted work. No other disclosures were reported.

Funding/Support: Brigham and Women’s Hospital provided internal investigator-initiated funding support for COVID-19 surveys and follow-up (Dr Sesso). The Women’s Health Study (WHS) is supported by grants CA047988, UM1 CA182913, HL043851, HL080467, and HL099355 from the NIH. The Vitamin D and Omega-3 Trial (VITAL) is supported by grants U01 CA138962, R01 CA138962, and R01 AT011729 from the NIH. Pharmavite LLC (vitamin D 3 ) and Pronova BioPharma/BASF (omega-3 fatty acids) donated the study agents, matching placebos, and packaging. Quest Diagnostics performed the serum 25-hydroxyvitamin D and plasma phospholipid omega-3 measurements at no additional cost. The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, Incorporated, dedicated to nutrition research and products, which included infrastructure support and the donation of study pills and packaging. Pfizer Consumer Healthcare (now part of GSK Consumer Healthcare) provided support through the partial provision of study pills and packaging. COSMOS is also supported in part by grants AG050657, AG071611, EY025623, and HL157665 from the NIH and contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005 from the NIH through the Women’s Health Initiative. This study was supported by grant K24AT009282 from the National Center for Complementary and Integrated Health, NIH (Dr Wayne).

Role of the Funder/Sponsor: The funders had no role in 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.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We thank the COSMOS, VITAL, and WHS study participants and research staff for their tremendous dedication and commitment.

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Long Covid ‘brain fog’ may be due to leaky blood-brain barrier, study finds

If barrier controlling substances entering and exiting brain is off balance, it can drive changes in neural function

From forgetfulness to difficulties concentrating, many people who have long Covid experience “brain fog”. Now researchers say the symptom could be down to the blood-brain barrier becoming leaky.

The barrier controls which substances or materials enter and exit the brain. “It’s all about regulating a balance of material in blood compared to brain,” said Prof Matthew Campbell, co-author of the research at Trinity College Dublin.

“If that is off balance then it can drive changes in neural function and if this happens in brain regions that allow for memory consolidation/storage then it can wreak havoc.”

Writing in the journal Nature Neuroscience , Campbell and colleagues report how they analysed serum and plasma samples from 76 patients who were hospitalised with Covid in March or April 2020, as well 25 people before the pandemic.

Among other findings, the team discovered that samples from the 14 Covid patients who self-reported brain fog contained higher levels of a protein called S100β than those from Covid patients without this symptom, or people who had not had Covid.

This protein is produced by cells within the brain, and is not normally found in the blood, suggesting these patients had a breakdown of the blood-brain barrier.

The researchers then recruited 10 people who had recovered from Covid and 22 people with long Covid – 11 of whom reported having brain fog. None had, at that point, received a Covid vaccine, or been hospitalised for Covid.

These participants underwent an MRI scan in which a dye was administered intravenously.

The results reveal long Covid patients with brain fog did indeed show signs of a leaky blood-brain barrier, but not those without this symptom, or who had recovered.

Campbell added that it was possible people with a tighter blood-brain barrier might be better protected from brain fog should they develop long Covid, explaining why the symptom did not arise in all patients.

Further work in a subgroup of participants revealed long Covid patients with brain fog also showed signs of increased levels of proteins involved in clotting.

Campbell said the results were not a surprise as disruptions to proteins involved in clotting could go hand in hand with disruption to cells that lined blood vessels. “The whole concept that a lot of these neurological conditions, including brain fog, could be treated by simply regulating the integrity of the blood-brain barrier is really exciting,” he said.

While the study focuses on long Covid patients, Campbell said the results might have relevance to people with brain fog relating to other conditions – such as ME – although extensive work would be needed to confirm that.

Prof Paul Harrison from the University of Oxford, an author of earlier work suggesting blood clots in the brain may be one cause of brain fog in people with long Covid, said the new study was important.

“It shows that abnormalities in the lining of blood vessels in the brain occur in people with post-Covid brain fog, and adds to the evidence that abnormal blood clotting also contributes,” he said.

But he added that the results came from patients who had Covid in the first wave, meaning it was plausible but unclear whether the same mechanisms occurred in others, such as those with later variants of the virus, or who were vaccinated.

Harrison said: “Likely, a range of processes explain brain fog and other features of post-Covid syndrome.”

Prof Claire Steves of King’s College London said the small number of participants involved meant it was possible that findings of differences between groups were due to chance, while brain fog was not clearly defined and was self-reported by participants.

“Therefore it is difficult to be sure how applicable these results are to the millions of people who have experienced this phenomenon,” she said.

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Pfizer, left, and Moderna bivalent COVID-19 vaccines are readied for use at a clinic, Nov. 17, 2022, in Richmond, Va. (AP)

Pfizer, left, and Moderna bivalent COVID-19 vaccines are readied for use at a clinic, Nov. 17, 2022, in Richmond, Va. (AP)

Sara Swann

Experts say mRNA COVID-19 vaccines have saved millions of lives, not caused mass deaths

If your time is short.

The research paper was based on COVID-19 vaccine claims that are false and misleading, experts told us. 

The mRNA COVID-19 vaccines have been rigorously tested and monitored for years, and public health experts worldwide have found them to be safe and effective. Adverse effects are rare.

The World Health Organization estimated that in 2021 alone the COVID-19 vaccines saved more than 14.4 million lives globally.

  • No spin, just facts you can trust. Here’s how we do it.

In the more than three years since COVID-19 vaccines first became available, billions of doses have been administered worldwide, protecting against severe disease and death. Still, social media posts claim the vaccines are causing more harm than good.

A Feb. 4 Instagram post shared a headline from conservative news outlet The Epoch Times that said, "mRNA COVID-19 vaccines caused more deaths than saved: study."

Another Instagram post shared a related headline that said, "Scientists call for global moratorium on mRNA vaccines, immediate removal from childhood schedule." The headline was from the Children’s Health Defense, a legal advocacy organization known for spreading vaccine misinformation. (The organization was created by Robert F. Kennedy Jr., who earned PolitiFact’s 2023 Lie of the Year for his movement to legitimize conspiracy theories.)

These Instagram posts were flagged as part of Meta’s efforts to combat false news and misinformation on its News Feed. (Read more about our partnership with Meta , which owns Facebook and Instagram.)

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(Screengrab from Instagram)

The Epoch Times and Children’s Health Defense articles referred to a Jan. 24 research paper that said "for every life saved, there were nearly 14 times more deaths caused by" the mRNA COVID-19 vaccines. Two of the paper’s authors, Steve Kirsch and Peter McCullough , have often spread misinformation related to COVID-19 and the vaccine.

Experts on infectious diseases and vaccines told PolitiFact that the paper’s conclusion is based on misleading and false information about the mRNA COVID-19 vaccines. The paper repeats multiple claims that PolitiFact and other fact-checkers have debunked.

The paper "stands in contrast" to the global public health community’s consensus that the mRNA vaccines are safe and effective, said Dr. William Schaffner, a Vanderbilt University infectious diseases professor.

"And so, you have to ask why (the paper) is such an outlier," said Schaffner, who is also a spokesperson for the National Foundation for Infectious Diseases . "The reason it’s an outlier is … it’s a deeply flawed study."

The peer-reviewed research paper was published on Cureus, which Schaffner called "an obscure journal" that he’d never heard of in his 40 years of public health research. A 2022 Emory University study described Cureus as a "predatory" and "controversial" journal.

The paper claimed the Pfizer COVID-19 vaccine saved two lives and caused 27 deaths per 100,000 vaccinations. It said the Moderna vaccine saved 3.9 lives and caused 10.8 deaths per 100,000 vaccinations.

The paper’s authors based this conclusion on data from the Pfizer and Moderna COVID-19 vaccine clinical trials in the United States and reports of adverse effects from the United Kingdom. Although the datasets came from two different countries, the paper said, "it is unlikely that the adverse event rates would be different between the two populations."

The adverse effects reports came from the U.K.’s Yellow Card system , which lets members of the public report suspected safety concerns related to vaccines, medicines and medical devices.

This system is similar to the U.S. government’s Vaccine Adverse Event Reporting System , which the paper also cites to suggest the COVID-19 vaccines are unsafe.

With VAERS, anyone can report health effects after a vaccination, whether or not those effects are caused by the vaccine, the CDC said . And unlike other government data sources, these reports aren’t screened before they’re made public, making VAERS fertile ground for vaccine misinformation .

The paper claims the mRNA COVID-19 vaccines did not undergo adequate safety and efficacy testing.

This is inaccurate. We have rated multiple claims about this False or Pants on Fire, including  that mRNA technology was never tested in humans ; that the vaccines were released after only two months of testing in healthy humans; and that a safe vaccine can’t be developed in eight to 10 months.

Featured Fact-check

research paper covid

The Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines were thoroughly evaluated in clinical trials before receiving emergency use authorization from the U.S. Food and Drug Administration in December 2020. Since then, public health authorities have continued to closely monitor the vaccines’ safety.

"These vaccines have met rigorous scientific standards for safety and effectiveness. The available data continue to demonstrate that the benefits of these vaccines outweigh their risks," said Cherie Duvall-Jones, an FDA spokesperson.

Another claim in the paper is mRNA vaccines contain "DNA contamination." We previously fact-checked a similar claim and rated it False.

Decades of research has shown that the "biologically insignificant amounts of DNA" in the vaccines pose no known safety risk, said Dan Wilson, senior associate scientist at Janssen, which also developed a COVID-19 vaccine . Wilson also hosts "Debunk the Funk with Dr. Wilson," a YouTube show that covers science misinformation.

It’s not unusual for vaccines to contain DNA fragments. The measles, mumps, rubella, varicella and rotavirus vaccines also have minuscule amounts of DNA, said Dr. Paul Offit, director of the Vaccine Education Center and infectious diseases physician at Children’s Hospital of Philadelphia.

The chance that these DNA fragments could integrate into a person’s DNA is "zero," Offit said. "So, it’s just all a lot of hand-waving."

The paper also claims the spike proteins produced by COVID-19 vaccination linger in the body and cause adverse effects. PolitiFact has fact-checked several false claims that the spike proteins are harmful or toxic.

All coronaviruses, including COVID-19, have spikes known as spike proteins on their surfaces, which the viruses use to bind to cells and cause infection, the CDC said .

The mRNA vaccines contain neither the COVID-19 virus nor the spike protein. The vaccines’ mRNA technology gives the body genetic instructions for producing copies of the spike protein, which are harmless. Then, the body breaks down the mRNA and it leaves the body as waste.

The spike proteins trigger the body’s immune response, sparking antibody production. This helps the body recognize and fight off the real COVID-19 virus in future infections.

Schaffner said the spike protein claim is "far-fetched" because there’s no evidence the spike protein produced from the vaccines has caused adverse effects.

Public health authorities in the U.S. and worldwide have repeatedly found COVID-19 vaccines to be safe and effective.

The World Health Organization reported that as of November, more than 13 billion doses of the COVID-19 vaccine had been administered worldwide. In the U.S. alone, more than 676 million doses of the vaccine had been administered as of May. 

In 2021, the first full year the vaccines were widely available, the WHO estimated that COVID-19 vaccinations saved more than 14.4 million lives worldwide.

In rare instances, adverse effects, including myocarditis, or inflammation of the heart muscle, have been linked to mRNA COVID-19 vaccines, the CDC said . Myocarditis cases were more common among adolescent and young men within a week of receiving a second dose of the COVID-19 vaccine. Most patients had mild cases and recovered quickly .

An Instagram post claimed a research paper shows that "mRNA COVID-19 vaccines caused more deaths" than lives saved.

Experts said the paper’s conclusion is based on false and misleading claims. These claims have been repeatedly fact-checked and rated False by PolitiFact and other news outlets.

The COVID-19 vaccines have been rigorously tested and monitored for years and public health authorities worldwide continue to find them safe and effective. Billions of doses have been administered worldwide. The vaccines have saved millions of lives, and adverse effects are rare.

We rate this claim Pants on Fire!

Our Sources

Instagram post ( archived ), Feb. 4, 2024

Instagram post ( archived ), Feb. 5, 2024

Interview with Dr. William Schaffner, an infectious diseases professor at Vanderbilt University and spokesperson for the National Foundation for Infectious Diseases, Feb. 7, 2024

Interview with Dr. Paul Offit, director of the Vaccine Education Center and physician in the Division of Infectious Diseases at the Children’s Hospital of Philadelphia, Feb. 7, 2024

Email interview with Dan Wilson, a senior associate scientist at Janssen and host of the YouTube show " Debunk the Funk with Dr. Wilson ," Feb. 7, 2024

Email interview with Cherie Duvall-Jones, spokesperson for the U.S. Food and Drug Administration, Feb. 7, 2024

The Epoch Times, " mRNA COVID-19 Vaccines Caused More Deaths Than Saved: Study ," Feb. 6, 2024

Children’s Health Defense, " Scientists Call for Global Moratorium on mRNA Vaccines, Immediate Removal From Childhood Schedule ," Jan. 29, 2024

Cureus, " COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign ," Jan. 24, 2024

The Centers for Disease Control and Prevention, " CDC COVID Data Tracker ," May 11, 2023

The Centers for Disease Control and Prevention, " End of the Federal COVID-19 Public Health Emergency (PHE) Declaration ," Sept. 12, 2023

The Centers for Disease Control and Prevention, " Clinical Considerations: Myocarditis after COVID-19 Vaccines ," Oct. 10, 2023

The Centers for Disease Control and Prevention, " Myocarditis and Pericarditis After mRNA COVID-19 Vaccination ," Nov. 3, 2023

The Centers for Disease Control and Prevention, " Reporting Adverse Events to VAERS | Vaccine Safety ," March 13, 2023

The Centers for Disease Control and Prevention, " How Protein Subunit COVID-19 Vaccines Work ," accessed Feb. 8, 2024 

Vaccine Adverse Event Reporting System website , accessed Feb. 8, 2024

The U.S. Food and Drug Administration, " Emergency Use Authorization for Vaccines Explained ," Nov. 20, 2020 

The U.S. Food and Drug Administration, " Janssen COVID-19 Vaccine ," June 2, 2023

The World Health Organization, " COVID-19 vaccines | WHO COVID-19 dashboard ," Nov. 26, 2023

The World Health Organization, " COVID-19 Vaccines Advice ," Dec. 5, 2023

U.K. Medicines and Healthcare products Regulatory Agency, " Yellow Card system ," accessed Feb. 8, 2024

Emory University, " Assessing Predatory Journal Publishing Within Health Sciences Authors ," August 2022

PolitiFact, " Robert F. Kennedy Jr.’s campaign of conspiracy theories: PolitiFact’s 2023 Lie of the Year ," Dec. 21, 2023

PolitiFact, " No, the COVID-19 vaccine is not the deadliest vaccine ever made ," Dec. 10, 2021

PolitiFact, " No evidence of COVID-19 vaccines causing deaths ," Sept. 20, 2021

PolitiFact, " Activist misuses federal data to make Pants on Fire claim that COVID-19 vaccines killed 676,000 ," Aug. 14, 2023

PolitiFact, " mRNA COVID-19 vaccines were tested in humans, have proven to be safe, effective ," June 25, 2021

PolitiFact, " COVID-19 vaccine testing included people with underlying health conditions ," Aug. 31, 2021

PolitiFact, " Yes, data shows COVID-19 vaccines are safe despite quick timeline ," March 26, 2021

PolitiFact, " Experts rebut claims that mRNA COVID-19 vaccines are ‘adulterated’ ," Oct. 27, 2023

PolitiFact, " Ditch the detox. The spike proteins produced from COVID-19 vaccination aren’t toxins. ," Aug. 2, 2023

PolitiFact, " Claim that children will be harmed by spike proteins from COVID-19 vaccines is false ," Jan. 7, 2022

PolitiFact, " Claim that spike proteins will cause illness to spread like wildfires in kids is False ," Nov. 2, 2021

PolitiFact, " No sign that the COVID-19 vaccines’ spike protein is toxic or ‘cytotoxic’ ," June 16, 2021

PolitiFact, " Snarky posts about Travis Kelce’s heart-hand gesture mislead about COVID-19 vaccine effects ," Jan. 29, 2024

NPR, " As the pandemic winds down, anti-vaccine activists are building a legal network ," May 4, 2023

Agence France-Presse, " US cardiologist makes sweeping false claims about effects of Covid-19 vaccinations ," Nov. 8, 2023

Read About Our Process

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ScienceAlert

Largest COVID Vaccine Study Ever Reveals The Actual Health Risks You Face

T he largest global vaccine safety study has linked COVID-19 vaccines with small increases in health conditions involving the brain, blood, and heart.

The international team of researchers emphasizes that the chances of getting any of these conditions are still very low. It's important to note that extensive research shows COVID-19 vaccines protect against serious illness, death, and long COVID symptoms.

Across just under 100 million COVID-19-vaccinated people in eight countries, potential links called safety signals were identified by comparing observed rates of 13 specific conditions following vaccination to what we'd expect to see based on prior rates, or 'background risk' of the conditions – the rates that these conditions are expected to occur in the absence of COVID-19 vaccines.

"The risk up to 42 days after vaccination was generally similar to the background risk for the majority of outcomes," the authors write in their published paper .

The authors say their multi-country analysis confirmed pre-established links between COVID-19 vaccinations and low risks of myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. But the enormous size of the study also meant there was a higher chance of them spotting rarer safety signals that prior studies may have missed.

Since the World Health Organization declared the COVID-19 pandemic on March 11, 2020 , nearly 7 million people have died from the disease, including more than 1 million in the US. Over 13.5 billion doses of COVID-19 vaccines have been given, with at least 70.6 percent of the world's population having received at least one dose.

Vaccine rollouts usually identify common and moderate side effects, after excluding dangerous ones during clinical trials . But even in huge clinical trials, extremely rare side effects can go undetected.

"This unparalleled scenario underscores the pressing need for comprehensive vaccine safety monitoring, as very rare adverse events associated with COVID-19 vaccines may only come to light after administration to millions of individuals," the authors write.

Their study sought safety signals observed within the 42 days after receiving viral-vector vaccines (such as AstraZeneca) or mRNA vaccines (such as Pfizer-BioNTech). Health datasets from before the COVID-19 vaccines were used to determine the rates of these conditions that were expected in the general population prior to vaccine rollout, and the observed rates were derived from the same dataset after vaccination.

In the wake of viral-vector vaccines, the team discovered a statistically significant rise in cases of Guillain-Barre syndrome ; a rare immune system disorder that affects nerves. Within the group that had these vaccines , 66 cases were expected, and 190 were observed. This increase was not seen after mRNA vaccines.

Following a first dose of the AstraZeneca vaccine, there was a 3.2 times greater-than-expected risk of cerebral venous sinus thrombosis (a type of blood clot in the brain) observed in 69 events, compared to an expected 21. The risks were 1.49 times higher after the Pfizer vaccine's first dose, and 1.25 times higher after second doses.

In March 2021 , some countries in Europe suspended the AstraZeneca COVID-19 vaccine after observed versus expected analysis identified thrombosis with thrombocytopenia syndrome as a safety signal.

The analysis found a higher risk of heart inflammation called myocarditis after mRNA vaccines, with observed rates highest after a second dose of Moderna's vaccine. These vaccines instruct cells to produce a protein that resembles the SARS-CoV-2 virus , giving the immune system a preview and prompting it to create antibodies to protect the body.

In rare cases, this immune response can result in heart muscle inflammation. Though COVID-19 vaccine-induced instances have mostly been mild, 28 deaths have occurred .

After a first dose of mRNA vaccines, the risk for pericarditis – inflammation of tissue surrounding the heart – was 1.7 times higher than expected, and it became 2.6 times higher after a fourth dose.

Potential safety signals were found for transverse myelitis (inflammation of part of the spinal cord) after viral-vector vaccines, and for acute disseminated encephalomyelitis (inflammation and swelling in the brain and spinal cord) after both types of vaccines.

Compared to an expected two cases, seven cases of acute disseminated encephalomyelitis were observed after mRNA vaccines.

"The size of the population in this study increased the possibility of identifying rare potential vaccine safety signals," says first author Kristýna Faksová, an epidemiologist at the Department of Epidemiology Research in Denmark.

"Single sites or regions are unlikely to have a large enough population to detect very rare signals."

Vaccines have saved countless lives by preventing the spread of the COVID-19 pandemic , and there is strong evidence that they are safe in the majority of cases and effective. A recent study found that if everyone in the UK was fully vaccinated, about 7,180 out of 40,393 severe outcomes (including deaths) from COVID-19 could have been avoided.

"We have a number of studies underway to build upon our understanding of vaccines and how we understand vaccine safety using big data," says Steven Black, an infectious disease scientist at the Global Vaccine Data Network (GVDN).

Anyone can view the methodology and complete results of this analysis on the GVDN's interactive data dashboards .

The study has been published in the journal Vaccine .

Generic vials of covid vaccine

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  • NATURE PODCAST
  • 17 December 2020

Coronapod: The big COVID research papers of 2020

  • Benjamin Thompson ,
  • Noah Baker &
  • Traci Watson

You can also search for this author in PubMed   Google Scholar

Benjamin Thompson, Noah Baker and Traci Watson discuss some of 2020's most significant coronavirus research papers.

In the final Coronapod of 2020, we dive into the scientific literature to reflect on the COVID-19 pandemic. Researchers have discovered so much about SARS-CoV-2 – information that has been vital for public health responses and the rapid development of effective vaccines. But we also look forward to 2021, and the critical questions that remain to be answered about the pandemic.

Papers discussed

A Novel Coronavirus from Patients with Pneumonia in China, 2019 - New England Journal of Medicine, 24 January

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China - The Lancet , 24 January

A pneumonia outbreak associated with a new coronavirus of probable bat origin - Nature , 3 February

A new coronavirus associated with human respiratory disease in China - Nature , 3 February

Temporal dynamics in viral shedding and transmissibility of COVID-19 - Nature Medicine , 15 April

Spread of SARS-CoV-2 in the Icelandic Population - New England Journal of Medicine , 11 June

High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice — Skagit County, Washington, March 2020 - Morbidity & Mortality Weekly Report , 15 August

Respiratory virus shedding in exhaled breath and efficacy of face masks - Nature Medicine , 3 April

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1 - New England Journal of Medicine , 13 April

Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period - Science , 22 May

Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe - Nature, 8 June

The effect of large-scale anti-contagion policies on the COVID-19 pandemic - Nature , 8 June

Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis - The Lancet, 20 June

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 - New England Journal of Medicine , 3 June

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 - JAMA , 2 September

Immunological memory to SARS-CoV-2 assessed for greater than six months after infection - bioRxiv, 16 November

Coronavirus Disease 2019 (COVID-19) Re-infection by a Phylogenetically Distinct Severe Acute Respiratory Syndrome Coronavirus 2 Strain Confirmed by Whole Genome Sequencing - Clinical Infectious Diseases , 25 August

Nature’s COVID research updates – summarising key coronavirus papers as they appear

Never miss an episode: Subscribe to the Nature Podcast on Apple Podcasts , Google Podcasts , Spotify or your favourite podcast app. Head here for the Nature Podcast RSS feed .

doi: https://doi.org/10.1038/d41586-020-03609-2

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Reproductive rights in America

Research at the heart of a federal case against the abortion pill has been retracted.

Selena Simmons-Duffin

Selena Simmons-Duffin

research paper covid

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy. Anna Moneymaker/Getty Images hide caption

The Supreme Court will hear the case against the abortion pill mifepristone on March 26. It's part of a two-drug regimen with misoprostol for abortions in the first 10 weeks of pregnancy.

A scientific paper that raised concerns about the safety of the abortion pill mifepristone was retracted by its publisher this week. The study was cited three times by a federal judge who ruled against mifepristone last spring. That case, which could limit access to mifepristone throughout the country, will soon be heard in the Supreme Court.

The now retracted study used Medicaid claims data to track E.R. visits by patients in the month after having an abortion. The study found a much higher rate of complications than similar studies that have examined abortion safety.

Sage, the publisher of the journal, retracted the study on Monday along with two other papers, explaining in a statement that "expert reviewers found that the studies demonstrate a lack of scientific rigor that invalidates or renders unreliable the authors' conclusions."

It also noted that most of the authors on the paper worked for the Charlotte Lozier Institute, the research arm of anti-abortion lobbying group Susan B. Anthony Pro-Life America, and that one of the original peer reviewers had also worked for the Lozier Institute.

The Sage journal, Health Services Research and Managerial Epidemiology , published all three research articles, which are still available online along with the retraction notice. In an email to NPR, a spokesperson for Sage wrote that the process leading to the retractions "was thorough, fair, and careful."

The lead author on the paper, James Studnicki, fiercely defends his work. "Sage is targeting us because we have been successful for a long period of time," he says on a video posted online this week . He asserts that the retraction has "nothing to do with real science and has everything to do with a political assassination of science."

He says that because the study's findings have been cited in legal cases like the one challenging the abortion pill, "we have become visible – people are quoting us. And for that reason, we are dangerous, and for that reason, they want to cancel our work," Studnicki says in the video.

In an email to NPR, a spokesperson for the Charlotte Lozier Institute said that they "will be taking appropriate legal action."

Role in abortion pill legal case

Anti-abortion rights groups, including a group of doctors, sued the federal Food and Drug Administration in 2022 over the approval of mifepristone, which is part of a two-drug regimen used in most medication abortions. The pill has been on the market for over 20 years, and is used in more than half abortions nationally. The FDA stands by its research that finds adverse events from mifepristone are extremely rare.

Judge Matthew Kacsmaryk, the district court judge who initially ruled on the case, pointed to the now-retracted study to support the idea that the anti-abortion rights physicians suing the FDA had the right to do so. "The associations' members have standing because they allege adverse events from chemical abortion drugs can overwhelm the medical system and place 'enormous pressure and stress' on doctors during emergencies and complications," he wrote in his decision, citing Studnicki. He ruled that mifepristone should be pulled from the market nationwide, although his decision never took effect.

research paper covid

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017. AP hide caption

Matthew Kacsmaryk at his confirmation hearing for the federal bench in 2017.

Kacsmaryk is a Trump appointee who was a vocal abortion opponent before becoming a federal judge.

"I don't think he would view the retraction as delegitimizing the research," says Mary Ziegler , a law professor and expert on the legal history of abortion at U.C. Davis. "There's been so much polarization about what the reality of abortion is on the right that I'm not sure how much a retraction would affect his reasoning."

Ziegler also doubts the retractions will alter much in the Supreme Court case, given its conservative majority. "We've already seen, when it comes to abortion, that the court has a propensity to look at the views of experts that support the results it wants," she says. The decision that overturned Roe v. Wade is an example, she says. "The majority [opinion] relied pretty much exclusively on scholars with some ties to pro-life activism and didn't really cite anybody else even or really even acknowledge that there was a majority scholarly position or even that there was meaningful disagreement on the subject."

In the mifepristone case, "there's a lot of supposition and speculation" in the argument about who has standing to sue, she explains. "There's a probability that people will take mifepristone and then there's a probability that they'll get complications and then there's a probability that they'll get treatment in the E.R. and then there's a probability that they'll encounter physicians with certain objections to mifepristone. So the question is, if this [retraction] knocks out one leg of the stool, does that somehow affect how the court is going to view standing? I imagine not."

It's impossible to know who will win the Supreme Court case, but Ziegler thinks that this retraction probably won't sway the outcome either way. "If the court is skeptical of standing because of all these aforementioned weaknesses, this is just more fuel to that fire," she says. "It's not as if this were an airtight case for standing and this was a potentially game-changing development."

Oral arguments for the case, Alliance for Hippocratic Medicine v. FDA , are scheduled for March 26 at the Supreme Court. A decision is expected by summer. Mifepristone remains available while the legal process continues.

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A Review of Coronavirus Disease-2019 (COVID-19)

Tanu singhal.

Department of Pediatrics and Infectious Disease, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India

There is a new public health crises threatening the world with the emergence and spread of 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus originated in bats and was transmitted to humans through yet unknown intermediary animals in Wuhan, Hubei province, China in December 2019. There have been around 96,000 reported cases of coronavirus disease 2019 (COVID-2019) and 3300 reported deaths to date (05/03/2020). The disease is transmitted by inhalation or contact with infected droplets and the incubation period ranges from 2 to 14 d. The symptoms are usually fever, cough, sore throat, breathlessness, fatigue, malaise among others. The disease is mild in most people; in some (usually the elderly and those with comorbidities), it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction. Many people are asymptomatic. The case fatality rate is estimated to range from 2 to 3%. Diagnosis is by demonstration of the virus in respiratory secretions by special molecular tests. Common laboratory findings include normal/ low white cell counts with elevated C-reactive protein (CRP). The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is essentially supportive; role of antiviral agents is yet to be established. Prevention entails home isolation of suspected cases and those with mild illnesses and strict infection control measures at hospitals that include contact and droplet precautions. The virus spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. The global impact of this new epidemic is yet uncertain.

Introduction

The 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) as it is now called, is rapidly spreading from its origin in Wuhan City of Hubei Province of China to the rest of the world [ 1 ]. Till 05/03/2020 around 96,000 cases of coronavirus disease 2019 (COVID-19) and 3300 deaths have been reported [ 2 ]. India has reported 29 cases till date. Fortunately so far, children have been infrequently affected with no deaths. But the future course of this virus is unknown. This article gives a bird’s eye view about this new virus. Since knowledge about this virus is rapidly evolving, readers are urged to update themselves regularly.

Coronaviruses are enveloped positive sense RNA viruses ranging from 60 nm to 140 nm in diameter with spike like projections on its surface giving it a crown like appearance under the electron microscope; hence the name coronavirus [ 3 ]. Four corona viruses namely HKU1, NL63, 229E and OC43 have been in circulation in humans, and generally cause mild respiratory disease.

There have been two events in the past two decades wherein crossover of animal betacorona viruses to humans has resulted in severe disease. The first such instance was in 2002–2003 when a new coronavirus of the β genera and with origin in bats crossed over to humans via the intermediary host of palm civet cats in the Guangdong province of China. This virus, designated as severe acute respiratory syndrome coronavirus affected 8422 people mostly in China and Hong Kong and caused 916 deaths (mortality rate 11%) before being contained [ 4 ]. Almost a decade later in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV), also of bat origin, emerged in Saudi Arabia with dromedary camels as the intermediate host and affected 2494 people and caused 858 deaths (fatality rate 34%) [ 5 ].

Origin and Spread of COVID-19 [ 1 , 2 , 6 ]

In December 2019, adults in Wuhan, capital city of Hubei province and a major transportation hub of China started presenting to local hospitals with severe pneumonia of unknown cause. Many of the initial cases had a common exposure to the Huanan wholesale seafood market that also traded live animals. The surveillance system (put into place after the SARS outbreak) was activated and respiratory samples of patients were sent to reference labs for etiologic investigations. On December 31st 2019, China notified the outbreak to the World Health Organization and on 1st January the Huanan sea food market was closed. On 7th January the virus was identified as a coronavirus that had >95% homology with the bat coronavirus and > 70% similarity with the SARS- CoV. Environmental samples from the Huanan sea food market also tested positive, signifying that the virus originated from there [ 7 ]. The number of cases started increasing exponentially, some of which did not have exposure to the live animal market, suggestive of the fact that human-to-human transmission was occurring [ 8 ]. The first fatal case was reported on 11th Jan 2020. The massive migration of Chinese during the Chinese New Year fuelled the epidemic. Cases in other provinces of China, other countries (Thailand, Japan and South Korea in quick succession) were reported in people who were returning from Wuhan. Transmission to healthcare workers caring for patients was described on 20th Jan, 2020. By 23rd January, the 11 million population of Wuhan was placed under lock down with restrictions of entry and exit from the region. Soon this lock down was extended to other cities of Hubei province. Cases of COVID-19 in countries outside China were reported in those with no history of travel to China suggesting that local human-to-human transmission was occurring in these countries [ 9 ]. Airports in different countries including India put in screening mechanisms to detect symptomatic people returning from China and placed them in isolation and testing them for COVID-19. Soon it was apparent that the infection could be transmitted from asymptomatic people and also before onset of symptoms. Therefore, countries including India who evacuated their citizens from Wuhan through special flights or had travellers returning from China, placed all people symptomatic or otherwise in isolation for 14 d and tested them for the virus.

Cases continued to increase exponentially and modelling studies reported an epidemic doubling time of 1.8 d [ 10 ]. In fact on the 12th of February, China changed its definition of confirmed cases to include patients with negative/ pending molecular tests but with clinical, radiologic and epidemiologic features of COVID-19 leading to an increase in cases by 15,000 in a single day [ 6 ]. As of 05/03/2020 96,000 cases worldwide (80,000 in China) and 87 other countries and 1 international conveyance (696, in the cruise ship Diamond Princess parked off the coast of Japan) have been reported [ 2 ]. It is important to note that while the number of new cases has reduced in China lately, they have increased exponentially in other countries including South Korea, Italy and Iran. Of those infected, 20% are in critical condition, 25% have recovered, and 3310 (3013 in China and 297 in other countries) have died [ 2 ]. India, which had reported only 3 cases till 2/3/2020, has also seen a sudden spurt in cases. By 5/3/2020, 29 cases had been reported; mostly in Delhi, Jaipur and Agra in Italian tourists and their contacts. One case was reported in an Indian who traveled back from Vienna and exposed a large number of school children in a birthday party at a city hotel. Many of the contacts of these cases have been quarantined.

These numbers are possibly an underestimate of the infected and dead due to limitations of surveillance and testing. Though the SARS-CoV-2 originated from bats, the intermediary animal through which it crossed over to humans is uncertain. Pangolins and snakes are the current suspects.

Epidemiology and Pathogenesis [ 10 , 11 ]

All ages are susceptible. Infection is transmitted through large droplets generated during coughing and sneezing by symptomatic patients but can also occur from asymptomatic people and before onset of symptoms [ 9 ]. Studies have shown higher viral loads in the nasal cavity as compared to the throat with no difference in viral burden between symptomatic and asymptomatic people [ 12 ]. Patients can be infectious for as long as the symptoms last and even on clinical recovery. Some people may act as super spreaders; a UK citizen who attended a conference in Singapore infected 11 other people while staying in a resort in the French Alps and upon return to the UK [ 6 ]. These infected droplets can spread 1–2 m and deposit on surfaces. The virus can remain viable on surfaces for days in favourable atmospheric conditions but are destroyed in less than a minute by common disinfectants like sodium hypochlorite, hydrogen peroxide etc. [ 13 ]. Infection is acquired either by inhalation of these droplets or touching surfaces contaminated by them and then touching the nose, mouth and eyes. The virus is also present in the stool and contamination of the water supply and subsequent transmission via aerosolization/feco oral route is also hypothesized [ 6 ]. As per current information, transplacental transmission from pregnant women to their fetus has not been described [ 14 ]. However, neonatal disease due to post natal transmission is described [ 14 ]. The incubation period varies from 2 to 14 d [median 5 d]. Studies have identified angiotensin receptor 2 (ACE 2 ) as the receptor through which the virus enters the respiratory mucosa [ 11 ].

The basic case reproduction rate (BCR) is estimated to range from 2 to 6.47 in various modelling studies [ 11 ]. In comparison, the BCR of SARS was 2 and 1.3 for pandemic flu H1N1 2009 [ 2 ].

Clinical Features [ 8 , 15 – 18 ]

The clinical features of COVID-19 are varied, ranging from asymptomatic state to acute respiratory distress syndrome and multi organ dysfunction. The common clinical features include fever (not in all), cough, sore throat, headache, fatigue, headache, myalgia and breathlessness. Conjunctivitis has also been described. Thus, they are indistinguishable from other respiratory infections. In a subset of patients, by the end of the first week the disease can progress to pneumonia, respiratory failure and death. This progression is associated with extreme rise in inflammatory cytokines including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα [ 15 ]. The median time from onset of symptoms to dyspnea was 5 d, hospitalization 7 d and acute respiratory distress syndrome (ARDS) 8 d. The need for intensive care admission was in 25–30% of affected patients in published series. Complications witnessed included acute lung injury, ARDS, shock and acute kidney injury. Recovery started in the 2nd or 3rd wk. The median duration of hospital stay in those who recovered was 10 d. Adverse outcomes and death are more common in the elderly and those with underlying co-morbidities (50–75% of fatal cases). Fatality rate in hospitalized adult patients ranged from 4 to 11%. The overall case fatality rate is estimated to range between 2 and 3% [ 2 ].

Interestingly, disease in patients outside Hubei province has been reported to be milder than those from Wuhan [ 17 ]. Similarly, the severity and case fatality rate in patients outside China has been reported to be milder [ 6 ]. This may either be due to selection bias wherein the cases reporting from Wuhan included only the severe cases or due to predisposition of the Asian population to the virus due to higher expression of ACE 2 receptors on the respiratory mucosa [ 11 ].

Disease in neonates, infants and children has been also reported to be significantly milder than their adult counterparts. In a series of 34 children admitted to a hospital in Shenzhen, China between January 19th and February 7th, there were 14 males and 20 females. The median age was 8 y 11 mo and in 28 children the infection was linked to a family member and 26 children had history of travel/residence to Hubei province in China. All the patients were either asymptomatic (9%) or had mild disease. No severe or critical cases were seen. The most common symptoms were fever (50%) and cough (38%). All patients recovered with symptomatic therapy and there were no deaths. One case of severe pneumonia and multiorgan dysfunction in a child has also been reported [ 19 ]. Similarly the neonatal cases that have been reported have been mild [ 20 ].

Diagnosis [ 21 ]

A suspect case is defined as one with fever, sore throat and cough who has history of travel to China or other areas of persistent local transmission or contact with patients with similar travel history or those with confirmed COVID-19 infection. However cases may be asymptomatic or even without fever. A confirmed case is a suspect case with a positive molecular test.

Specific diagnosis is by specific molecular tests on respiratory samples (throat swab/ nasopharyngeal swab/ sputum/ endotracheal aspirates and bronchoalveolar lavage). Virus may also be detected in the stool and in severe cases, the blood. It must be remembered that the multiplex PCR panels currently available do not include the COVID-19. Commercial tests are also not available at present. In a suspect case in India, the appropriate sample has to be sent to designated reference labs in India or the National Institute of Virology in Pune. As the epidemic progresses, commercial tests will become available.

Other laboratory investigations are usually non specific. The white cell count is usually normal or low. There may be lymphopenia; a lymphocyte count <1000 has been associated with severe disease. The platelet count is usually normal or mildly low. The CRP and ESR are generally elevated but procalcitonin levels are usually normal. A high procalcitonin level may indicate a bacterial co-infection. The ALT/AST, prothrombin time, creatinine, D-dimer, CPK and LDH may be elevated and high levels are associated with severe disease.

The chest X-ray (CXR) usually shows bilateral infiltrates but may be normal in early disease. The CT is more sensitive and specific. CT imaging generally shows infiltrates, ground glass opacities and sub segmental consolidation. It is also abnormal in asymptomatic patients/ patients with no clinical evidence of lower respiratory tract involvement. In fact, abnormal CT scans have been used to diagnose COVID-19 in suspect cases with negative molecular diagnosis; many of these patients had positive molecular tests on repeat testing [ 22 ].

Differential Diagnosis [ 21 ]

The differential diagnosis includes all types of respiratory viral infections [influenza, parainfluenza, respiratory syncytial virus (RSV), adenovirus, human metapneumovirus, non COVID-19 coronavirus], atypical organisms (mycoplasma, chlamydia) and bacterial infections. It is not possible to differentiate COVID-19 from these infections clinically or through routine lab tests. Therefore travel history becomes important. However, as the epidemic spreads, the travel history will become irrelevant.

Treatment [ 21 , 23 ]

Treatment is essentially supportive and symptomatic.

The first step is to ensure adequate isolation (discussed later) to prevent transmission to other contacts, patients and healthcare workers. Mild illness should be managed at home with counseling about danger signs. The usual principles are maintaining hydration and nutrition and controlling fever and cough. Routine use of antibiotics and antivirals such as oseltamivir should be avoided in confirmed cases. In hypoxic patients, provision of oxygen through nasal prongs, face mask, high flow nasal cannula (HFNC) or non-invasive ventilation is indicated. Mechanical ventilation and even extra corporeal membrane oxygen support may be needed. Renal replacement therapy may be needed in some. Antibiotics and antifungals are required if co-infections are suspected or proven. The role of corticosteroids is unproven; while current international consensus and WHO advocate against their use, Chinese guidelines do recommend short term therapy with low-to-moderate dose corticosteroids in COVID-19 ARDS [ 24 , 25 ]. Detailed guidelines for critical care management for COVID-19 have been published by the WHO [ 26 ]. There is, as of now, no approved treatment for COVID-19. Antiviral drugs such as ribavirin, lopinavir-ritonavir have been used based on the experience with SARS and MERS. In a historical control study in patients with SARS, patients treated with lopinavir-ritonavir with ribavirin had better outcomes as compared to those given ribavirin alone [ 15 ].

In the case series of 99 hospitalized patients with COVID-19 infection from Wuhan, oxygen was given to 76%, non-invasive ventilation in 13%, mechanical ventilation in 4%, extracorporeal membrane oxygenation (ECMO) in 3%, continuous renal replacement therapy (CRRT) in 9%, antibiotics in 71%, antifungals in 15%, glucocorticoids in 19% and intravenous immunoglobulin therapy in 27% [ 15 ]. Antiviral therapy consisting of oseltamivir, ganciclovir and lopinavir-ritonavir was given to 75% of the patients. The duration of non-invasive ventilation was 4–22 d [median 9 d] and mechanical ventilation for 3–20 d [median 17 d]. In the case series of children discussed earlier, all children recovered with basic treatment and did not need intensive care [ 17 ].

There is anecdotal experience with use of remdeswir, a broad spectrum anti RNA drug developed for Ebola in management of COVID-19 [ 27 ]. More evidence is needed before these drugs are recommended. Other drugs proposed for therapy are arbidol (an antiviral drug available in Russia and China), intravenous immunoglobulin, interferons, chloroquine and plasma of patients recovered from COVID-19 [ 21 , 28 , 29 ]. Additionally, recommendations about using traditional Chinese herbs find place in the Chinese guidelines [ 21 ].

Prevention [ 21 , 30 ]

Since at this time there are no approved treatments for this infection, prevention is crucial. Several properties of this virus make prevention difficult namely, non-specific features of the disease, the infectivity even before onset of symptoms in the incubation period, transmission from asymptomatic people, long incubation period, tropism for mucosal surfaces such as the conjunctiva, prolonged duration of the illness and transmission even after clinical recovery.

Isolation of confirmed or suspected cases with mild illness at home is recommended. The ventilation at home should be good with sunlight to allow for destruction of virus. Patients should be asked to wear a simple surgical mask and practice cough hygiene. Caregivers should be asked to wear a surgical mask when in the same room as patient and use hand hygiene every 15–20 min.

The greatest risk in COVID-19 is transmission to healthcare workers. In the SARS outbreak of 2002, 21% of those affected were healthcare workers [ 31 ]. Till date, almost 1500 healthcare workers in China have been infected with 6 deaths. The doctor who first warned about the virus has died too. It is important to protect healthcare workers to ensure continuity of care and to prevent transmission of infection to other patients. While COVID-19 transmits as a droplet pathogen and is placed in Category B of infectious agents (highly pathogenic H5N1 and SARS), by the China National Health Commission, infection control measures recommended are those for category A agents (cholera, plague). Patients should be placed in separate rooms or cohorted together. Negative pressure rooms are not generally needed. The rooms and surfaces and equipment should undergo regular decontamination preferably with sodium hypochlorite. Healthcare workers should be provided with fit tested N95 respirators and protective suits and goggles. Airborne transmission precautions should be taken during aerosol generating procedures such as intubation, suction and tracheostomies. All contacts including healthcare workers should be monitored for development of symptoms of COVID-19. Patients can be discharged from isolation once they are afebrile for atleast 3 d and have two consecutive negative molecular tests at 1 d sampling interval. This recommendation is different from pandemic flu where patients were asked to resume work/school once afebrile for 24 h or by day 7 of illness. Negative molecular tests were not a prerequisite for discharge.

At the community level, people should be asked to avoid crowded areas and postpone non-essential travel to places with ongoing transmission. They should be asked to practice cough hygiene by coughing in sleeve/ tissue rather than hands and practice hand hygiene frequently every 15–20 min. Patients with respiratory symptoms should be asked to use surgical masks. The use of mask by healthy people in public places has not shown to protect against respiratory viral infections and is currently not recommended by WHO. However, in China, the public has been asked to wear masks in public and especially in crowded places and large scale gatherings are prohibited (entertainment parks etc). China is also considering introducing legislation to prohibit selling and trading of wild animals [ 32 ].

The international response has been dramatic. Initially, there were massive travel restrictions to China and people returning from China/ evacuated from China are being evaluated for clinical symptoms, isolated and tested for COVID-19 for 2 wks even if asymptomatic. However, now with rapid world wide spread of the virus these travel restrictions have extended to other countries. Whether these efforts will lead to slowing of viral spread is not known.

A candidate vaccine is under development.

Practice Points from an Indian Perspective

At the time of writing this article, the risk of coronavirus in India is extremely low. But that may change in the next few weeks. Hence the following is recommended:

  • Healthcare providers should take travel history of all patients with respiratory symptoms, and any international travel in the past 2 wks as well as contact with sick people who have travelled internationally.
  • They should set up a system of triage of patients with respiratory illness in the outpatient department and give them a simple surgical mask to wear. They should use surgical masks themselves while examining such patients and practice hand hygiene frequently.
  • Suspected cases should be referred to government designated centres for isolation and testing (in Mumbai, at this time, it is Kasturba hospital). Commercial kits for testing are not yet available in India.
  • Patients admitted with severe pneumonia and acute respiratory distress syndrome should be evaluated for travel history and placed under contact and droplet isolation. Regular decontamination of surfaces should be done. They should be tested for etiology using multiplex PCR panels if logistics permit and if no pathogen is identified, refer the samples for testing for SARS-CoV-2.
  • All clinicians should keep themselves updated about recent developments including global spread of the disease.
  • Non-essential international travel should be avoided at this time.
  • People should stop spreading myths and false information about the disease and try to allay panic and anxiety of the public.

Conclusions

This new virus outbreak has challenged the economic, medical and public health infrastructure of China and to some extent, of other countries especially, its neighbours. Time alone will tell how the virus will impact our lives here in India. More so, future outbreaks of viruses and pathogens of zoonotic origin are likely to continue. Therefore, apart from curbing this outbreak, efforts should be made to devise comprehensive measures to prevent future outbreaks of zoonotic origin.

Compliance with Ethical Standards

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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