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COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign

Affiliations.

1 Biology and Nutritional Epidemiology, Independent Research, Copper Hill, USA.
2 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, USA.
3 Biostatistics and Epidemiology, Independent Research, Research Triangle Park, USA.
4 Immunology and Public Health Research, Independent Research, Ottawa, CAN.
5 Epidemiology and Biostatistics, Independent Research, Basel, CHE.
6 Data Science, Independent Research, Los Angeles, USA.
7 Cardiology, Epidemiology, and Public Health, McCullough Foundation, Dallas, USA.
8 Cardiology, Epidemiology, and Public Health, Truth for Health Foundation, Tucson, USA.
PMID: 38274635
PMCID: PMC10810638
DOI: 10.7759/cureus.52876

Retraction in

Retraction: COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign. Mead MN, Seneff S, Wolfinger R, Rose J, Denhaerynck K, Kirsch S, McCullough PA. Mead MN, et al. Cureus. 2024 Feb 26;16(2):r137. doi: 10.7759/cureus.r137. eCollection 2024 Feb. Cureus. 2024. PMID: 38414517 Free PMC article.

Our understanding of COVID-19 vaccinations and their impact on health and mortality has evolved substantially since the first vaccine rollouts. Published reports from the original randomized phase 3 trials concluded that the COVID-19 mRNA vaccines could greatly reduce COVID-19 symptoms. In the interim, problems with the methods, execution, and reporting of these pivotal trials have emerged. Re-analysis of the Pfizer trial data identified statistically significant increases in serious adverse events (SAEs) in the vaccine group. Numerous SAEs were identified following the Emergency Use Authorization (EUA), including death, cancer, cardiac events, and various autoimmune, hematological, reproductive, and neurological disorders. Furthermore, these products never underwent adequate safety and toxicological testing in accordance with previously established scientific standards. Among the other major topics addressed in this narrative review are the published analyses of serious harms to humans, quality control issues and process-related impurities, mechanisms underlying adverse events (AEs), the immunologic basis for vaccine inefficacy, and concerning mortality trends based on the registrational trial data. The risk-benefit imbalance substantiated by the evidence to date contraindicates further booster injections and suggests that, at a minimum, the mRNA injections should be removed from the childhood immunization program until proper safety and toxicological studies are conducted. Federal agency approval of the COVID-19 mRNA vaccines on a blanket-coverage population-wide basis had no support from an honest assessment of all relevant registrational data and commensurate consideration of risks versus benefits. Given the extensive, well-documented SAEs and unacceptably high harm-to-reward ratio, we urge governments to endorse a global moratorium on the modified mRNA products until all relevant questions pertaining to causality, residual DNA, and aberrant protein production are answered.

Keywords: autoimmune; cardiovascular; covid-19 mrna vaccines; gene therapy products; immunity; mortality; registrational trials; risk-benefit assessment; sars-cov-2 (severe acute respiratory syndrome coronavirus -2); serious adverse events.

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Conflict of interest statement

Steve Kirsch is the founder of the Vaccine Safety Research Foundation or VSRF (vacsafety.org) but receives no income from this entity

Figure 1. Analysis of Pfizer trial’s weekly…

Figure 1. Analysis of Pfizer trial’s weekly mortality over a 33-week period

This representation of…

Figure 2. Charts illustrating Pfizer trial irregularities…

Figure 2. Charts illustrating Pfizer trial irregularities in reporting of COVID-19 cases and humoral immune…

Figure 3. Cleveland Clinic study showing increasing…

Figure 3. Cleveland Clinic study showing increasing COVID-19 cases with increasing mRNA vaccinations

Cleveland Clinic…

Figure 4. Cleveland Clinic study showing increased…

Figure 4. Cleveland Clinic study showing increased COVID-19 cases for subjects most "up to date"…

Figure 5. VAERS reports of autoimmune disease…

Figure 5. VAERS reports of autoimmune disease per million doses of COVID-19 mRNA (2021-2023) compared…

Figure 6. Factors contributing to COVID-19 mRNA…

Figure 6. Factors contributing to COVID-19 mRNA vaccine inefficacy

COVID-19 vaccines may lose efficacy in…

Figure 7. Myocarditis reports in VAERS Domestic…

Figure 7. Myocarditis reports in VAERS Domestic Data as of September 29, 2023, plotted by…

Figure 8. Registrational trial for Pfizer, projected…

Figure 8. Registrational trial for Pfizer, projected three-year mortality If the six-month Pfizer trial had…

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Research article
Open access
Published: 04 June 2021

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

PRISMA flow diagram

Characteristics of included reviews

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

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

Population and study designs

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

Systematic review findings

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

A meta-analysis of the prevalence of mortality

Clinical symptoms

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

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

World Health Organization. Timeline - COVID-19: Available at: https://www.who.int/news/item/29-06-2020-covidtimeline . Accessed 1 June 2021.

COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Available at: https://coronavirus.jhu.edu/map.html . Accessed 1 June 2021.

Anzai A, Kobayashi T, Linton NM, Kinoshita R, Hayashi K, Suzuki A, et al. Assessing the Impact of Reduced Travel on Exportation Dynamics of Novel Coronavirus Infection (COVID-19). J Clin Med. 2020;9(2):601.

Chinazzi M, Davis JT, Ajelli M, Gioannini C, Litvinova M, Merler S, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020;368(6489):395–400. https://doi.org/10.1126/science.aba9757 .

Article CAS PubMed PubMed Central Google Scholar

Fidahic M, Nujic D, Runjic R, Civljak M, Markotic F, Lovric Makaric Z, et al. Research methodology and characteristics of journal articles with original data, preprint articles and registered clinical trial protocols about COVID-19. BMC Med Res Methodol. 2020;20(1):161. https://doi.org/10.1186/s12874-020-01047-2 .

EPPI Centre . COVID-19: a living systematic map of the evidence. Available at: http://eppi.ioe.ac.uk/cms/Projects/DepartmentofHealthandSocialCare/Publishedreviews/COVID-19Livingsystematicmapoftheevidence/tabid/3765/Default.aspx . Accessed 1 June 2021.

NCBI SARS-CoV-2 Resources. Available at: https://www.ncbi.nlm.nih.gov/sars-cov-2/ . Accessed 1 June 2021.

Gustot T. Quality and reproducibility during the COVID-19 pandemic. JHEP Rep. 2020;2(4):100141. https://doi.org/10.1016/j.jhepr.2020.100141 .

Article PubMed PubMed Central Google Scholar

Kodvanj, I., et al., Publishing of COVID-19 Preprints in Peer-reviewed Journals, Preprinting Trends, Public Discussion and Quality Issues. Preprint article. bioRxiv 2020.11.23.394577; doi: https://doi.org/10.1101/2020.11.23.394577 .

Dobler CC. Poor quality research and clinical practice during COVID-19. Breathe (Sheff). 2020;16(2):200112. https://doi.org/10.1183/20734735.0112-2020 .

Article Google Scholar

Bastian H, Glasziou P, Chalmers I. Seventy-five trials and eleven systematic reviews a day: how will we ever keep up? PLoS Med. 2010;7(9):e1000326. https://doi.org/10.1371/journal.pmed.1000326 .

Lunny C, Brennan SE, McDonald S, McKenzie JE. Toward a comprehensive evidence map of overview of systematic review methods: paper 1-purpose, eligibility, search and data extraction. Syst Rev. 2017;6(1):231. https://doi.org/10.1186/s13643-017-0617-1 .

Pollock M, Fernandes RM, Becker LA, Pieper D, Hartling L. Chapter V: Overviews of Reviews. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane. 2020. Available from www.training.cochrane.org/handbook .

Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions version 6.1 (updated September 2020). Cochrane. 2020; Available from www.training.cochrane.org/handbook .

Pollock M, Fernandes RM, Newton AS, Scott SD, Hartling L. The impact of different inclusion decisions on the comprehensiveness and complexity of overviews of reviews of healthcare interventions. Syst Rev. 2019;8(1):18. https://doi.org/10.1186/s13643-018-0914-3 .

Pollock M, Fernandes RM, Newton AS, Scott SD, Hartling L. A decision tool to help researchers make decisions about including systematic reviews in overviews of reviews of healthcare interventions. Syst Rev. 2019;8(1):29. https://doi.org/10.1186/s13643-018-0768-8 .

Hunt H, Pollock A, Campbell P, Estcourt L, Brunton G. An introduction to overviews of reviews: planning a relevant research question and objective for an overview. Syst Rev. 2018;7(1):39. https://doi.org/10.1186/s13643-018-0695-8 .

Pollock M, Fernandes RM, Pieper D, Tricco AC, Gates M, Gates A, et al. Preferred reporting items for overviews of reviews (PRIOR): a protocol for development of a reporting guideline for overviews of reviews of healthcare interventions. Syst Rev. 2019;8(1):335. https://doi.org/10.1186/s13643-019-1252-9 .

Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Open Med. 2009;3(3):e123–30.

Krnic Martinic M, Pieper D, Glatt A, Puljak L. Definition of a systematic review used in overviews of systematic reviews, meta-epidemiological studies and textbooks. BMC Med Res Methodol. 2019;19(1):203. https://doi.org/10.1186/s12874-019-0855-0 .

Puljak L. If there is only one author or only one database was searched, a study should not be called a systematic review. J Clin Epidemiol. 2017;91:4–5. https://doi.org/10.1016/j.jclinepi.2017.08.002 .

Article PubMed Google Scholar

Gates M, Gates A, Guitard S, Pollock M, Hartling L. Guidance for overviews of reviews continues to accumulate, but important challenges remain: a scoping review. Syst Rev. 2020;9(1):254. https://doi.org/10.1186/s13643-020-01509-0 .

Covidence - systematic review software. Available at: https://www.covidence.org/ . Accessed 1 June 2021.

Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008.

Borges do Nascimento IJ, et al. Novel Coronavirus Infection (COVID-19) in Humans: A Scoping Review and Meta-Analysis. J Clin Med. 2020;9(4):941.

Article PubMed Central Google Scholar

Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020;9(1):29. https://doi.org/10.1186/s40249-020-00646-x .

Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020;57:279–83. https://doi.org/10.1016/j.jcrc.2020.03.005 .

Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020;109(5):531–8. https://doi.org/10.1007/s00392-020-01626-9 .

Article CAS PubMed Google Scholar

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577–83. https://doi.org/10.1002/jmv.25757 .

Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis. 2020;63(3):390–1. https://doi.org/10.1016/j.pcad.2020.03.001 .

Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med. 2020;75:107–8. https://doi.org/10.1016/j.ejim.2020.03.014 .

Lippi G, Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chim Acta. 2020;505:190–1. https://doi.org/10.1016/j.cca.2020.03.004 .

Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta. 2020;506:145–8. https://doi.org/10.1016/j.cca.2020.03.022 .

Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088–95. https://doi.org/10.1111/apa.15270 .

Lupia T, Scabini S, Mornese Pinna S, di Perri G, de Rosa FG, Corcione S. 2019 novel coronavirus (2019-nCoV) outbreak: a new challenge. J Glob Antimicrob Resist. 2020;21:22–7. https://doi.org/10.1016/j.jgar.2020.02.021 .

Marasinghe, K.M., A systematic review investigating the effectiveness of face mask use in limiting the spread of COVID-19 among medically not diagnosed individuals: shedding light on current recommendations provided to individuals not medically diagnosed with COVID-19. Research Square. Preprint article. doi : https://doi.org/10.21203/rs.3.rs-16701/v1 . 2020 .

Mullins E, Evans D, Viner RM, O’Brien P, Morris E. Coronavirus in pregnancy and delivery: rapid review. Ultrasound Obstet Gynecol. 2020;55(5):586–92. https://doi.org/10.1002/uog.22014 .

Pang J, Wang MX, Ang IYH, Tan SHX, Lewis RF, Chen JIP, et al. Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel coronavirus (2019-nCoV): a systematic review. J Clin Med. 2020;9(3):623.

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623. https://doi.org/10.1016/j.tmaid.2020.101623 .

Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients. AJR Am J Roentgenol. 2020;215(1):87–93. https://doi.org/10.2214/AJR.20.23034 .

Sun P, Qie S, Liu Z, Ren J, Li K, Xi J. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis. J Med Virol. 2020;92(6):612–7. https://doi.org/10.1002/jmv.25735 .

Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–5. https://doi.org/10.1016/j.ijid.2020.03.017 .

Bassetti M, Vena A, Giacobbe DR. The novel Chinese coronavirus (2019-nCoV) infections: challenges for fighting the storm. Eur J Clin Investig. 2020;50(3):e13209. https://doi.org/10.1111/eci.13209 .

Article CAS Google Scholar

Hwang CS. Olfactory neuropathy in severe acute respiratory syndrome: report of a case. Acta Neurol Taiwanica. 2006;15(1):26–8.

Google Scholar

Suzuki M, Saito K, Min WP, Vladau C, Toida K, Itoh H, et al. Identification of viruses in patients with postviral olfactory dysfunction. Laryngoscope. 2007;117(2):272–7. https://doi.org/10.1097/01.mlg.0000249922.37381.1e .

Rajgor DD, Lee MH, Archuleta S, Bagdasarian N, Quek SC. The many estimates of the COVID-19 case fatality rate. Lancet Infect Dis. 2020;20(7):776–7. https://doi.org/10.1016/S1473-3099(20)30244-9 .

Wolkewitz M, Puljak L. Methodological challenges of analysing COVID-19 data during the pandemic. BMC Med Res Methodol. 2020;20(1):81. https://doi.org/10.1186/s12874-020-00972-6 .

Rombey T, Lochner V, Puljak L, Könsgen N, Mathes T, Pieper D. Epidemiology and reporting characteristics of non-Cochrane updates of systematic reviews: a cross-sectional study. Res Synth Methods. 2020;11(3):471–83. https://doi.org/10.1002/jrsm.1409 .

Runjic E, Rombey T, Pieper D, Puljak L. Half of systematic reviews about pain registered in PROSPERO were not published and the majority had inaccurate status. J Clin Epidemiol. 2019;116:114–21. https://doi.org/10.1016/j.jclinepi.2019.08.010 .

Runjic E, Behmen D, Pieper D, Mathes T, Tricco AC, Moher D, et al. Following Cochrane review protocols to completion 10 years later: a retrospective cohort study and author survey. J Clin Epidemiol. 2019;111:41–8. https://doi.org/10.1016/j.jclinepi.2019.03.006 .

Tricco AC, Antony J, Zarin W, Strifler L, Ghassemi M, Ivory J, et al. A scoping review of rapid review methods. BMC Med. 2015;13(1):224. https://doi.org/10.1186/s12916-015-0465-6 .

COVID-19 Rapid Reviews: Cochrane’s response so far. Available at: https://training.cochrane.org/resource/covid-19-rapid-reviews-cochrane-response-so-far . Accessed 1 June 2021.

Cochrane. Living systematic reviews. Available at: https://community.cochrane.org/review-production/production-resources/living-systematic-reviews . Accessed 1 June 2021.

Millard T, Synnot A, Elliott J, Green S, McDonald S, Turner T. Feasibility and acceptability of living systematic reviews: results from a mixed-methods evaluation. Syst Rev. 2019;8(1):325. https://doi.org/10.1186/s13643-019-1248-5 .

Babic A, Poklepovic Pericic T, Pieper D, Puljak L. How to decide whether a systematic review is stable and not in need of updating: analysis of Cochrane reviews. Res Synth Methods. 2020;11(6):884–90. https://doi.org/10.1002/jrsm.1451 .

Lovato A, Rossettini G, de Filippis C. Sore throat in COVID-19: comment on “clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis”. J Med Virol. 2020;92(7):714–5. https://doi.org/10.1002/jmv.25815 .

Leung C. Comment on Li et al: COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(9):1431–2. https://doi.org/10.1002/jmv.25912 .

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. Response to Char’s comment: comment on Li et al: COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(9):1433. https://doi.org/10.1002/jmv.25924 .

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Acknowledgments

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

This research received no external funding.

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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

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

Thilo Caspar von Groote

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

Hebatullah Mohamed Abdulazeem

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

Ishanka Weerasekara

Department of Physiotherapy, Faculty of Allied Health Sciences, University of Peradeniya, Peradeniya, Sri Lanka

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Ana Marusic, Irena Zakarija-Grkovic & Tina Poklepovic Pericic

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Livia Puljak

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

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

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

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

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

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

Additional file 5: Appendix 5.

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

Additional file 6: Appendix 6.

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

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

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Introduction
Conclusions
Article Information

Research fields of highly cited studies on COVID-19, including duplicates between each period, are presented.

Publication numbers are given over the entire study period for institutions with the most publications in A, May to June 2020 and B, November to December 2022.

Research fields are presented for the top affiliated institution in A, May to June 2020 (Huazhong University of Science and Technology) and B, November to December 2022 (Harvard University).

eFigure 1. Top Research Fields of Highly Cited Studies on COVID-19

eFigure 2. Top 5 Countries Producing Highly Cited Studies on COVID-19 Using Full Counting Method

eFigure 3. Top 5 Countries of Corresponding Authors Producing Highly Cited Studies on COVID-19

eFigure 4. Top 5 Institutional Affiliations Producing Highly Cited Studies on COVID-19 Using Full Counting Method

eFigure 5. Top 5 Institutional Affiliations of Corresponding Authors Producing Highly Cited Studies on COVID-19

Data Sharing Statement

Incorrect Institution Name in Author Affiliations JAMA Network Open Correction October 16, 2023

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Funada S , Yoshioka T , Luo Y, et al. Global Trends in Highly Cited Studies in COVID-19 Research. JAMA Netw Open. 2023;6(9):e2332802. doi:10.1001/jamanetworkopen.2023.32802

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Global Trends in Highly Cited Studies in COVID-19 Research

1 Department of Health Promotion and Human Behavior, School of Public Health, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2 Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
3 Population Health and Policy Research Unit, Medical Education Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
4 Office of Evidence and Analysis, Japan Science and Technology Agency, Tokyo, Japan
5 Division of Surveillance and Policy Evaluation, National Cancer Center Institute for Cancer Control, Tokyo, Japan
Correction Incorrect Institution Name in Author Affiliations JAMA Network Open

Question What is the global trend of highly cited studies investigating COVID-19 since its outbreak?

Findings This cross-sectional study found that the number of highly cited studies peaked at 1292 studies at the end of 2021 and declined to 649 studies at the end of 2022. Highly cited studies from China showed a decreasing trend, while those from the US and UK showed an increasing trend.

Meaning These findings suggest that as the COVID-19 pandemic evolved in the 3 years since its outbreak, there were important shifts in trends of the number and origin of high-profile COVID-19 studies.

Importance Since the onset of the COVID-19 outbreak, an extremely high number of studies have been published worldwide, with variable quality. Research trends of highly cited papers may enable identification of influential research, providing insights for new research ideas; it is therefore important to investigate trends and focus on more influential publications in COVID-19–related studies.

Objective To examine research trends of highly cited studies by conducting a bibliometric analysis of highly cited studies in the previous 2 months about COVID-19.

Design, Setting, and Participants In this cross-sectional study, Essential Science Indicators (ESI) and Web of Science (WOS) Core Collection were used to find studies with a focus on COVID-19 that were identified as highly cited studies from Clarivate Analytics. Highly cited studies were extracted from the ESI database bimonthly between January 2020 and December 2022. Bibliographic details were extracted from WOS and combined with ESI data using unique accession numbers. The number of highly cited studies was counted based on the fractional counting method. Data were analyzed from January through July 2023.

Main Outcomes and Measures The number of publications by research field, country, and institutional affiliation.

Results The number of published COVID-19–related highly cited studies was 14 studies in January to February 2020, peaked at 1292 studies in November to December 2021, and showed a downward trend thereafter, reaching 649 studies in November to December 2022. China had the highest number of highly cited studies per 2-month period until July to August 2020 (138.3 studies vs 103.7 studies for the US, the second highest country), and the US had the greatest number of highly cited studies afterward (159.9 studies vs 157.6 studies for China in September to October 2020). Subsequently, the number of highly cited studies per 2-month period published by China declined (decreasing from 179.7 studies in November to December 2020 to 40.7 studies in September to October 2022), and the UK produced the second largest number of such studies in May to June 2021 (171.3 studies). Similarly, the top 5 institutional affiliations in May to June 2020 by highly cited studies per 2-month period were from China (Huazhong University: 14.7 studies; University of Hong Kong: 6.8 studies; Wuhan University: 4.8 studies; Zhejiang University: 4.5 studies; Fudan University: 4.5 studies), while in November to December 2022, the top 5 institutions were in the US and UK (Harvard University: 15.0 studies; University College London: 11.0 studies; University of Oxford: 10.2 studies; University of London: 9.9 studies; Imperial College London: 5.8 studies).

Conclusions and Relevance This study found that the total number of highly cited studies related to COVID-19 peaked at the end of 2021 and showed a downward trend until the end of 2022, while the origin of these studies shifted from China to the US and UK.

Since the outbreak of COVID-19 in December 2019, numerous studies have been conducted and published worldwide in response to the pandemic. 1 This trend may have been amplified by the use of preprint systems, such as medRxiv 2 and bioRxiv, 3 during the pandemic, as well as by the proliferation of predatory journals. 4 As a result, the total number of COVID-19–related publications, including preprints, has increased dramatically and now exceeds 350 000 studies. 5 The dissemination of COVID-19 research is highly active and constantly evolving. In such an expanding research environment, investigating research trends may help identify knowledge gaps and provide insightful research directions. 6 In addition, comparing trends across countries and institutional affiliations may support scientific policy and research management. 7

However, as previously found in 2020, 8 the increase in COVID-19–related publications has not necessarily been associated with increased high-quality evidence, and this concern has become a reality in 2023. A citation analysis of studies published in predatory journals found that 60% of publications had not attracted any citations and 38% were cited only up to 10 times. 9 The COVID-19 pandemic has seemingly been associated with an exacerbated issue of waste of studies (ie, doing unnecessary or poorly designed studies), 10 making the proper assessment and synthesis of research trends in COVID-19 research challenging. Therefore, some filtering system may be essential to efficiently narrow down desired publications from the vast collection and ensure that relevant and valuable studies are selected.

One way to address this challenge is to analyze highly cited studies, or hot papers, which refers to studies published within the previous 2 years that have received a considerable number of citations in the previous 2 months, placing them in the top 0.1% of studies in the same field. 11 High citation counts indicate that these studies have garnered significant attention from researchers. Furthermore, the list is updated every 2 months, allowing researchers to keep up with the latest trends and analyze them over time to capture shifts in the research landscape. Examining research trends of highly cited studies may allow the identification of influential studies, providing valuable insights for generating new research ideas. Bibliometrics is a scientific domain focused on measuring and quantifying various features in publications by examining the productivity of researchers, affiliations, and countries in specific fields. 12 Therefore, a bibliometric analysis may be appropriate for examining features of highly cited studies in COVID-19 research. To our knowledge, there have been no studies analyzing the trend of COVID-19–related highly cited studies.

This study aimed to investigate research trends of highly cited studies by conducting a bibliometric analysis of these studies on COVID-19 research. Additionally, by presenting these studies in chronological order, we aimed to identify changes in COVID-19 research trends.

This cross-sectional study was a bibliometric analysis of highly cited studies and followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. According to the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan, institutional review board approval and participant consent were not required for this study because it used only published data.

We included all studies with a focus on COVID-19 identified as highly cited studies from Clarivate Analytics. We excluded studies that contained keywords related to COVID-19 in the text but did not investigate COVID-19. There was no restriction on the type of studies included.

This study used the following 5 selection steps for identifying highly cited studies on COVID-19. In step 1, we extracted a total of 18 periods of highly cited studies from the Essential Science Indicators (ESI) (Clarivate Analytics) database bimonthly from January 2020 to December 2022 (January to February 2020 through November to December 2020, January to February 2021 through November to December 2021, and January to February 2022 through November to December 2022). In step 2, based on a unique accession number associated with each highly cited study record in the ESI, we combined bibliographic details, such as abstract, document type, and others, from the Web of Science (WOS) Core Collection (Clarivate Analytics) with ESI data. The accession number is an identification number assigned to each study in WOS, and an individual study is identified by searching with the accession number in WOS. In step 3, we identified highly cited studies with a focus on COVID-19 from their titles and abstracts using the following search terms: “COVID-19” or “2019-nCoV” or “NOVEL 2019” or “CORONAVIRUS DISEASE 2019” or “SARS-COV-2” or “n-COV” or “COVID” or “CORONAVIRUS” or “SARS.” We excluded highly cited studies that did not contain predetermined keywords as non-COVID-19–related highly cited studies. In step 4, a total of 4 researchers (T.I., C.M., N.Y., and H.Y.) making pairs in rotation each independently reviewed titles, abstracts, and full texts and included COVID-19–related highly cited studies that fit eligibility criteria. Any disagreements or ambiguity between pairs were resolved through discussion or cross-check consultation with another researcher if required. In step 5, the same 4 researchers (T.I., C.M., N.Y., and H.Y.) checked how many duplicates were counted as highly cited studies between each period. We conducted this selection step once for each of 18 periods between January 2020 and December 2022.

We collected the following bibliographic information from the WOS database: titles, authors, corresponding authors, affiliations, publication journal, publication date, and research field. Based on this information, we used 3 variables to measure the trend of COVID-19–related research as follows: (1) The research fields variable included 22 ESI categories (agricultural science; biology and biochemistry; chemistry; clinical medicine; computer science; ecology/environment; economics and business; engineering; geosciences; immunology; materials science; mathematics; microbiology; molecular biology and genetics; multidisciplinary; neuroscience and behavior; pharmacology; physics; plant and animal science; psychiatry/psychology; social sciences, general; and space science). 13 Each journal is assigned to 1 field, and the research published in that journal adopts that field assignment. (2) The countries variable included countries of affiliation of all co-authors for each study. (3) The affiliations variable included affiliations of all co-authors for each study.

The bibliometric analysis descriptively summarizes the number of COVID-19–related highly cited studies. We counted the number of highly cited studies based on the fractional counting method. Compared with the full counting method, which counts the full number of each co-author and institutional affiliation, the fractional counting method had a fractional weight of each co-author and institutional affiliation, and each publication had a total weight of 1. 14 Highly cited study counts were compared between research fields, countries, and affiliations. As a sensitivity analysis, we performed the full counting method instead of the fractional counting method. We also performed the fractional counting method on countries and affiliations of corresponding authors as a sensitivity analysis. Data were analyzed using R statistical software version 4.3.1 (R Project for Statistical Computing). Data were analyzed from January through July 2023.

Figure 1 shows the selection step for highly cited studies on COVID-19 research. We identified 73 079 highly cited studies from the ESI database in 18 periods every 2 months between January 2020 and December 2022. From 73 079 highly cited studies, we excluded 57 236 highly cited studies by keyword search and 581 highly cited studies by title, abstract, and full text review. Finally, we identified 15 262 highly cited studies with duplicates and 4131 such studies without duplicates.

Figure 2 shows the number of highly cited studies for COVID-19 research in each period. The total number of highly cited studies exhibited gradual growth, from 3412 studies in January to February 2020 to 4389 studies in November to December 2022. Regarding COVID-19–related highly cited studies, the initial count was 14 studies in January to February 2020, increasing to 1292 studies in November- to December 2021. However, there was a subsequent decline to 649 studies in November to December 2022.

The top 10 research fields of highly cited studies of COVID-19 in each period are given in eFigure 1 in Supplement 1 . Although highly cited studies were predominantly from the clinical medicine field in January to February 2020 (9 of 14 studies [64.3%]), there was a gradual decrease in studies in this field starting in March to April 2022 (427 studies) until November to December 2022 (246 studies). Studies in other fields increased in number over time, with a particular increase in the fields of general social science, psychiatry and psychology, immunology, and molecular biology and genetics. For example, highly cited studies in general social science increased from 0 studies in January to February 2020 to 73 studies in July to August 2022.

Figure 3 shows the top 5 countries with the highest number of highly cited studies. China recorded the highest number of publications per 2-month period from January to February 2020 through July to August 2020 (138.3 studies), with the US following closely behind (103.7 studies during this period) and gradually increasing its output, overtaking China in September to October 2020 (159.9 studies vs 157.6 studies). China’s highly cited study output per 2-month period has been declining since November to December 2020 (decreasing from 179.7 studies in that period to 40.7 studies in September to October 2022), while there has been a steady increase in publications from the UK, increasing from 86.5 studies in November to December 2020 to ultimately overtake China in May to June 2021 (171.3 studies vs 166.6 studies). Starting in March to April 2022 until November to December 2022, the US, UK, and China had substantially reduced numbers of highly cited studies, and the downward trend continued until November to December 2022. The decrease in the number of highly cited studies per 2-month period from March to April 2022 to November to December 2022 was 366.8 studies to 190.6 studies for the US, 243.7 studies to 158.3 studies for the UK, and 107.5 studies to 45.5 studies for China. The trend remained the same using the full counting method (eFigure 2 in Supplement 1 ) and counting corresponding authors’ countries (eFigure 3 in Supplement 1 ) in sensitivity analyses.

Figure 4 shows the distribution of highly cited studies based on institutional affiliation across periods. Figure 4 A and Figure 4 B depict the top 5 facilities in terms of highly cited study publication numbers in May to June 2020 and November to December 2022, respectively. The top 5 institutional affiliations by highly cited studies per 2-month period in May to June 2020 were based in China (Huazhong University: 14.7 studies; University of Hong Kong: 6.8 studies; Wuhan University: 4.8 studies; Zhejiang University: 4.5 studies; Fudan University: 4.5 studies); however, by 2021, they all displayed a decreasing trend ( Figure 4 A). Conversely, in November to December 2022, the top 5 affiliations by highly cited studies per 2-month period were based in the US or the UK (Harvard University: 15.0 studies; University College London: 11.0 studies; University of Oxford: 10.2 studies; University of London: 9.9 studies; Imperial College London: 5.8 studies) ( Figure 4 B). Although there was some turnover, the trend remained the same in sensitivity analyses. There were more facilities in China in May to June 2020 by the full counting method (eFigure 4 in Supplement 1 ) and by affiliations of corresponding authors (eFigure 5 in Supplement 1 ) and more facilities in the US or UK in November to December 2022 by the full counting method (eFigure 4 in Supplement 1 ) and by affiliations of corresponding authors (eFigure 5 in Supplement 1 ).

Figure 5 provides an overview of the research fields of affiliations with the highest number of highly cited studies in May to June 2020 ( Figure 5 A) and November to December 2022 ( Figure 5 B). Huazhong University of Science and Technology published the greatest number of highly cited studies in May to June 2020, with 27 of 34 studies in the clinical medicine field. In contrast, the top highly cited studies in November to December 2022 were from Harvard University, with 73, 13, and 9 highly cited studies in the fields of clinical medicine, molecular biology and genetics, and psychiatry and psychology, respectively.

This cross-sectional study evaluated trends in COVID-19 research by analyzing highly cited studies every 2 months from January 2020 to December 2022. As the pandemic progressed, the number of highly cited studies related to COVID-19 increased sharply. Nevertheless, after reaching a peak at the end of 2021, the number of highly cited studies exhibited a declining trend. In addition, while most highly cited studies were initially from the field of clinical medicine, we observed an increase in the number of publications from other fields through the observational period. Over time, there was a shift in the ranking of countries, with the US overtaking China to produce the highest number of highly cited studies since September to October 2020. The number of highly cited studies from China showed a decreasing trend, while those from the UK exhibited an increasing trend. Institutions that published the greatest number of highly cited studies at the beginning of the pandemic were from China; however, their number of publications gradually decreased, and the top institutions were replaced by those from the US and UK.

To our knowledge, no studies to date have conducted a bibliometric analysis of highly cited studies related to COVID-19 over the past 3 years. However, a bibliometric analysis using the COVID-19 Open Research Dataset (CORD-19) 15 reported that COVID-19 studies, not just highly cited studies, published in 2020 came mostly from the US, China, and UK, which received more than 60% of citations. Similar to our research, that study found that the US steadily increased the number of studies and took the top spot, China had initially led COVID-19 research but experienced a substantial decline in research output over time, and the UK showed the opposite trend, starting with a slow pace of publications and gradually increasing its contributions throughout the year. Another study 16 examined the association of COVID-19–related publications with overall publication rates in high-impact factor journals. They showed that studies related to COVID-19 accounted for approximately 10% to 50% of the total number of publications in each high-impact journal from 2020 to 2021. Additionally, a gradual decline in COVID-19–related publications was observed at the end of 2020. Notably, this declining trend was detected earlier in that study than in our analysis, suggesting a lag in citations given that highly cited studies are determined based on the number of citations after publication.

As reported in a previous study, 17 an increase in COVID-19 cases in a region or country was associated with increased COVID-19–related research activity in that area. This may be associated with 2 factors: the need for data and increased government funding for research to control the pandemic. In addition, our findings of a gradual downward trend in highly cited studies related to COVID-19 may have been associated with a decrease in global attention to COVID-19 research. This trend may also suggest that researchers have gained a better understanding of the etiology and treatment of COVID-19, leading to decreased interest or fatigue with the topic. 18 Changes in distribution, top affiliations, and research fields of highly cited studies suggest a gradual shift in interest in COVID-19 research toward more diversified and broader research areas. Based on results of this investigation, we expect a sustained reduction in the number of highly cited studies on COVID-19. Furthermore, we speculate that the research focus may further diversify, and we intend to examine this hypothesis through ongoing analysis. A bibliometric analysis using highly cited studies may be an appropriate method to capture trends in research by examining high-profile studies every 2 months. Similar methods used in this study may be useful for analyzing research trends in other fields.

This study has several strengths. First, to our knowledge, it is the first bibliometric analysis of highly cited studies related to COVID-19. Investigations of highly cited studies (ie, those with the top 0.1% of citations) may be of greater interest than studies that analyze the total number of COVID-19–related studies. Using this method, we can exclude studies with low scientific impact, such as those published in predatory journals. In addition, highly cited studies are updated every 2 months, allowing the tracking of trends over time. Second, this study used fractional counting rather than full counting. While full counting is widely used in bibliometric analysis, fractional counting allows for field normalization and takes into account effects of aggregating large studies, particularly at the level of countries and research organizations. A comparative study 14 recommended fractional counting in such bibliometric studies.

This study also has several limitations. First, while fractional counting is a strength, it can also be a limitation given that full counting is more widely used, making it challenging to compare our results with those of other studies. However, we also performed full counting as sensitivity analyses and observed no substantial difference in trends compared with fractional counting. This suggests that the difference in counting methods may not be a serious issue. Second, highly cited studies are limited to the top 0.1% of citations and are not representative of all published literature. In addition, the number of citations does not necessarily guarantee the quality of the research. Therefore, it should be noted that this study’s findings represent only trends in influential research. Third, although we used ESI categories to define research fields, these categories do not classify highly cited studies in detail. For example, clinical medicine includes a very broad range of highly cited studies. A more detailed classification may be appropriate for a closer look at research trends. Fourth, although this study identified trends in COVID-19–related highly cited studies, it provides a broad overview rather than a detailed analysis. Several interesting aspects could not be explored in depth in this study, including comparisons with non-COVID-19–related highly cited studies and the evolution of characteristic topics over time, such as lockdown policies and vaccines. To address these gaps, we need further analyses in the future.

In this cross-sectional study, a bibliometric analysis of highly cited studies found that as the COVID-19 pandemic evolved over the 3 years since its outbreak, there was a shift in trends in COVID-19 research. The increase and decrease in the number of highly cited studies related to COVID-19 may suggest shifting interests of researchers. Meanwhile, there was a noticeable increase in the number of topics covered by field, including not only clinical medicine but also a diverse range of topics.

Accepted for Publication: July 31, 2023.

Published: September 8, 2023. doi:10.1001/jamanetworkopen.2023.32802

Correction: This article was corrected on October 16, 2023, to fix the name of an institution in the author affiliations.

Corresponding Author: Satoshi Funada, MD, PhD, Department of Health Promotion and Human Behavior, School of Public Health, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan ( [email protected] ).

Author Contributions: Dr Yoshida had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Funada, Yoshida, Katanoda.

Acquisition, analysis, or interpretation of data: Funada, Yoshioka, Luo, Iwama, Mori, Yamada, Yoshida, Furukawa.

Drafting of the manuscript: Funada, Iwama, Katanoda.

Critical review of the manuscript for important intellectual content: Yoshioka, Luo, Mori, Yamada, Yoshida, Furukawa.

Statistical analysis: Funada, Yoshioka, Mori, Yamada, Yoshida.

Obtained funding: Katanoda.

Administrative, technical, or material support: Mori.

Supervision: Yoshida, Katanoda, Furukawa.

Conflict of Interest Disclosures: Dr Funada reported receiving grants from the Japan Society for the Promotion of Science (JSPS), KDDI Foundation, and Pfizer Health Research Foundation outside the submitted work. Dr Yoshioka reported receiving grants from the JSPS and Japan National Cancer Center outside the submitted work. Dr Luo reported receiving grants from the JSPS outside the submitted work. Dr Furukawa reported receiving personal fees from Boehringer-Ingelheim, DT Axis, Kyoto University Original, Shionogi, and Sony and grants from Shionogi outside the submitted work and having patents pending for 2020-548587, 2022-082495, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. No other disclosures were reported.

Funding/Support: We acknowledged the support by grant JPMH21HA201 from the Japan Ministry of Health, Labour and Welfare Research Program on Emerging and Reemerging Infectious Diseases and the Japan National Institute of Public Health for language editing and article publishing charges.

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 Editage for providing English language editing. This company was paid a fee for these services.

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Collection 29 March 2022

2021 Top 25 COVID-19 Articles

The 25 most downloaded Nature Communications articles* on COVID-19 published in 2021 illustrate the collaborative efforts of the international community to combat the ongoing pandemic. These papers highlight valuable research into the biology of coronavirus infection, its detection, treatment as well as into vaccine development and the epidemiology of the disease.

Browse all Top 25 subject area collections here .

*Data obtained from SN Insights (based on Digital Science's Dimensions) and normalised to account for articles published later in the year.

Microscopic view of 3D spherical viruses

Research highlights

Anti-spike antibody response to natural SARS-CoV-2 infection in the general population

Most people who are infected with SARS-CoV-2 seroconvert within a few weeks, but the determinants and duration of the antibody response are not known. Here, the authors characterise these features of the immune response using data from a large representative community sample of the UK population.

Philippa C. Matthews
the COVID-19 Infection Survey team

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

Cathrine Axfors
Andreas M. Schmitt
Lars G. Hemkens

Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia

Vaccination is an effective strategy in suppressing COVID-19 pandemic, but rare adverse effects have been reported, including cerebral venous thrombosis. Here the authors report two cases of middle cerebral artery infarct within 9-10 days following ChAdOx1 nCov-19 vaccination that also manifest pulmonary and portal vein thrombosis.

M. De Michele
M. Iacobucci

Correlation of SARS-CoV-2-breakthrough infections to time-from-vaccine

The duration of effectiveness of SARS-CoV-2 vaccination is not yet known. Here, the authors present preliminary evidence of BNT162b2 vaccine waning across all age groups above 16, with a higher incidence of infection in people who received their second dose early in 2021 compared to later in the year.

Barak Mizrahi
Tal Patalon

COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants

Emerging SARS-CoV-2 variants contain mutations in the spike protein that may affect vaccine efficacy. Here, Jalkanen et al . show, using sera from 180 BNT162b2-vaccinated health care workers, that neutralization of SARS-CoV2 variant B.1.1.7 is not affected, while neutralization of B.1.351 variant is five-fold reduced.

Pinja Jalkanen
Pekka Kolehmainen
Ilkka Julkunen

Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection

T cells compose a critical component of the immune response to coronavirus infection with SARS-CoV-2. Here the authors characterise the T cell response to SARS CoV-2 in patients and their close contacts, and show the presence of SARS-CoV-2 specific T cells in the absence of detectable virus infection.

Zhongfang Wang
Xiaoyun Yang

Rapid decline of neutralizing antibodies against SARS-CoV-2 among infected healthcare workers

The humoral immune response to SARS-CoV-2 infection is not yet fully understood. Here, Marot et al. monitor the longitudinal profile and neutralizing activity of IgG, IgA, and IgM among 26 healthcare workers and provide evidence for a short-lasting humoral immune protection due to a decrease of neutralizing antibody titers within 3 months.

Stéphane Marot
Isabelle Malet
Anne-Geneviève Marcelin

Efficacy and tolerability of bevacizumab in patients with severe Covid-19

In this single-arm clinical trial, the authors show that treatment of COVID-19 patients with bevacizumab, an anti-vascular endothelial growth factor drug, can improve PaO 2 /FiO 2 ratios and oxygen-support status. Relative to an external control group, bevacizumab shows clinical efficacy by improving oxygenation.

Jiaojiao Pang

Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in Southeast Asia

A bat origin for SARS-CoV-2 has been proposed. Here, by sampling wild Rhinolophus acuminatus bats from Thailand, the authors identified a SARS-CoV-2-related coronavirus (SC2r-CoV), designated as RacCS203, with 91.5% genome similarity to SARS-CoV-2, and show that sera obtained from bats and Malayan pangolin neutralize SARS-CoV-2.

Supaporn Wacharapluesadee
Chee Wah Tan
Lin-Fa Wang

SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes

The SARS-CoV-2 gene set remains unresolved, hindering dissection of COVID-19 biology. Comparing 44 Sarbecovirus genomes provides a high-confidence protein-coding gene set. The study characterizes protein-level and nucleotide-level evolutionary constraints, and prioritizes functional mutations from the ongoing COVID-19 pandemic.

Irwin Jungreis
Rachel Sealfon
Manolis Kellis

Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival

Antibody responses are critical for protection from developing severe COVID-19 following SARS-CoV-2 infection. Here the authors show that antibody responses against SARS-CoV-2 spike protein correlate with neutralizing capacity and protection, are not affected by heterologous boosting of influenza or common cold immunity, and can last up to 8 months.

Stefania Dispinseri
Massimiliano Secchi
Gabriella Scarlatti

New-onset IgG autoantibodies in hospitalized patients with COVID-19

Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.

Sarah Esther Chang
Paul J. Utz

SARS-CoV-2 vaccine breakthrough infections with the alpha variant are asymptomatic or mildly symptomatic among health care workers

Several COVID-19 vaccines have shown good efficacy in clinical trials. Here, the authors provide real world effectiveness data in a group of BNT162b2 vaccinated health care workers and find that breakthrough infections are asymptomatic or mild.

Francesca Rovida
Irene Cassaniti
Fausto Baldanti

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19)

Duration of infectious SARS-CoV-2 shedding is an important measure for improved disease control. Here, the authors use virus cultures of respiratory tract samples from COVID-19 patients and observe a median shedding duration of 8 days and a drop below 5% after 15,2 days post onset of symptoms.

Jeroen J. A. van Kampen
David A. M. C. van de Vijver
Annemiek A. van der Eijk

A novel SARS-CoV-2 related coronavirus in bats from Cambodia

In this study, Delaune et al., isolate and characterise a SARS-CoV-2-related coronavirus from two bats sampled in Cambodia. Their findings suggest that the geographic distribution of SARS-CoV-2-related viruses is wider than previously reported.

Deborah Delaune
Veasna Duong

Neutralizing antibody titres in SARS-CoV-2 infections

Here, the authors perform plaque reduction neutralization (PRNT) assays quantitating SARS-CoV-2 specific neutralizing antibodies from 195 patients in different disease states and find that patients with severe disease exhibit higher peaks of neutralizing antibody titres than patients with mild or asymptomatic infections and that serum neutralizing antibody persists for over 6 months in most people.

Eric H. Y. Lau
Owen T. Y. Tsang
Malik Peiris

SARS-CoV-2 antibody dynamics and transmission from community-wide serological testing in the Italian municipality of Vo’

Vo’, Italy, is a unique setting for studying SARS-CoV-2 antibody dynamics because mass testing was conducted there early in the pandemic. Here, the authors perform two follow-up serological surveys and estimate seroprevalence, the extent of within-household transmission, and the impact of contact tracing.

Ilaria Dorigatti
Enrico Lavezzo
Andrea Crisanti

Discrete SARS-CoV-2 antibody titers track with functional humoral stability

The extent of antibody protection against SARS-CoV-2 remains unclear. Here, using a cohort of 120 seroconverted individuals, the authors longitudinally characterize neutralization, Fc-function, and SARS-CoV-2 specific T cell responses, which they show to be prominent only in those subjects that elicited receptor-binding domain (RBD)-specific antibody titers above a certain threshold, suggesting that development of T cell responses to be related to anti-RBD Ab production.

Yannic C. Bartsch
Stephanie Fischinger
Galit Alter

Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Shark antibodies (Variable New Antigen Receptors, VNARs) are the smallest naturally occurring antibody fragments. Here, the authors screen a VNAR phage display library against the SARS-CoV2 receptor binding domain (RBD) and identify VNARs that neutralize the SARSCoV-2 virus and discuss their mechanisms of viral neutralization.

Obinna C. Ubah
Eric W. Lake
Caroline J. Barelle

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand

New Zealand has been relatively successful in controlling COVID-19 due to implementation of strict non-pharmaceutical interventions. Here, the authors demonstrate a striking decline in reports of influenza and other non-influenza respiratory pathogens over winter months in which the interventions have been in place.

Q. Sue Huang
Richard J. Webby

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

Neutralizing nanobodies (Nb) are of considerable interest as therapeutic agents for COVID-19 treatment. Here, the authors functionally and structurally characterize Nbs that bind with high affinity to the receptor binding domain of the SARS-CoV-2 spike protein and show that an engineered homotrimeric Nb prevents disease progression in a Syrian hamster model of COVID-19 when administered intranasally.

Jiandong Huo
Halina Mikolajek
Raymond J. Owens

Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance

Cas13b can be harnessed to target and degrade RNA transcripts inside a cellular environment. Here the authors reprogram Cas13b to target SARSCoV-2 transcripts in infected mammalian cells and reveal its resilience to variants thanks to single mismatch tolerance.

Mohamed Fareh
Joseph A. Trapani

SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells

T cells are instrumental to protective immune responses against SARS-CoV-2, the pathogen responsible for the COVID-19 pandemic. Here the authors show that, in convalescent COVID-19 patients, memory T cell responses are detectable up to 317 days post-symptom onset, in which the presence of stem cell-like memory T cells further hints long-lasting immunity.

Jae Hyung Jung
Min-Seok Rha
Eui-Cheol Shin

Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses

Long-term characterisation of SARS-CoV-2 antibody kinetics is needed to understand the protective role of the immune response. Here the authors describe antibody levels and neutralisation activity in healthcare workers over seven months and investigate the role of immunity to endemic human coronaviruses.

Natalia Ortega
Marta Ribes
Carlota Dobaño

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and is used as a drug to treat COVID19 patients. Here, the authors provide insights into the mechanism of remdesivir-induced RdRp stalling by determining the cryo-EM structures of SARS-CoV-2 RdRp with bound RNA molecules that contain remdesivir at defined positions and observe that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation.

Goran Kokic
Hauke S. Hillen
Patrick Cramer

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Study reveals early immune responses to SARS-CoV-2, offering insights for future COVID-19 treatments

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In a recent study published in the journal Nature , a group of researchers analyzed early cellular response dynamics to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in seronegative individuals using single-cell multi-omics profiling, identifying key cellular states and immune responses associated with different infection outcomes.

Background

Coronavirus 2019 (COVID-19), caused by SARS-CoV-2, is a potentially fatal disease that has become a severe global health emergency. Severe outcomes are linked to disrupted antiviral and immune responses, including impaired type I interferon responses and altered T lymphocyte (T) and B lymphocyte (B) cell dynamics. Accurate detection of immune responses is challenging due to heterogeneous factors such as viral dose, strain, and clinical features like comorbidities. Understanding the dynamics of SARS-CoV-2 infection, particularly early phases of exposure, is crucial. Studies often miss capturing these early events in natural infections, making pinpointing antigen-responding T cell activation and expansion difficult. Further research is needed to accurately delineate early immune response dynamics to SARS-CoV-2 to better understand and mitigate severe COVID-19 outcomes.

About the study

Sixteen healthy adults aged 18-30 years, seronegative for SARS-CoV-2, participated in a human SARS-CoV-2 challenge study for Single-cell RNA sequencing (scRNA-seq) sample processing and analysis. This study, conducted by a government task force, Imperial College London, Royal Free London NHS Foundation Trust, University College London, and hVIVO, took place from June to August 2021. Additionally, 20 healthy adults from earlier cohorts had blood and nasal samples processed for bulk Ribonucleic Acid (RNA)-seq, with 10 receiving pre-emptive remdesivir. Volunteers were screened for anti-SARS-CoV-2 antibodies and excluded if positive. The study followed ethical guidelines, and informed consent was obtained from all volunteers.

a, Illustration of the study design and cohort composition. b,c, Uniform manifold approximation and projection (UMAP) plots of all nasopharyngeal cells (n = 234,182), colour coded by their broad cell-type annotation (b), by the infection group (c, top) and by days since inoculation (c, bottom). Only cells from sustained infection cases are shown in c, bottom. Treg, regulatory T cell; AS–DC, AXL+SIGLEC6+ dendritic cell. d,e, UMAP plots as in b and c, but showing all PBMCs (n = 371,892). CTL, cytotoxic T lymphocyte; DN, double negative. f, Fold changes in abundance of nasopharynx-resident broad immune cell-type categories. Immune cell abundance was scaled to the total amount of detected epithelial cells in every sample before calculating the fold changes over days since inoculation compared with pre-infection (day –1) by fitting a GLMM on scaled abundance. Fitted fold changes are colour coded and we used the local true sign rate and Benjamini–Hochberg procedure to calculate false-discovery rates (FDRs), which are shown as the size of each dot. The mean cell-type proportions over all cells and samples are shown in the green heatmap to the right of the dot plot to aid the interpretation of changes in cell-type abundance. Illustration in a was created using BioRender (https://www.biorender.com).

Participant 11, who had low pre-inoculation antibody levels, was classified as having an abortive infection, which did not alter the study's conclusions. Participants were followed for one year post-inoculation, with no long- COVID symptoms reported at the final time point. Physiological observations were normal. After discharge, two participants reported receiving a vaccine or a community infection before their day 28 follow-up. Enzyme-Linked ImmunoSpot (ELISpot) tests revealed immune responses in subsequent samples. Participants were intranasally inoculated with a wild-type pre-Alpha SARS-CoV-2 virus, and nasal and throat samples were collected to evaluate viral kinetics. Nasopharyngeal swabs and Peripheral Blood Mononuclear Cells (PBMCs) were processed for single-cell sequencing to analyze immune responses.

Study results

In the present study, 16 seronegative young adults were intranasally inoculated with a pre-Alpha SARS-CoV-2 virus strain. Extensive screening excluded participants with severe disease risk factors or comorbidities. Participants received the lowest quantifiable inoculum dose, resulting in no serious adverse events and resolved symptoms.

The study analyzed local and systemic immune responses at single-cell resolution. Baseline measurements were taken before inoculation, followed by time series analyses of cellular responses in blood and nasopharynx. Six participants developed sustained infections, defined by consecutive viral load detections and symptoms. Three individuals had sporadic positive polymer chain reaction (PCR) tests and were classified as transient infections. Seven participants remained PCR-negative but showed early innate immune responses, termed abortive infections. The infection rate was comparable to that in a closed household of unvaccinated individuals.

scRNA-seq and single-cell T cell receptor (TCR) and B cell receptor (BCR) sequencing were performed at up to seven time points. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) quantified 123 surface proteins in PBMCs. More than 600,000 single-cell transcriptomes were generated, including 371,892 PBMCs and 234,182 nasopharyngeal cells. Predictive models and marker gene expression annotated 202 cell states, enabling detailed local and systemic response analysis.

Generalized linear mixed models (GLMMs) quantified changes in cell-type abundance over time. Immune cell types infiltrated the inoculation site after SARS-CoV-2 exposure. Sustained infections showed immune infiltration starting at day 5, while transient infections had immediate infiltration at day 1. Abortive infections showed minimal changes except for early Cluster of Differentiation (CD)4+ and CD8+ T cell infiltration.

Gene expression analysis revealed that interferon response genes were the dominant infection-induced module in sustained infections. Interferon signaling was activated in all cell types in both blood and nasopharynx, peaking earlier in blood. This rapid systemic response was validated with bulk RNA-seq data. Myeloid cell redistribution between circulation and tissues was observed during early infection. Mucosal-Associated Invariant T (MAIT) cell activation was detected across all infection groups, indicating rapid viral sensing. Viral RNA peaked at day 7, with hyperinfected ciliated cells identified as major virion producers.

Ciliated cells showed dynamic responses, including acute-phase and interferon-stimulated states. Activated T cells, identified through peptide-Major Histocompatibility Complex (MHC) staining and scRNA-seq, expanded significantly at day 10 after inoculation, resembling a typical antigen-specific adaptive immune response.

Conclusions

The study revealed multiple immune response states that precede clinical symptoms, including MAIT cell activation and a decrease in inflammatory monocytes. These responses emerged even when SARS-CoV-2 exposure did not lead to COVID-19, suggesting their potential as biomarkers of immediate immune response. In sustained infections, a new acute phase response (APR) in ciliated cells and a distinct state for activated T cells with SARS-CoV-2-specific TCRs were identified. Interferon signaling was activated globally in circulating immune cells before the site of infection. These findings provide a detailed time-resolved description of early immune responses to SARS-CoV-2.

Lindeboom, R.G.H., Worlock, K.B., Dratva, L.M. et al. Human SARS-CoV-2 challenge uncovers local and systemic response dynamics. Nature (2024). DOI- 10.1038/s41586-024-07575-x, https://www.nature.com/articles/s41586-024-07575-x

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Antibodies , Antibody , Antigen , B Cell , B Lymphocyte , Blood , Cell , Coronavirus , Coronavirus Disease COVID-19 , Dendritic Cell , Enzyme , Gene , Gene Expression , Genes , Global Health , Immune Response , Interferon , Lymphocyte , Nasopharyngeal , Receptor , Remdesivir , Research , Respiratory , Ribonucleic Acid , RNA , RNA Sequencing , SARS , SARS-CoV-2 , Severe Acute Respiratory , Severe Acute Respiratory Syndrome , Syndrome , T Lymphocyte , Throat , Vaccine , Virus

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.

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Why Are Some People Seemingly Immune to Covid-19? Scientists May Now Have an Answer

Researchers tracked the immune responses of 16 people intentionally exposed to SARS-CoV-2 and pinpointed a gene that seems to help resist the virus before it can take hold

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Daily Correspondent

A female doctor in a mask and visor gives a nasal swab to a male patient.

More than four years after Covid-19 was declared a pandemic that has since totaled more than 775 million cumulative cases worldwide, scientists are shedding light on the specific immune responses that have made some people seemingly resistant to catching the virus.

New research emerging from the United Kingdom, conducted as part of the Covid-19 Human Challenge Study and the Human Cell Atlas project, has found that a combination of robust nasal cell defense and high activity of a particular gene work together to ward off the virus in some individuals before it can take hold.

The research, published last week in the journal Nature , provides clarity on the timeline of the human body’s immune response to SARS-CoV-2 and other infectious diseases.

“These findings shed new light on the crucial early events that either allow the virus to take hold or rapidly clear it before symptoms develop,” Marko Nikolić , the study’s senior author and an honorary consultant in respiratory medicine at University College London (UCL), says in a statement . “We now have a much greater understanding of the full range of immune responses, which could provide a basis for developing potential treatments and vaccines that mimic these natural protective responses.”

Conducted in 2021, the study began with the researchers spraying a low dosage of the original SARS-CoV-2 variant up the noses of 36 healthy adult volunteers who were both unvaccinated and had never had the virus before.

From this group, researchers collected 16 volunteers’ nasal and blood samples on multiple occasions—before exposure and several times in the following 28 days—to track the spread of the virus and the participants’ immune responses. Sequencing these samples, the team produced a data set containing more than 600,000 individual cells and their behaviors before, during and after exposure.

The volunteers’ responses fell into three distinct categories. Six people became ill and displayed symptoms; three people briefly tested positive for Covid-19 but were asymptomatic, known as a transient infection; and seven people consistently tested negative and displayed no symptoms, but built up an immune response to the virus—what the team called an abortive infection.

In these latter two groups, participants showed high baseline activity of a gene called HLA-DQA2, which helps to efficiently alert the immune system to potential threats.

“These cells will take a little bit of the virus and show it to immune cells and say: ‘This is foreign: You need to go and sort it out,’” Kaylee Worlock , a molecular biologist and post-doctoral research fellow at UCL, tells the Guardian ’s Hannah Devlin.

Another common trait among people in the two latter groups related to the production of interferon, or proteins that help bolster the body’s immune system. For these volunteers, interferon was produced in the blood before it appeared in the upper nasal region.

The people with transient and abortive responses developed a quick immune response—built up within about one day—inside their noses. Meanwhile, those who tested positive for Covid-19 took an average of five days to build up a nasal immune response.

Notably, the participants were not immune to getting Covid-19—some later caught the virus in the community, after the research concluded. And now, several other variants of SARS-CoV-2 are circulating—not just the original variant that was tested. But scientists say the research offers important clues to immune resistance.

“This study serves as a unique resource of previously uninfected SARS-CoV-2 participants due to its carefully controlled design and real understanding of ‘time zero’ for when the infection took place in order to measure the immune responses that follow,” José Ordovas-Montanes , an immunologist at the Harvard Stem Cell Institute who was not involved in the research, tells New Scientist ’s Sonali Roy.

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Christian Thorsberg | READ MORE

Christian Thorsberg is an environmental writer and photographer from Chicago. His work, which often centers on freshwater issues, climate change and subsistence, has appeared in Circle of Blue , Sierra magazine, Discover magazine and Alaska Sporting Journal .

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Immune response study explains why some people don’t get Covid

19 June 2024

High levels of a key gene in volunteers who managed to fight off infection quickly suggests it has a protective effect against SARS-CoV-2, according to a new study from researchers at UCL, the Wellcome Sanger Institute and Imperial College London.

The study, published in Nature , provides the most detailed view of how the body responds when exposed to an infectious disease. The researchers used single-cell sequencing technology to observe immune responses against SARS-CoV-2 infection in healthy adult volunteers, as part of the COVID-19 human challenge study 1 . Not all exposed participants went on to develop a COVID-19 infection, allowing the team to uncover unique immune responses associated with resisting sustained viral infection and disease.

SARS-CoV-2 has infected millions of people across the world since the beginning of the COVID-19 pandemic in 2019. While it is potentially fatal, many people who came into contact with someone who had tested positive for COVID-19 have managed to avoid getting ill themselves, whether remaining negative on PCR testing or having an asymptomatic case of the disease.

While previous studies have examined COVID-19 patients after the onset of symptoms, for the first time researchers have been able to document immune responses from the exact moment of exposure to the virus.

As part of the UK COVID-19 Human Challenge study with Imperial College London, 36 healthy adult volunteers without previous history of COVID-19 were administered SARS-CoV-2 virus through the nose.

Researchers performed detailed monitoring in the blood and lining of their noses, tracking the entire infection as well as the immune cell activity prior to the infection event itself for 16 volunteers. The teams at the Wellcome Sanger Institute and UCL then used single-cell sequencing to generate a dataset of over 600,000 individual cells.

Across all participants, the team discovered previously unreported responses involved in immediate virus detection. This included activation of specialised mucosal immune cells in the blood and a reduction in inflammatory white blood cells that normally engulf and destroy pathogens.

Individuals who immediately cleared the virus 2 did not show a typical widespread immune response, but instead mounted subtle, never-seen-before innate immune responses.

The results suggest that high levels of a gene called HLA-DQA2 before exposure helped people prevent a sustained infection from taking hold. People with high levels of this gene cleared the virus so effectively that they didn’t return a positive PCR test at all and had no symptoms, while another group tested positive intermittently and had very mild symptoms.

In contrast, the six individuals who developed a sustained SARS-CoV-2 infection exhibited a rapid immune response in the blood but a slower immune response in the nose, allowing the virus to establish itself there.

The researchers further identified common patterns among activated T cell receptors, which recognise and bind to virus-infected cells, offering insights into immune cell communication that could potentially be useful for developing targeted T cell therapies against COVID-19 and other infectious diseases.

Dr Kaylee Worlock, co-first author of the study from UCL Division of Medicine, said: “Studies so far have only offered a snapshot of what is going on during COVID-19, whereas our approach allowed us to study the evolution of infection in three distinct infection groups prior to and during infection, right through to the resolution, in unprecedented detail.”

Dr Marko Nikolić, senior author of the study and Honorary Consultant in Respiratory Medicine from UCL Division of Medicine, said: “These findings shed new light on the crucial early events that either allow the virus to take hold or rapidly clear it before symptoms develop. We now have a much greater understanding of the full range of immune responses, which could provide a basis for developing potential treatments and vaccines that mimic these natural protective responses.”

This study is part of the Human Cell Atlas initiative to map every cell type in the human body.

Dr Sarah Teichmann, senior author of the study, formerly at the Wellcome Sanger Institute, Co-founder of the Human Cell Atlas and now based at the Cambridge Stem Cell Institute, University of Cambridge, said: “As we’re building the Human Cell Atlas we can better identify which of our cells are critical for fighting infections and understand why different people respond to coronavirus in varied ways. Future studies can compare with our reference dataset to understand how a normal immune response to a new pathogen compares to a vaccine-induced immune response.”

This research was supported by Wellcome, Action Medical Research and Medical Research Council. For full funding acknowledgements, please refer to the publication.

Human challenge studies involve deliberate human infection ‘challenge’ of a small number of low-risk volunteers (healthy, young adults) under highly controlled settings. The Human COVID-19 Challenge study, pioneered by the government task force, Imperial College London, and Royal Free London NHS Foundation Trust enrolled participants from June to August 2021. For more information about the COVID-19 Human Challenge Study, please refer to the publication. The full list of inclusion and exclusion criteria and further details regarding the challenge set up and ethics can be found at https://www.nature.com/articles/s41591-022-01780-9
An abortive infection occurs when the body manages to prevent the onset of viral spread despite being exposed to the virus, defined in the study by all negative RT-qPCR results. The study further identified a new group of infection ‘intermediates,’ where low levels of the virus were detected. In these cases, a transient infection occurs, involving a brief period where the virus is present and partially replicates but fails to establish a significant infection or cause noticeable symptoms. In this intermediate group, they observed an immediate immune response in the nose that likely prevented the onset of a sustained infection.
Dr Kaylee Worlock's ResearchGate profile
Dr Marko Nikolic's academic profile
UCL Division of Medicine
UCL Faculty of Medical Sciences
The Human Cell Atlas
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Dr matt midgley.

E: m.midgley [at] ucl.ac.uk

Open access
Published: 21 June 2024

COVID-19 healthcare success or failure? Crisis management explained by dynamic capabilities

Ritva Rosenbäck 1 &
Kristina M. Eriksson 1

BMC Health Services Research volume 24 , Article number: 759 ( 2024 ) Cite this article

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Introduction

This paper presents a structured review of the use of crisis management, specifically examining the frameworks of surge capacity, resilience, and dynamic capabilities in healthcare organizations. Thereafter, a novel deductive method based on the framework of dynamic capabilities is developed and applied to investigate crisis management in two hospital cases during the COVID-19 pandemic.

The COVID-19 pandemic distinguishes itself from many other disasters due to its global spread, uncertainty, and prolonged duration. While crisis management in healthcare has often been explained using the surge capacity framework, the need for adaptability in an unfamiliar setting and different information flow makes the dynamic capabilities framework more useful.

The dynamic capabilities framework’s microfoundations as categories is utilized in this paper for a deductive analysis of crisis management during the COVID-19 pandemic in a multiple case study involving two Swedish public hospitals. A novel method, incorporating both dynamic and static capabilities across multiple organizational levels, is developed and explored.

The case study results reveal the utilization of all dynamic capabilities with an increased emphasis at lower organizational levels and a higher prevalence of static capabilities at the regional level. In Case A, lower-level managers perceived the hospital manager as brave, supporting sensing, seizing, and transformation at the department level. However, due to information gaps, sensing did not reach regional crisis management, reducing their power. In Case B, with contingency plans not initiated, the hospital faced a lack of management and formed a department manager group for patient care. Seizing was robust at the department level, but regional levels struggled with decisions on crisis versus normal management. The novel method effectively visualizes differences between organizational levels and cases, shedding light on the extent of cooperation or lack thereof within the organization.

The researchers conclude that crisis management in a pandemic, benefits from distributed management, attributed to higher dynamic capabilities at lower organizational levels. A pandemic contingency plan should differ from a plan for accidents, supporting the development of routines for the new situation and continuous improvement. The Dynamic Capabilities framework proved successful for exploration in this context.

Peer Review reports

The COVID-19 pandemic is a disaster [ 1 ]. However, it differs from many other disasters by the worldwide spread, the uncertainty about the patient treatment, especially in the beginning, and the long duration. The healthcare crisis management challenges in a long duration pandemic are different from management in short duration disaster like an earthquake or a major accident. The management in shorter crises or disasters is described in the research of surge capacity (SuC) [ 2 , 3 ], but the COVID-19 pandemic revealed that successful management in a pandemic, needs to be different [ 4 ]. Further, pandemics differ from other long-duration disasters like war or severe air pollution, due to the uncertainty of the type of healthcare and knowledge needed. Merely, the infected patients appear at the hospital, thus the first to receive information about both the number of patients and their needs are the professionals at the hospitals [ 4 ]. Usually the flow of information comes from a rescue leader through the regional management that prioritizes and distributes the patients to the hospitals [ 5 ]. The hospital management needs to use the in-house knowledge and improve the mobility at the hospital [ 6 ]. Thus, the management’s need in a pandemic is less hierarchical and more learning and innovative [ 4 , 7 , 8 ].

SuC expresses the demand of unusually high capacity caused by crisis and disasters [ 2 , 3 ]. The concept of SuC seems to be the base for the worldwide used NATO standard for crisis management, with a hierarchic structure and strong rules of communication [ 5 ]. Resilience (R) is the most used management framework in healthcare organizations, defined as the capacity to absorb shocks while maintaining function, focusing on two categories i.e., robustness and rapidity [ 7 , 9 ]. The strategic “inside-out” Resource-based view, focus on how the resources on hand could be used to the market “inside-out” and have developed during time to the organization’s ability to renew competences to adjust to changes in the surroundings, and include understanding of the requirements from the market or environment (“outside-in”) [ 10 ]. The different flow of information and the constant need for learning and development in an unknown and continuously changing environment could make the hierarchic system of SuC too static and less successful. Therefore, in a disaster such as the COVID-19 pandemic other approaches to crisis management need to be considered. The Dynamic Capability (DC) framework was designed to explain how organizations achieve and sustain competitive advantages by adjusting resources and adapting to changing environments. Originating from a resource-based view, Dynamic Capabilities (DCs) emphasize an organization’s ability to adapt resources to new conditions. From this perspective the DC framework has been limited applied in healthcare management research before the COVID-19 pandemic [ 11 , 12 , 13 ]. However, the possibilities of DCs in the context of the public sector have gained research interest, e.g., Furnival et al. [ 12 ] suggest further research into using the microfoundations and Pablo et al. [ 13 ] ask for more research on how managers or organizations can enable DC in the public sector. The application of the DC framework in health care organizations are thus gaining research interest and to understand the applicability of DCs in health care, especially in relation to unpredictable and long duration disasters, further research into the field is called for. Contributions to the field, demonstrating results from in-dept studies with hospital management expertise at different management levels may be especially valuable for building knowledge toward meeting future long-duration disasters and crises with similar characteristics. This study adopts and develops the DC framework to investigate effective resource utilization and how the DC framework could be more usable, especially in long-duration pandemics. This prompts the research question: How can the DC framework explain the disaster management in healthcare organizations during the COVID-19 pandemic? The research presented develops the concept of the DC framework, which is applied to a multiple qualitative case study to understand the management changes during the COVID-19 pandemic.

The paper starts with an overview of applied crisis management theories, thereafter the results from a structured review of the use of SuC, R and DC in healthcare research, especially focusing of disasters and pandemics, is presented. The methodology of a qualitative multiple case study and the two cases are outlined and thereafter the findings are reported. The discussion and conclusion wrap up the paper.

Crisis management in literature

SuC expresses the demand of unusually high capacity caused by crisis and disasters [ 2 , 3 ]. SuC have been studied over the last decade, mostly in healthcare organizations, but can be generalized to other systems involving complex activities [ 9 ]. The management part of SuC is carefully stated with solid rules concerning how and to whom to communicate and incorporates a hierarchy of decisions [ 5 ].

R was originally used to describe ecological systems’ ability to resist disturbances [ 9 ]. The theories of R have been developed in crisis management science with the aim of improving performance of systems during crisis. R should include all resources that need to be safeguarded from expected or unexpected disturbances and can be described both as being robust during change, but also as the ability to absorb uncertainty [ 9 ]. Kruk, et al. [ 14 ] describe the need during the outbreak of a disease or other disasters resulting in a surge demand for healthcare. The conclusion is that a resilient health system needs to be aware, diverse, self-regulating, integrated, and adaptive [ 14 ]. During the COVID-19 pandemic, R could be described by three required preconditions; global solidarity, legal framework, and workforce policies [ 15 ], which are aligned with the research of Kruk et al. [ 14 ] and Therrien et al. [ 9 ]. McDaniels et al. [ 7 ] recommend using R instead of SuC in healthcare organizations, due to the described less static management.

DCs focuses both on the perspective of how the market (outside) influences the organization (inside) and the perspective that the organization needs to adapt to the chosen market [ 16 ], but also to the inside-out perspective which values the organization’s knowledge and resources in the choice of strategy and marketplace [ 10 , 17 ]. Teece, et al. [ 18 ], considered founders of the DC framework, describe the resource based view as static, when organizations in the short term are stuck with existing knowledge and structure. DCs are a special class of capabilities that describe change and innovation essential when organizations need to sustain performance in a changing environment [ 19 ]. The aspect of cyclicity and moving through the DC phases in several iterations may be necessary for organizations to be able to continuously develop [ 12 ] and reach a higher level of understanding of their specific organizations planning characteristics, such as shown by Eriksson, et al. [ 20 ]. Pablo et al. [ 13 ] describe this iteration to learn and transform as experimenting.

Further, the importance of taking a holistic view of the organization is stressed as a prerequisite when moving towards the capability of transformation [ 20 ]. Developed DCs are difficult for competitors to replicate and will give a competitive advantage and innovative response in a rapidly changing market when time to market is critical [ 18 ]. Both inside-out and outside-in strategy capabilities need to be dynamic and constantly renewed [ 21 ]. For moderately dynamic markets it is possible with traditional routines to build on predictable and analytical processes and build DC from existing knowledge. However, for high-velocity markets, with unpredictable outcomes, DCs need to develop to be simpler, more experimental, and iteratively relying on situation specific knowledge within simple rules and are often described vaguely as “routines to learn routines” [ 11 ]. Capabilities that are not supporting changes is by a few scholars called static capabilities (SC), e.g., Dawson [ 22 ] is using SC for exploring knowledge management and Mortensen et al. [ 23 ] are using it to explore barriers for futures literacy. The DCs have advanced in different areas and hereafter the development over the last ten years in healthcare disaster management are focused and described.

Crisis management in healthcare literature

The COVID-19 made the healthcare business volatile and has caused an exponential increase in frequency of use of concepts of crisis management i.e., SuC, R, and DCs. A structured search in Scopus, searching “all fields” with the keywords “Healthcare” and “Disaster” (doted lines) or “Pandemic” (full lines) and “Surge Capacity”, “Resilience” or “Dynamic Capability” between 2010 and 2022, delivers a result of the amount of research papers applying the concepts, see Fig. 1 . Research studies investigating the use of R is more than ten times higher than SuC and DCs (left scale) and shall therefore be read at the right scale in Fig. 1 . SuC and R seem to have been used in healthcare crisis management research at least from the beginning of 2010th decade both for pandemics and disasters. The interest of R seems to rise in use especially in combination with disasters and the interest of DC started later, but the use in research increased after 2014. At the start of the COVID-19 pandemic in 2020 the research into all three concepts increased largely and DCs is the concept with the highest increase in publications between 2019 and 2022 (> 400 times) after which it exceeded the use of SuC. SuC declined between 2021 and 2022. Thus, exploring the DC concept in healthcare was found interesting.

Use of the crisis management concepts SuC, R and DCs

The search in Scopus was limited from all fields to; article title, abstract and the keywords was reduced to “healthcare” and “Dynamic capabilities” resulting in 88 papers (reduced from 5134 results). Further papers in the areas of computer science, focusing on simulations and analytics, were omitted, resulting in 54 papers. The abstracts of those 54 papers were read and 24 papers of the highest relevance were kept. All 24 papers were read in full, and the eight most interesting papers were studied in more detail in this research. In addition, five research papers, found outside of the Scopus search through snowball technique, were included because of additional interesting and highly relevant research. Thus, in total 13 papers, outlined in Table 1 , about DC in healthcare crisis management were studied in detail and used in the research presented in this paper.

Dynamic capabilities framework in healthcare

The DCs framework is usually divided into sensing, seizing and transformation [ 24 ]. However, other scholars express it differently as i.e., detection, understanding and reconfiguration [ 25 ] or i.e., dynamic managerial capabilities and dynamic organizational capabilities, where the latter is divided as described above, but the former divides into managerial cognition, managerial human capital, and managerial social capital [ 26 ]. Moreover, Sheng [ 27 ] divides the capabilities into three groups for the inside-out view. First the “system capabilities” with the content of written regulations, guidelines, and instructions. Secondly the “socialization capabilities” can be explained as the organizations shared ideology and basic values and influences how the members of the organization treat each other in a crisis. The third is expressed as “coordinating capabilities” and influences the number of fruitful contacts in the organization. For the outside-in view Sheng [ 27 ] describes “organizational sensemaking”, as a continuous process of how the organization is seeking information of the environment and how this is formed to common goals for the organization. Moreover, in a framework for decision-making in crisis in major projects, sensing is explored as an important framework category [ 28 ] In the developed method in this paper Teece’s [ 24 ] the microfoundations are used as framework categories i.e., sensing, seizing and transformation.

Sensing includes the identification of all kinds of risks and opportunities, e.g., technical advancements, suppliers’ possibilities to deliver and regulations, preferably before they arrive [ 12 , 29 ]. Research concerning sensing often refers to analytical and forecasting [ 30 ], and the need for real time data [ 8 ]. The capability of sensing focuses on service users, stakeholders, and suppliers [ 12 ] or on specific important factors e.g., problems detection, lack of coherence of safe routines or risk for high demand or exhaustion [ 31 ]. Ohrling et al. [ 8 ] describe the importance of rapidly understanding the unexpected during the COVID-19 pandemic and finding resources to increase the ability to analyze the situation and add that knowledge and experience to the emergency management team. Further, the communication to spread an always changing target and new information to the emergency management team and to everyone, to create a common understanding [ 8 ] could also be included in the DC of sensing. To make the sensing appear, meetings need to be highly frequent both in the organization and between organizations. However, it could be important to limit information due to a high and intense flow from different resources that may lead to misunderstandings [ 8 ].

Seizing can be seen as the enablers to make dynamic capabilities work and can both be already existent in the organization or newly developed. The DC of seizing provides a link between environmental change and internal adaptability [ 13 ] or it could be routines and processes for change [ 29 ]. A beforehand made contingency plan can be a part of the seizing; thus, these are often built on SuC and are therefore rather static and work against DC [ 32 ]. Seizing could also include culture and management capabilities in the managers’ choice of the competing priorities [ 12 ]. Routines could be how planning, evaluating and decision making should be done, how ideas are received and accredited and how leadership and teamwork are functioning in the organization [ 31 ]. Decentralization and a culture of rapidly responding from the information towards actions and more practically, routines and processes that enable higher frequency meetings, faster coordination, added experts and teamwork can be seen as parts of the DC of seizing [ 8 ].

The transformation includes implementing new processes and policies, for example, decentralization, co-specialization, or governance, and measuring improvement activities and reviewing plans and strategies [ 12 , 29 ]. . Moreover, some researchers refer to learning to respond to changes [ 31 ]. The transformation during a pandemic needs to be continuous with adjustments and rearrangements, due to changing information and environment and the activities need to be tightly followed and continuously evaluated to build flexibility [ 8 ]. The sensing, seizing and transformation as described here is hereafter used in this research.

The synchronization of microfoundations is necessary to make the DC perform [ 33 ]. An organization without seizing will become cosmetic and bureaucratic, and therefore ineffective to take decisions and fulfill the customer needs due to shortage of inter-relationships between the microfoundations. Further, a shortage of transformation will ensure customers and stakeholders that the service will be provided, but it never happens. Without sensing, the organization will appear arrogant and unwilling to seek ideas and knowledge from the outside, thus just focusing on internal plans and strategies [ 12 ]. Whereas, a strong sensing capability could lead to high expectations of seizing and transformation, causing a capability gap, which could be recognized by a lack of top management [ 18 , 29 ]. Moreover, they also mean that a strong sense and a strong transformation at local organizational level implies local unit-focused initiatives, thus, may suboptimize the local unit and not benefit the whole organization. If sensing and seizing capabilities are high, it leads to high barriers between local units, but could also lead to barriers between local units and the top management [ 29 ]. At the daily level, especially in healthcare, the transforming capability is strongest, and the staff will try their best to help the patients. However, a focus on operational tasks may lead to organizations with difficulties in verifying their capacity for change and responding quickly to changes in the surroundings [ 34 ]. Furnival et al. [ 12 ] suggest that organizations in a disaster are different, thus sensing will be more important to be able to rebuild organizational confidence and capability of movement. However, in non-crisis organizations, seizing may be of higher importance, where commitment and culture should help ensure continuous development.

Methodology for the case study and case description

The methodology applied in the research presented is multiple case study. The case study methodology includes the collection of internal hospital documentation, documentation from externa public sources and qualitative data collection through interviews. The case studies are considered suitable when capturing different and elusive aspect and perspectives from real context [ 35 , 36 ]. Thus, the method was chosen to capture and develop an encompassing view of capabilities for disaster management during the COVID-19 pandemic. The selection of case hospitals was meticulous. Several hospitals were considered before finalizing the choices [ 36 , 37 ]. Key diversity factors included hospital size, infection pressure, pandemic timing, collaboration ability, and management stability. The first case, a medium-sized hospital, faced high and early infection pressure, could transfer patients, and had a stable organization. The second case was chosen for its contrasting attributes: larger size, lower and later infection pressure, responsibility to assist other hospitals, and a recent management change. To understand the selected cases, internal documents regarding mission and organization both before and during the Covid-19 pandemic were studied. Further, documents from external public sources were gathered and studied, e.g., newspaper articles and information from national press conferences during the pandemic to increase the knowledge about the pandemic situation and the cases.

The multiple and qualitative case study was built on semi-structured interviews with managers that were conducted about a year after the start of the COVID-19 pandemic. The choice of semi-structured interviews as data collection method were considered valuable for the multiple qualitative case study, to gain focused data and the managers personal view of the management [ 36 ]. Case studies produce context-dependent knowledge, and the data could be used to understand the complex issues of the aspects of the managers dynamic management during the pandemic [ 38 ]. The narratives from managers of different levels were used to identify their opinion of the organization’s management practice.

Case descriptions

The first investigated case (A) is a middle-sized hospital with about 1300 employees, located in a large Swedish region, with several hospitals. The case hospital is an emergency hospital, but without an infection department and with few intensive care unit (ICU) beds. The increase of the COVID-19 infection rate in the catchment area was rapid in the beginning of the pandemic and sometimes the percentage of hospitalized citizens was the highest in the country [ 39 ]. The hospital was about to implement a new NATO standard with instructions for starting a regional command center (RCC) at the regional headquarters and local command centers (LCC), with static rules for how to communicate and make decisions [ 5 ] and concluded the implementation during the beginning of the pandemic.

The second case hospital (B) was chosen to be different, as sought to be advantageous for designing a multiple case study [ 36 ]. Case hospital B is the central hospital in a less populated region (compared to Case hospital A). This region also includes two local hospitals. Case B has about 5000 employees and have an infection department and the most ICU beds in the region. Just before the COVID-19 pandemic the healthcare director was replaced and the region was reorganized and a regional organization was implemented with some of the department’s management centralized to the main hospital, for example the departments of infection and the departments of ICU. The contingency plan was not updated to the new organization.

The interview sessions started in March 2021, one year after the onset of the pandemic, and were completed within a month for Case A and another month for Case B. At Case A, a total of twelve interviews from three organizational levels i.e., hospital manager group (3), department manager group ( 5) and unit manager group (4), were conducted. The presentation of the interviewees is found in Table 2 including the time of the interview. At case B, with a total of eight interviews were performed the hospital management were merged to a regional healthcare management group with the responsibility of the departments, directly reporting to the director of healthcare and hospital managers were not existing. Important functions were found at the regional level and therefore the three levels of management studied became i.e., regional manager group (RM, 3), regional healthcare manager group (2) and department manager group (3) and in total eight interviews were conducted. The presentation of the interviewees is found in Table 2 including the time of the interview.

The interviews were semi-structured, which means the interviewees were allowed to talk freely, and the interviewer avoided affecting the interviewees [ 37 ]. The same researcher moderated all interviews and used a semi structured interview guide as been described in earlier research [ 6 ], with topics of the feeling of the size of the disaster, the contingency plan, how they built capacity for the COVID-19 patients, management during the pandemic and the information flow, as support. Another researcher actively observed the interviews and used the interview guide to follow the completeness of the collection of information and sometimes added a few questions for completion. All interviews were conducted via video conferencing with both sound and video recording. The interviewees were later provided with feedback in the form of a lecture and a written report, to make sure the information gathered was correctly understood [ 40 ]. The recordings were verbatim transcribed and NVIVO14 was used to structure the data. Thereafter, the data were exported to Excel and further analyzed.

Methodology analytical development

The DC and SC frameworks were applied and further developed in this study to explore and analyze the management during the pandemic in the cases. To align the data in relation to the DC and SC frameworks it was suitable to perform the analyses deductively. Therefore, the data were deductively analyzed by selecting excerpts, from the interviews, that aligned with the different DC framework categories (microfoundations)i.e., sensing, seizing and transformation, and SC framework categories (microfoundations), i.e., non-sensing, non-seizing, and non-transformation following other scholars’ definitions and proposals in their research. Moreover, to be able to receive deeper knowledge about the organization and the different management groups’ viewpoint of the organization’s performance at different organizational levels, the data was divided into organizational levels, i.e., department, hospital, regional and national level in case A. In case B one additional level of regional healthcare was used necessary by the special organization, where the regional healthcare organization worked besides the RCC stated in the contingency plan. The hospital level contained a spontaneously developed group of department managers during the first wave of the COVID-19 pandemic. However, during later waves a LCC was started as stated in the contingency plan and emerged with the department managergroup at the hospital level. Table 3 shows the 42 different categories in the deductive analyze.

The interviewee’s excerpts were analyzed several times both from the transcription of the interviews and later from the framework categories. This procedure was conducted to enhance the rigor of the research [ 41 ]. To be able to analyze and present the findings both qualitatively and quantitatively, the excerpts from each interviewee were only coded once to one framework categories.

The deductive analysis of the excerpts in the interviews to the framework categories of DCs and SCs at different organization levels was suitable and the researchers found the method satisfactory. The imposed quantitative analysis is done according to the visualizations in Table 4 .

Findings: multiple case study

A qualitative analysis was conducted to clarify special phenomenon in each of the cases. Moreover, the data was quantitatively analyzed according to the developed method described above. The framework categories and examples of excerpt of each case, group of managers, organizational level are structural gathered in Tables 5 , 6 , 7 , 8 , 9 and 10 and are referred to in the text to prove different phenomenon in the organization. The use of the group of managers instead of a single title for every excerpt gives an improved overview of the management opinions at different organizational levels. Moreover it ensures keeping the anonymity of the hospital and their employees. The excerpts about the national level were fewer and were therefore excluded from the table. However, DC at a national level mostly referred to the national organizations of ICU and infection physicians, who made large efforts to gather important medical information and treatment of the COVID-19 patients and to spread the knowledge to other physicians through webinars once a week as the chief medical officer at case A expressed:

“The Swedish Association of Infectious Disease Physicians has taken on a great deal of responsibility and has held regular webinars with knowledge updates with leading researchers and clinicians in this field.” (Chief medical officer, case A).

Some DC was about the prognoses from the National Board of Social Affairs and Health and the public health authority that was helpful especially towards the end of the pandemic for example:

“During the late spring (2020) and just before the summer, more scenarios are brought up that were sort of adapted based on different regions that you could then work with” (The chief of staff at regional level, case B).

Thus, the SC excerpts describe lack of information and the continuously changing information from Swedish authorities for example:

“Quite shaky at first. Slightly different message. Message not coming … We felt it was messy”. (The chief of staff at regional level, case B).

Figure 2 visualizes the excerpts of each of the units and department managers of case A and there were about double as many as the excerpts of the hospital management. At case B the healthcare management had a slightly smaller number of excerpts. This needs to be remembered during the semi-quantitative analysis. Moreover, Fig. 2 envisions that the managers find the organizations to be more dynamic than static. The hospital manager and unit managers in case A and the healthcare managers in case B have proportionally fewer SC excerpts.

Number of excerpts/group of managers

Figure 3 visualizes the number of excerpts per organization level to show their dynamically respectively statically behavior during the pandemic. The department level in case A received the highest number of dynamic excerpts followed by the hospital level, however, the hospital level has a higher proportion of SC. The highest proportion of static behavior, showing nearly the same number of excerpts as DC, are found at the regional level. The examples of criticism was that they lately understood the severeness of the COVID-19 pandemic (Table 6 , RegLev: NonSensa), pushed to work use the NATO standard even if it was not implemented (Table 7 , RegLev: NonSeiza) and kept the structure of crisis management even when the disasterwere prolonged. However, further into the COVID-19 pandemic RCC lost power towards the normal group of hospitals directors, which made the hospital managers more positive towards the regional level. (Table 7 , RegLev: Trans). Examples of criticism from the department managers towards the regional level appears later in the COVID-19 pandemic when the politicians changed focus and made the cooperation over the region work less effective (Table 6 , RegLev: NonSeizb). The politicians also caused dissatisfaction among the professionals by building an ICU at a fair hall outside the hospitals which was never used.

Number of excerpts/organization level

In case B the highest numbers of dynamic excerpts were at the hospital level and at the regional level, but the proportion of SC at the regional level was higher. The healthcare level had the highest proportion of SC with slightly the same number as the DC correlative to the situation at the regional level at case A. The healthcare level got criticised both from the department and the regional managers, for example one regional manager’s questioned the active decision at the healthcare level to have their own regional crisis management beside the RCC and that they did not start an LCC at the case hospital (Table 10 , RegHealthLev: NonSeiza; Table 8 , RegHealthLev: NonSeiza). Further, the regional management had a high proportion of SC especially from the healthcare level, because of the regional levels strong statement of a contingency plan that maybe was not appropriate in a pandemic (Table 9 , RegLev: NonSeiza). The regional healthcare level pushed for management more as usual as in line with the hospital managers at case A (Table 9 , RegHealthLev: Seiza). Thus, the department managers started an local manager group at the hospital for practical decisions and needs without any mandate and official agreement (Table 8 , RegHealthLev: NonSeizb).

Number of interviewees excerpts for each group of managers/organizational level

When looking closer of how different management groups assesses each organization level (Fig. 4 ) the cases differ even more. In Case A the managers consider their level with positive eyes as well as the level nearest above, for example when the department manager group praised the hospital manager for his braveness (Table 6 , HospLev: Seiza) or when the department manager group talked about their thoughts of getting the employees to act with the managers spirit (Table 6 , DepLev: Seiza). However, the most SC also appeared for the level directly above, for example, that the department level underestimated the COVID-19 changings (Table 5 , DepLev: NonSens) and the lack of tools for keeping employees at the working place in a stressing environment (Table 6 , HospLev: NonSeiza). However, the unit managers evaluates the second nearest hospital level dynamic and comment on the short distance to the hospital director, known by everyone (Table 5 , HospLev: Seiz).

All manager groupsof Case B seem to be self-critical and considered their own level as being somewhat static, for example the department managers reflection that the idea to start a new department was not the best choice (Table 8 , DepLev: NonTrans) or the regional managers reflection of their poor management when the healthcare LCC was not started in the beginning of the pandemic (Table 10 , RegLev: NonSeiz). The regional manager group seem to be self-confident about their own level (Table 10 , RegLev: Seiz), but the number of excerpts from the regional managers reflected that the healthcare level has higher proportion of SC than DC caused by the special crisis management group at healthcare regional level as described before. The healthcare manager group have a high number of dynamic excerpts towards the hospital level, who they found transformed by building additional beds at ICU (Table 9 , HospLev: Trans), but do not have many comments about the department level. The proportion of SC is high from the healthcare managers towards the regional level arguing that a pandemic need to be managed by normal healthcare management (Table 9 , RegLev: Nonseizb). Caused by interviewing the regional management of case B, the excerpts about the national level are present in higher numbers – both positive and negative.

At hospital A the sensing and transformation occurred more frequently at lower organization levels (Fig. 5 ) with a descending occurrence at higher levels. At the department level in case A they listened to the international network and because of their closeness to the production they saw the changing number of patients and clearly sensed the level of worry and stress on the organization (Table 6 , DepLev: Sensa). Further, they early on realized that a long duration pandemic made the situation different from other disasters (Table 6 , DepLev: Sensb). The proportion of transformation was high and for example they managed an increase in employment at the ICU from 160 to 320 (Table 6 , DepLev: Transb). Moreover, they changed working procedures, for example agreeing on an allowance to shout out into the corridor when you needed something to avoid taking the Personal Protection Equipment (PPE) off and on again (Table 6 , DepLev: Transa). Examples of non-transforming capabilities were overusing PPE, the infection spread between employees, the shortage of employees at the critical units and the shortage of training before work a shift at a new position (Table 5 , DepLev: NonTrans; HospLev: NonTrans).

Excerpt/organization level, case A

At the hospital level they sensed the employees’ anxiety and worries about the risk of infection for themselves and relatives and the knowledge shortage when moving to other tasks and transformed by arranging psychological help for the employees (Table 7 , HospLev: Transa). Moreover, they helped with recruitment, moved employees to the units needed, built education and hygiene rounds, and started and stopped planned surgery several times (Table 7 , HospLev: Transb). The meetings became digital and the number of employees in the coffee rooms at once was reduced and they reconstructed several departments. The non-transformation was rather high at the hospital level, possibly a sign that transformation was too late or not large enough (Table 7 , HospLev: NonTrans).

The seizing was found equally at department and hospital level. Hospital, department, and unit levels of case A increased the frequency of meetings to daily or even more. (Table 5 , DepLev: Seiz). The unit managers used the existing dynamic quality of the organization including single rooms at the wards (Table 6 , DepLev: Seizb), the united management of all wards and the knowledgeable management of ICU to take necessary decisions and execute them. The cooperation between the hospital departments increased and there was a focus on healthcare and all other questions were not prioritized (Table 7 , HospLev: Transc). The non-seizing was the most occurring static behaviour, and it increased in occurrence with higher organization level. Thus, the structure for moving employees to even out the pressure, for example agreements of compensation and individual education, were not in place and were not working properly (Table 6 , HospLev: NonSeizb). Moreover, department managers responsible for the reduced planned healthcare were not allowed to use their free time to develop their organization and they also commented that the focus of staffing at ICU was too high and that the decisions about the start of surgery in between the waves came to late (Table 6 , HospLev: NonTrans). The non-seizing towards the regional level was higher than the seizing. The criticism was that there was too little capacity at ICU in the region, neither agreements for cooperation between the public hospitals nor between the private and public hospitals were in place (Table 6 , RegLev: NonSeiza). Moreover, the contingency plans structured methods of communication, built for short term disasters, caused a lot of questions, especially during the first wave and no one listened to the managers respond about what happened at the hospital (Table 7 , RegLev: NonSeizb). The excerpts of seizing described the appreciation when the production group later became more powerful. Moreover, the ICU managers met over the region at a regional level and made decisions (Table 6 , RegLev: Trans).

The DC and SC excerpts pattern/organization level in case B were different compared to case A (Fig. 6 ). Instead of the highest number of excerpts about transformation near the production, the transformation in case B seems to have been high at department, hospital, and regional level and lower at the healthcare level. The number of excepts about sensing was surprisingly highest at the regional level, which possibly is due to the highly experienced and knowledgeable regional chief hygienist physician’s high and his trust and a good international network (Table 8 , RegLev: Sens). Moreover, the chief hygiene physician contributed to merely transforming the organization by decisions to decrease the infection between employees and at elderly homes (Table 10 , RegLev: Trans), which also caused the high number of transformation excerpts at the regional level. The number of excerpts for non-seizing is high both at the healthcare level and the regional level due to the earlier mentioned argumentation unclearness of documentation about where decisions were made (Table 10 , RegHealthLev: NonSeizb) and this meant a focus of seizing at hospital level. The non-transformation was rather high both at the healthcare level and at the regional level.

Excerpts/organization level Case B

The discussion is divided into discussion about the developed research method and discussion about the result of the multiple qualitative case study.

Research method

The research presented developed the use of DC in a qualitative deductive analysis of interviews and is novel especially in healthcare organizations. The data were analyzed with framework categories (microfoundations)of DC i.e., sensing, seizing and transformation following other scholars’ approach, e.g., Teece et al. [ 18 ]. , . In addition to this proven application of DC the interviewees’ excerpts, which narrate a static behavior, were coded as framework categories (microfoundations) of SC i.e., non-sensing, non-seizing, and non-transformation to increase the visibility of malfunctions in the disaster management analysis [ 22 , 23 ]. The coding of both DC and SC contributes to a more encompassing analysis of the organizations’ development during the COVID-19 pandemic. The introduction of SC shows important insight also into occurrences that may reverse the movement towards transformation of the organization. Further, the coding was divided by management group and organization levels, which revealed a visualization of the dynamics in between the management levels which had not been found in earlier research. The excerpts were only coded once and therefore the qualitative analysis could partly be quantitative even if some excerpts might contain several items. The method was used to analyze multiple cases and successfully revealed differences between the organizations when using this developed technique of analysis.

Multiple case study

The professionals working in production in both cases clearly sensed the situation when the COVID-19 patients arrived and the organization rapidly transformed to save lives, in line with research by Teece [ 34 ] and Ohrling et al. [ 8 ]. The early sensing at department level in case A, due to an international network made the organization transform even before the first patient arrived. These occurrences of sensing made the response to changes in demand possible even with high focus on operational tasks, despite such situations can be proved to be non-resilient [ 12 , 34 ].

All DCs were, according to the managers narratives, present at the department level in case A and the occurrence of high seizing impeded the suboptimizing of the local unit over the whole organization that could occur with strong sensing and transformation [ 18 , 29 ]. Moreover, seizing, which Furnival et al. [ 12 ] mean is advantageous when working with continuous development, might be a sign of a higher need of continuous development in a long-lasting pandemic than in a short crisis.

The highest occurrence of sense in case A was found at the department level and led to high expectations of seizing and transformation, which according to our research was not delivered from the regional or national level, which is aligned with situations described by other scholars [ 8 , 18 , 29 ]. In fact, the quota between the number of interviewees’ excerpts/framework categories of seizing and non-seizing decreases with higher organization level in case A, which suggests that the top management was less dynamic. The low sense at the regional level made the mistrust high, possibly because that they appeared arrogant and unwilling to change, in line with the study of Furnival et al. [ 12 ]. When the RCC was overtaken by the hospital managers, this production group made the organization more dynamic, and the sense of the situation was more easily transferred to the regional level. Later, when the politicians started to interfere with the organizations, the cooperation between the hospitals decreased, which resulted in suboptimization of the local units in the organization, which decreased the overall organizational efficiency, as also expressed by Ljungquist [ 29 ].

However, the situation in case B, where the non-official department management group originated in the absence of a strong hospital manager or a working LCC, became different. The department management group sensed the situation and transformed accordingly, which according to Ljungquist [ 29 ] and Teece et al. [ 19 ] research could cause suboptimization of the regional cooperation as well as high barriers between the department managers and the regional healthcare management. However, because the sense was high at the regional level the barriers between the department manager’s group and regional management were not seen. The chief hygiene physician at regional level early sensed the situation, by his international network and reacted fast, transformed, and successfully reduced the infection rate also outside the hospital. His placement at the top of the organization, far away from the production, was of a less hindrance due to his and his team members’ high frequency and trustful contacts with the organization’s lower management levels. The lower occurrence of sensing in case B, except for the regional level, is probably the cause of the decreased confidence between the organization levels, which is in line with Furnival et al. [ 12 ]. Moreover, Ljungquist [ 29 ] and Teece et al. [ 18 ] discuss that a higher occurrence of seize could mean higher barriers and mistrust both between local units and the units and top management, which is also recognized in case B. The low sense at healthcare level made the mistrust even higher possibly due to the appearance of arrogancy and unwillingness to change [ 12 ].

When the knowledge increased, and the COVID-19 infections changed, the transformation continued in cycles, as Eriksson et al. [ 20 ] highlighted in their research, for example when the surgery started stopped and restarted several times in case A. Another cyclic change occurred in case B when the launching of a new infection department failed due to problems with staffing. This proved an important learning point for the next step of transformation when instead an old inpatient unit was transferred, which follows the experimentation work described by Pablo et al. [ 13 ].

The information flow during the COVID-19 pandemic was enormous especially in case A with the higher and earlier breakout and the recommendations often changed and made the information channels break down. Using integrated information from different sources from different management levels like Ohrling et al. [ 8 ] suggest could probably also in our case reduce the amount of information and reduce misunderstandings.

The contingency plans, which the regional crisis management at both cases insisted on following were designed to manage a short-term crisis and seemed to be built according to a static and hierarchical SuC. However, this and other studies reveal a need for more distributed management in a long-term disasters [ 4 , 7 , 8 ]. Reality often differs from beforehand plans and if the plans are followed too strictly the organization will be static and not able to follow the dynamic changes [ 32 ]. The regional level’s insisting on sticking to the contingency plan excluded them from supporting the pandemic. Moreover, in case B the contingency plan caused a lot of argumentations about the plan instead of looking at the reality and developing a sound cooperation between the levels in the extended work caused by the pandemic. However, the regional healthcare level in case B insisted on keeping normal management routines, but because of the low sensing at regional healthcare level in case B this did not function. Whereas in Case A this approach worked well. The focus on following the plan in Case B possibly made the management levels less sensitive to the situation [ 12 ]. The suggestion from Eisenhardt et al. [ 11 ] to have “routines to learn routines” could build a more successful disaster management in a next pandemic.

Concluding discussion multiple case study

Case A had at department and hospital level well developed and synchronized DCs and managed the high pressure of the COVID-19 pandemic successfully, as foreseen by other scholars [ 12 , 33 ]. The managers in case A described that they and their employees became more self-confident and took decisions independently, which is in line with the reasoning by Ohrling et al. [ 8 ] about decision space as a success factor during the COVID-19 pandemic. The cooperation and trust at department and hospital levels increased during the pandemic, which is in line with research by Ohrling et al. [ 8 ] and Pablo et al. [ 13 ]. Higher management levels lacked developed DCs, which grew mistrust between the hospitals in the region and the regional management.

However, in case B the seizing and non-seizing were the strongest capabilities, which could be the sign of a concentration and discussion of routines in the overall organization rather than supporting a transforming at department level to save lives. The seen self-criticism in case B could be a sign that the management was malfunctioning, and they were looking for what was wrong at their position. To conclude, Case B coped well with the pandemic, however, they might have had problems succeeding if encountering the higher infection rate, such as in case A.

Conclusion/relevance/contribution

The method, using a deductive analysis of analyzing with DC and SC, different management groups and organization levels, has successfully been used when explaining the crisis management in healthcare organizations during a long-term disaster as a pandemic. This novel way of analyzing data facilitated a structured and detailed explanation of organizational behavior and has not been found in earlier research.

The case hospitals studied showed major differences, when evaluated with the promising DC-method; In case A the hospital manager was considered by the lower-level managers to be brave and strong and supported the professions sensing, seizing and transformation at the department level. Due to the information developed at profession level, the sensing did not reach the regional disaster management, thus could not appropriately support the transformation and their power was reduced in favor of the normal management and cooperation between hospital managers in the region. However, in case B, where the contingency plans stated LCC were not started, the hospital suffered from lack of management and started their own department manager group to be able to take care of the incoming patients. The seizing was high in the organization with the department management developing their own routines, while the regional level and regional hospital level got stuck in discissions about the best choice of management between disaster management or normal management. However, both cases did use DC’s and the capabilities were synchronized enough to withstand the COVID-19 pandemic at the level needed.

The managerial contributions from thisresearch are in line with other scholars.Crisis management in a pandemic need to be more distributed and dynamic and this view need to be the starting point for top management to develop a contingency plan specialized for pandemics. The pandemic plan should manage to develop routines according to the demand from an ongoing pandemic, develop and use DC’s in the whole organization to support the profession to sense, seize and transform. Moreover, building professional networks could help reaching an early sensing, where two examples are, the one that made case A start early to build capacity and the one at case B that reduced the infection rate, which will give an opportunity to save lives. In a long-lasting pandemic, cyclic and continuous improvement seems to be needed.

Limitations and future research

A limitation of this paper,, is its potential to generalize the findings from two Swedish hospitals’ case studies to other healthcare facilities or different organizations. THowever, this limitation is somewhat outweighed by the successful intention of obtaining rich data coupled with an in-depth analysis based on interviews with different manager groups’ view of the management at different organizational levels, which contributes an encompassing view of the applicability of the DC framework in health care. Nevertheless, additional research is needed to enhance the promising method’s effectiveness and support its broader development. It is highly recommended to conduct further studies in this area, expanding its application to diverse types of organizations and environments. It would be interesting to supplement the data with further inquiries about the current application of lessons learned during the pandemic. Especially what was learnt about the possibilities for flexible organizations to make multiple transformation to follow the changing environment during av pandemic. Not just that they transformed but also why some managers was able to build trust and avoid power games and negative story telling in the organisation. To summarize it is important that the insights gained from the COVID-19 pandemic should be carefully refined to strengthen disaster management, thus improving our readiness for future pandemics.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Dynamic Capabilities

Static Capabilities

Surge capacity

Framework categories

Transformation

Non-Sensing

Non-Seizing

Non-Transformation

Local command centre

Regional command centre

Department level

Regional healthcare level

Hospital level

Regional level

Intensive care unit

Personal protective equipment

Iftikhar R, Müller R. (2019). Taxonomy among triplets: Opening the black box. Int. J. Manag. 2019; 10(2).

Barbisch DF, Koenig KL. Understanding surge capacity: essential elements. Acad Emerg Med. 2006;13(11):1098–102.

Article PubMed Google Scholar

Hick JL, Hanfling D, Burstein JL, DeAtley C, Barbisch D, Bogdan GM, Cantrill S. Healthcare facility and community strategies for patient care surge capacity. Ann Emerg Med. 2004;44(3):253–61.

Article PubMed PubMed Central Google Scholar

Rosenbäck R, Svensson A. (2024). Management learning in public healthcare during pandemics. Learn org. 2024.

NATO [Internet]. 2022 Aug 11 [cited 2023 Apr 14]. https://nso.nato.int/nso/home/main/home .

Rosenbäck RG, Svensson A. Resilience in keeping the balance between demand and capacity in the COVID-19 pandemic, a case study at a Swedish middle-sized hospital. BMC Health Serv Res. 2023;23(1):202.

McDaniels T, Chang S, Cole D, Mikawoz J, Longstaff H. Fostering resilience to extreme events within infrastructure systems: characterizing decision contexts for mitigation and adaptation. Global Environ Change. 2008;2:310.

Article Google Scholar

Ohrling M, Solberg Carlsson K, Brommels M. No man is an island: management of the emergency response to the SARS-CoV-2 (COVID-19) outbreak in a large public decentralized service delivery organisation. BMC Health Serv Res. 2022;22(1):1–17.

Therrien MC, Normandin JM, Denis JL. Bridging complexity theory and resilience to develop surge capacity in health systems. J Health Organ Manag. 2017;31(1):96–109.

Barney J. Firm resources and sustained competitive advantage. J Manag. 1991;17(1):99–120.

Google Scholar

Eisenhardt KM, Martin JA. Dynamic capabilities: what are they? Strateg Manag J. 2000;21(10/11):1105–21.

Furnival J, Boaden R, Walshe K. A dynamic capabilities view of improvement capability. J Health Organ Manag. 2019;22(7/8):821–34.

Pablo AL, Reay T, Dewald JR, Casebeer AL. Identifying, enabling and managing dynamic capabilities in the public sector. J Manag Stud. 2007;44(5):687–708.

Kruk ME, Myers M, Varpilah ST, Dahn BT. What is a resilient health system? Lessons from Ebola. Lancet. 2015;385(9980):1910–2.

Sundararaman T, Muraleedharan VR, Ranjan A. Pandemic resilience and health systems preparedness: lessons from COVID-19 for the twenty-first century. J Soc Econ Dev. 2021;23:290–300.

Article CAS PubMed PubMed Central Google Scholar

Porter ME. Competitive strategy. New York: The Free; 1985.

Hunt SD, Morgan RM. The comparative advantage theory of competition. J Mark. 1995;59(2):1–15.

Teece DJ, Pisano G, Shuen A. Dynamic capabilities and strategic management. Strateg Manag J. 1997;18(7):509–33.

Evans JM, Brown A, Baker GR. Organizational knowledge and capabilities in healthcare: deconstructing and integrating diverse perspectives. SAGE Open Med. 2017.

Eriksson K, Carlsson L, Olsson AK. To digitalize or not? Navigating and merging human- and technology perspectives in Production Planning. Int J Adv Manuf Technol. 2022;122(11–12):4365–73. https://doi.org/10.1007/s00170-022-09874-x .

Hunt SD, Madhavaram S. Adaptive marketing capabilities, dynamic capabilities, and renewal competences: the outside vs. inside and static vs. dynamic controversies in strategy. Ind Mark Manag. 2020;89:129–39.

Dawson R. Knowledge capabilities as the focus of organisational development and strategy. J Knowl Manag. 2000;4(4):320–7.

Mortensen JK, Larsen N, Kruse M. Barriers to developing futures literacy in organisations. Futures. 2021;132:102799.

Teece DJ. Explicating dynamic capabilities: the Nature and microfoundations of (sustainable) enterprise performance. Strateg Manag J. 2007;28(13):1319–50.

Loureiro R, Ferreira JJ, Simoes J. Understanding healthcare sector organizations from a dynamic capabilities perspective. Eur J Innov Manag. 2023;26(2):588–614.

Karali E, Angeli F, Sidhu JS, Volberda H. Understanding healthcare innovation through a dynamic capabilities lens. Healthcare entrepreneurship. Routledge; 2018. pp. 108–43.

Sheng ML. A dynamic capabilities-based framework for organizational sensemaking through combinative capabilities towards exploratory and exploitative product innovation in turbulent environments. Ind Mark Manag. 2017;65:28–38.

Iftikhar R, Momeni K, Ahola T. Decision-making in crisis during megaprojects. J Mod Proj Manag, 2022; 9 (3).

Ljungquist U. Unbalanced dynamic capabilities as obstacles of organizational efficiency: implementation issues in innovative technology adoption. Innov. 2014;16(1):82–95.

Chokshi A, Katz H. Emerging lessons from COVID-19 response in New York City. JAMA. 2020;323(20):1996–7.

Linden AI, Bitencourt C, Muller Neto HF. Contribution of knowing in practice to dynamic capabilities. Learn Organ. 2019;26(1):60–77.

Boin A, Hart P, Stern E, Sundelius B. The politics of Crisis Management: Public Leadership under pressure. Cambridge: Cambridge University Press; 2016.

Book Google Scholar

Sirmon DG, Hitt MA, Ireland RD. Managing firm resources in dynamic environments to create value: looking inside the black box. Acad Manag Rev. 2007;32(1):273–92.

Teece DJ. Business models and dynamic capabilities. Long Range Plann. 2018;51(1):40–9.

Bell E, Bryman A, Harley B. Business research methods. 5th ed. Oxford, United Kingdom: Oxford University Press; 2019.

Yin RK. Case study research and applications design and methods, sixth edition. Sage; 2018.

Gioia D, Corley K, Hamilton A. Seeking qualitative rigor in Inductive Research: notes on the Gioia Methodology. Organ Res Methods. 2012;16(1):15–31.

Flyvbjerg B. Five misunderstandings about case-study research. Qual Inq. 2006;12(2):219–45.

Folkhälsomyndigheten. Presskonferenser [Internet]. 2023 Apr 14 [cited 2023 Apr 14]. https://www.folkhalsomyndigheten.se/sok/?q=presskonferenser .

Walsham G. Doing interpretive research. Eur J Inf Syst. 2006;15(3):320–30.

Carroll JM, Swatman PA. Structured-case: a methodological framework for building theory in information systems research. Eur J Inf Syst. 2000;9(4):235–42.

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R.R initiated the paper, planned, and collected the empirical data. Both authors conceptualized, analyzed, and wrote the paper. K.E. contributed with guidance and improving readability of the paper.

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Rosenbäck, R., Eriksson, K.M. COVID-19 healthcare success or failure? Crisis management explained by dynamic capabilities. BMC Health Serv Res 24 , 759 (2024). https://doi.org/10.1186/s12913-024-11201-x

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Timely research on the economic health impacts of COVID-19 through funding to the National Bureau of Economic Research
Research on county-level disparities in COVID-19 morbidity and mortality through a contract with the Institute for Health Metrics and Evaluation

The Initiative also helped develop a community of investigators who produced valuable research findings, including—

Not All Homes Are Safe: Family Violence Following the Onset of the COVID-19 Pandemic (February 2022)
Risk for Depression Tripled During the COVID-19 Pandemic in Emerging Adults Followed for the Last 8 Years (April 2023)
Inequitable Access to General and Behavioral Healthcare in the U.S. During the COVID-19 Pandemic: A Role for Telehealth? (April 2023)
Blurred Border or Safe Harbor? Emotional Well-Being Among Sexual and Gender Minority Adults Working From Home During COVID-19 (April 2023)
COVID-19 Stress and Child Behavior: Examining Discrimination and Social Support in Racially Diverse ECHO Cohorts (August 2023)

A key product of the SBE COVID-19 Initiative is the SBE COVID Consortium , a hub for communication and collaboration among NIH-funded projects housed at the University of Michigan. The consortium focuses on disparities and vulnerable populations. It includes 15 research sites studying various aspects of SBE impacts of COVID, such as chronic disease care, school resources, parenting stress, drug use, maternal health, and mitigation policies.

The Consortium consists of two parts:

Individual population research projects supported by participating NIH institutes, centers, and offices
A Coordinating Center that develops research, dissemination, and data-sharing activities and serves as a catalyst for engagement across consortium projects and the broader research community

The Coordinating Center activities have produced a growing body of resources to inform policy. In the first three years, the Center—

Created a COVID Measure Archive to promote consistency and comparability across studies
Developed Common Data Elements for COVID mitigation policies to standardize data collection and ensure comparable results across studies
Awarded pilot grants to foster innovative measurement of SBE indicators related to the COVID-19 pandemic
Disseminated research through such activities as publication spotlights of funded research and webinars sharing findings and resources

In May 2024, the Coordinating Center held its annual meeting , which included presentations from grantees on their latest research results and findings. A key takeaway from nearly all the presentations was the significant disparities in how the COVID-19 pandemic affected people and groups. For example—

Elbel and colleagues found that in New York City public schools, early vaccine eligibility and COVID vaccine uptake increased math and English language arts scores and decreased potential sick days, outpatient visits, and COVID infections. These effects were most pronounced when the community infection rate was high.
Hung, Li, and colleagues examined trends in prenatal care access during the pandemic in states with differing telehealth policies. They found that in a state that loosened its telehealth policies (allowing for more prenatal telehealth visits), prenatal care remained at a stable, adequate level, whereas in a state that did not loosen telehealth policies, adequate prenatal care dropped substantially.

Resources such as the SBE COVID Consortium offer insights into the impacts of the COVID-19 pandemic that provide valuable information for future biological threats. We have gathered valuable lessons on best practices for mitigation, the impact of these efforts, and effective communication of vaccination and health information. Practices for developing measures and data resources are in place for easy adaptation to future needs. Most critically, we have modelled the importance of adopting a comprehensive approach that incorporates from the outset insights from the behavioral and social sciences.

31 Center Drive, Building 31, Room B1C19 Bethesda, MD 20892

Email: [email protected]

Phone: 301-402-1146

NIH Virtual Tour

We finally know why some people seem immune to catching covid-19

Unique cell responses mean some people may be immune to catching the coronavirus, even if they are unvaccinated

By Sonali Roy

19 June 2024

Volunteers have been exposed to the coronavirus that causes covid-19 as part of a scientific study

koto_feja/GETTY

Deliberately exposing people to the coronavirus behind covid-19 in a so-called challenge study has helped us understand why some people seem to be immune to catching the infection.

As part of the first such covid-19 study, carried out in 2021, a group of international researchers looked at 16 people with no known health conditions who had neither tested positive for the SARS-CoV-2 virus nor been vaccinated against it.

How to tell if your immune system is weak or strong

The…

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Coronavirus disease (COVID-19): a scoping review

1 School of Public Health, Lanzhou University, Lanzhou, China

2 These authors contributed equally to this work and share first authorship

3 Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China

Janne Estill

4 Institute of Global Health, University of Geneva, Geneva, Switzerland

5 Institute of Mathematical Statistics and Actuarial Science, University of Bern, Bern, Switzerland

Mengjuan Ren

Jianjian wang.

6 Department of Health Research Methods, Evidence and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada

Xiaohui Wang

7 College of Medical Information Engineering, Chengdu University of Traditional Chinese Medicine, Chengdu, China

8 School of Public Health, Chengdu Medical College, Chengdu, China

9 Department of Respiratory Diseases, Children’s Hospital of Chongqing Medical University, Chongqing, China

10 Chongqing Key Laboratory of Pediatrics, Chongqing, China

Xianzhuo Zhang

11 The First School of Clinical Medicine, Lanzhou University, Lanzhou, China

12 The First Hospital of Lanzhou University, Lanzhou, China

Xiaolong Qi

Yangqin xun, yaolong chen.

13 World Health Organization (WHO) Collaborating Centre for Guideline Implementation and Knowledge Translation, Lanzhou, China

14 Guideline International Network Asia, Lanzhou, China

15 Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou University, Lanzhou, China

16 Lanzhou University, an affiliate of the Cochrane China Network, Lanzhou, China

on behalf of the COVID-19 evidence and recommendations working group

17 The study collaborators are acknowledged at the end of the article

Associated Data

In December 2019, a pneumonia caused by a novel coronavirus (SARS-CoV-2) emerged in Wuhan, China and has rapidly spread around the world since then.

This study aims to understand the research gaps related to COVID-19 and propose recommendations for future research.

We undertook a scoping review of COVID-19, comprehensively searching databases and other sources to identify literature on COVID-19 between 1 December 2019 and 6 February 2020. We analysed the sources, publication date, type and topic of the retrieved articles/studies.

We included 249 articles in this scoping review. More than half (59.0%) were conducted in China. Guidance/guidelines and consensuses statements (n = 56; 22.5%) were the most common. Most (n = 192; 77.1%) articles were published in peer-reviewed journals, 35 (14.1%) on preprint servers and 22 (8.8%) posted online. Ten genetic studies (4.0%) focused on the origin of SARS-CoV-2 while the topics of molecular studies varied. Nine of 22 epidemiological studies focused on estimating the basic reproduction number of COVID-19 infection (R 0 ). Of all identified guidance/guidelines (n = 35), only ten fulfilled the strict principles of evidence-based practice. The number of articles published per day increased rapidly until the end of January.

The number of articles on COVID-19 steadily increased before 6 February 2020. However, they lack diversity and are almost non-existent in some study fields, such as clinical research. The findings suggest that evidence for the development of clinical practice guidelines and public health policies will be improved when more results from clinical research becomes available.

Introduction

A new type of coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) that began in Wuhan, China in late 2019 has spread across the world since then. The virus has caused an outbreak of viral pneumonia, which has been named Coronavirus disease (COVID-19). As of 24:00 on 6 February 2020, over 31,000 cases and 636 deaths had been confirmed in China [ 1 ]. Furthermore, more than 1,770,000 cases had been diagnosed in 213 countries, areas or territories as at 13 April 2020 [ 2 ]. On 23 January 2020, Chinese authorities imposed a lockdown of Wuhan [ 3 ]. On 30 January 2020, the World Health Organization (WHO) declared the outbreak a Public Health Emergency of International Concern (PHEIC) [ 4 ] and on 11 March 2020, a pandemic [ 5 ].

The WHO [ 6 - 9 ], the United States (US) Centers for Disease Control and Prevention (CDC) [ 10 , 11 ], the European Centre for Disease Prevention and Control (ECDC) [ 12 , 13 ] as well as Chinese researchers have issued several guidance documents or guidelines to help address the outbreaks. Meanwhile, many scientific journals have rapidly published a number of articles, comments, editorials and perspectives related to COVID-19. It may however be challenging for the global research community to find all the available evidence: many of the first studies on COVID-19 were published in Chinese, and because of the rapidly developing situation, the latest studies are often available on websites or preprint servers only [ 14 ].

Scoping reviews are regarded as a valid tool to map the available evidence on a given topic, to clarify the characteristics of body of literature, to organise the key concepts and their relationship and to analyse knowledge gaps [ 15 ]. The methodology continues to be developed, and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRSIMA) extension for Scoping Reviews (PRISMA-SCR) including reporting guidance was published in 2018 [ 16 ]. Given the urgency of the COVID-19 epidemic and the need to understand and access information about it, a scoping review was considered suitable for the situation. We therefore conducted this scoping review to help identify research gaps related to this new viral disease and propose recommendations for future research on COVID-19.

Search strategy

We performed a systematic search of MEDLINE via PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data and China Biology Medicine (CBM) on 27 February 2020 with the terms “COVID-19” OR “SARS-CoV-2” OR “2019 novel coronavirus” OR “2019-nCoV” OR “Wuhan coronavirus” OR “novel coronavirus” OR “Wuhan seafood market pneumonia virus” OR “Wuhan virus”, published between 1 December 2019 and 6 February 2020 (see Supplement S1 for details of search strategies). Because of potential delays in indexing of databases, we also searched selected infectious disease journals ( Supplementary Table S1 ). We also searched Google Scholar; the official websites of WHO ( https://www.who.int/ ), US CDC ( https://www.cdc.gov/ ), ECDC ( https://www.ecdc.europa.eu/en ), Public Health England (PHE) ( https://www.gov.uk/government/organisations/public-health-england ); some preprint servers, including BioRxiv ( https://www.biorxiv.org/ ), ChemRxiv ( https://chemrxiv.org/ ), medRxiv ( https://www.medrxiv.org/ ) and SSRN ( https://www.ssrn.com/index.cfm/en/ ); and reference lists of the identified articles to find reports of additional studies.

Inclusion and exclusion criteria

We included all literature related to COVID-19 published in English and Chinese between 1 December 2019 and 6 February 2020 without restrictions, including guidance/guidelines, reviews, clinical studies, basic research, epidemiological studies and comments. Documents and guidance/guidelines posted by international organisations, government institutions, associations and societies were also included. We excluded news reports that were not published in scientific journals, and articles where we failed to access full text despite contacting the authors.

Article selection and data extraction

Two reviewers (ML and XL) screened all titles, abstracts and full texts independently and solved disagreements by consensus or consultation with a third reviewer. Then the following information was extracted: (i) title, (ii) first author, (iii) whether peer-reviewed or not, (iv) journal, (v) publication or posted date, (vi) first author’s country (or international organisation), (vii) type of article/study and (viii) topic. The details are shown in Supplementary Table S2 .

Data analysis

We conducted a descriptive analysis of the characteristics of the included literature. We described the source where we found the article, publication date, type of article/study, and topic of article/study or guidance/guideline on COVID-19 to examine the existing gaps in research. We categorised the literature into guidance/guidelines and consensus statements, reviews, clinical studies (including randomised controlled trials and observational studies), basic research, epidemiological studies, editorial comments on COVID-19 and other categories if identified. We conducted this scoping review in accordance with the PRISMA-ScR Checklist [ 16 ] ( Supplementary Table S3 ).

Search results

We identified 1,511 records, 280 of which were excluded as duplicates. Title and abstract screening were conducted for the remaining 1,231 articles, 989 of which were excluded because of being unrelated to COVID-19. For two articles, we failed to access the full text after contacting the authors. We retrieved the full texts of the 242 remaining articles. After further screening and supplementary searching of articles published or posted between 31 January 2020 and 6 February 2020, we identified an additional 42 articles and a total of 249 articles were included in the review ( Figure 1 ).

An external file that holds a picture, illustration, etc.
Object name is 2000125-f1.jpg

Flowchart of selection process for the scoping review of coronavirus disease (COVID-19) articles/studies and results, 1 December 2019–6 February 2020

CBM: China Biology Medicine; CNKI: China National Knowledge Infrastructure.

Characteristics of included articles/studies

Of the 249 included articles/studies, 147 (59.0%) were from China. The article/study type varied vastly, which we broadly characterised into 11 types ( Table 1 ). Of these, guidance/guidelines and consensuses statements were the most common (n = 56; 22.5%).

Characteristic		Number of articles/studies	Percentage (%)
Publication platform	Journal	192	77.1
Publication platform	Other than journal	57	22.9
Journal (n = 192)		13	6.8
		12	6.3
		9	4.7
		9	4.7
		8	4.2
		7	3.6
		7	3.6
		5	2.6
		5	2.6
		5	2.6
		4	2.1
		4	2.1
		3	1.6
		3	1.6
		3	1.6
		3	1.6
		3	1.6
		3	1.6
		3	1.6
		3	1.6
	Other	80	41.7
First author’s country or international organisation	China	147	59.0
	United States	33	13.3
	United Kingdom	16	6.4
	WHO	10	4.0
	Canada	7	2.8
	Germany	6	2.4
	Other	30	12.1
Publication or posted date	10–15 Jan	6	2.4
	16–20 Jan	7	2.8
	21–25 Jan	38	15.3
	26–31 Jan	93	37.3
	1–6 Feb	105	42.2
Type of article/study	Guidance/guideline or consensus statement	56	22.6
	Review	39	15.7
	Basic research	35	14.1
	Letter	25	10.0
	Epidemiological study	22	8.8
	Editorial	20	8.0
	Comments	11	4.4
	News item	9	3.6
	Case report	9	3.6
	Cross-sectional study	7	2.8
	Case series	5	2.0
	Other	11	4.4
Topic	Prevention and control	33	13.3
	Outbreak reporting	30	12.0
	Genetics	22	8.8
	Transmissibility	22	8.8
	Clinical features	21	8.4
	Diagnosis and treatment	19	7.6
	Molecular biology	15	6.0
	Management	14	5.6
	Characteristics of SARS-CoV-2	11	4.4
	Drug-related	8	3.2
	Traditional Chinese medicine	8	3.2
	Lessons and challenges	7	2.8
	Transmission pattern	7	2.8
	Surveillance and screening	5	2.0
	Mental health	4	1.6
	Other	23	9.2

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; WHO: World Health Organization.

a Includes the websites of WHO, United States Centers for Disease Control and Prevention (US CDC), European Centre for Disease Prevention and Control (ECDC) and Public Heath England (PHE), and preprint servers.

b Other than cross-sectional studies.

c Includes reviews and correspondence that discussed the characteristics of the virus in general.

d Other than traditional Chinese medicine.

Sources of articles/studies

Of all included articles/studies, 192 (77.1%) were published in peer-reviewed journals, 35 (14.1%) were posted on preprint servers and 22 (8.8%) were published on the official websites of public health organisations. The journal with the highest number of articles was The Lancet, with 13 (6.8%) published articles. Of preprint articles, most (n = 28) were posted on BioRxiv. Articles published on official websites were mainly COVID-19 guidance/guidelines, including 10 WHO interim guidance documents, nine US CDC interim guidelines/guidance documents, two ECDC guidance documents and one Communicable Diseases Network Australia (CNDA) guideline.

Publication date

Figure 2 shows the cumulative number of articles published daily between 10 January 2020 and 6 February 2020. As at 6 February 2020, the number of articles on COVID-19 had been steadily increasing. Of the 192 articles that were published in peer-reviewed journals, the highest number of journal publications on a single day was on 30 January, with 24 articles (12.5%). For the 35 preprints, the number posted per day rose steadily from 19 January 2020 to 6 February 2020.

An external file that holds a picture, illustration, etc.
Object name is 2000125-f2.jpg

Cumulative number of coronavirus disease (COVID-19)-related articles/studies included in the scoping review, 10 January–6 February 2020 (n = 249)

Type of article/study

The types of articles/studies published on each day are shown in Figure 3 . The daily number of guidance/guidelines peaked between 29 January and 3 February whereas the number of published reviews showed an increasing trend since 29 January 2020. Only one systematic review was identified [ 17 ]. We found no randomised controlled studies or cohort studies.

An external file that holds a picture, illustration, etc.
Object name is 2000125-f3.jpg

Number of coronavirus disease (COVID-19)-related articles/studies published per day according to type, 10 January–6 February 2020 (n = 249)

a Including cross-sectional studies.

The different types of articles/studies focused on different topics. The basic research could be divided broadly into two categories: 21 genetic studies and 12 molecular biology studies. Ten genetic studies traced the origin of SARS-CoV-2 and tried to determine the possible virus reservoir. Among these, most suggested that SARS-CoV-2 evolved from a bat-CoV, namely bat-SL-CoVZC45, bat-SL-CoVZXC21, bat-SL-CoVZX45 and bat-CoV-RaTG13 as potential candidates [ 18 - 26 ]. However, Ji et al. [ 18 ] found snakes to be the most probable reservoir for SARS-CoV-2 while Guo et al. [ 26 ] suggested mink could be a candidate reservoir. Of the molecular studies, five [ 27 - 31 ] showed that the key receptor of SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2), which is highly expressed in lung type II alveolar cells (AT2) [ 27 ], positive cholangiocytes [ 29 ], upper oesophagus, stratified epithelial cells and absorptive enterocytes from ileum and colon [ 30 ]. The other studies included an assessment of the cross-reactivity of anti-SARS-CoV antibodies with SARS-CoV-2 spike protein [ 32 ], and SARS-CoV-2 main proteases [ 33 , 34 ].

The main topic of epidemiological studies was the estimation of the transmissibility of COVID-19. The value of the basic reproduction number (R 0 ) varied across studies [ 35 - 43 ], however, all estimated it to be higher than one, which indicates the potential for sustained human-to-human transmission. According to the nine articles [ 35 - 43 ], R 0 ranges between 2.2 and 3.9. Some studies showed that the transmissibility of SARS-CoV-2 is comparable to [ 37 , 44 ] or even higher [ 39 ] than SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). In addition, studies focused on the disease burden associated with COVID-19 [ 45 ] and the global patterns of disease dispersion [ 46 , 47 ].

Most reviews on COVID-19 gave a brief summary of the clinical features [ 48 - 51 ] and the characteristics of SARS-CoV-2 [ 52 - 54 ], as well as recommendations on how to prevent and control [ 55 - 60 ] this novel pneumonia. A systematic review [ 17 ] explored the possibility of using lopinavir/ritonavir (LPV/r) to treat COVID-19, with the results supporting the use of LPV/r as a part of an experimental regimen for COVID-19 pneumonia treatment. Clinical features were reported in 21 studies [ 48 - 51 , 61 - 77 ]. The main symptoms of patients with COVID-19 at onset were found to be fever and cough, with a reduced lymphocyte count, which is similar to previous beta coronavirus infections [ 78 , 79 ].

Seventeen of the 56 editorials, comments and letters [ 80 - 96 ] were first reports or comments on the situation of the COVID-19 epidemic. Some [ 97 - 101 ] also briefly introduced the general information and characteristics of the new virus. The mapping of article/study type and topics, as well as associated gaps, is shown in Table 2 .

Topic	Article type
Topic	Guidance/guideline or consensus statement (n)	Review (n)	Basic research (n)	Letter (n)	Epidemiological study (n)	Editorial (n)	Comments (n)	News item (n)	Case report (n)	Cross-sectional study (n)	Case series (n)	Other (n)
Prevention and control	23	6	0	2	2	0	0	0	0	0	0	0
Outbreak reporting	0	0	0	3	0	10	4	9	0	0	0	4
Genetics	0	1	21		0	0	0	0	0	0	0	0
Transmissibility	0	1	0	4	13	3	0	0	0	0	1	0
Clinical features	0	4	0	2	0	0	2	0	5	2	4	2
Diagnosis and treatment	11	3	0	1	0	1	0	0	2	0	0	1
Molecular biology	0	2	12	1	0	0	0	0	0	0	0	0
Management	12	2	0		0	0	0	0	0	0	0	0
Characteristics of SARS-CoV-2	0	4	0	1	0	3	1	0	1	0	0	1
Drug-related	0	2	2	3	0	0	0	0	0	0	0	1
Traditional Chinese medicine	0	8	0		0	0	0	0	0	0	0	0
Lessons and challenges	0	3	0	1	0	0	3	0	0	0	0	0
Transmission pattern	0	0	0	2	4	0	0	0	1	0	0	0
Surveillance and screening	2	0	0	3	0	0	0	0	0	0	0	0
Mental health	0	0	0	1	0	0	1	0	0	2	0	0
Other	8	3	0	1	3	3	0	0	0	3	0	2

a Other than cross-sectional studies.

b Includes perspectives, case-control study and investigation protocols.

c Other than traditional Chinese medicine.

d Guidance/guideline or consensus statement: guidance for laboratory biosafety, caring and travellers, and national capacity review tools; review: reviews on human resources of healthcare, the causes and counter-measures of Wuhan ‘stigma’, and public health; letter: outbreak assessment; epidemiology study: studies on disease burden, the number of unreported cases, and infection fatality; editorial: journal’s opinion on matters related to COVID-19, and incidence rate estimation; cross-sectional study: hazard vulnerability analyses, epidemiology reports, and studies on public attitudes and perception; other: investigation protocol.

Guidance/guidelines and consensus statements

Of the 56 published guidance/guidelines and consensuses statements, 35 were guidance/guidelines. Nine of the 35 addressed the treatment and management of COVID-19 infection, eight addressed prevention and five addressed diagnostics. Ten of the guidance/guidelines were interim guidance documents issued by the WHO, including those on COVID-19 prevention, surveillance, assessment, care, management and mask use [ 6 - 9 , 102 - 107 ]. The US CDC published nine interim guidance/guidelines documents for evaluating, preventing and managing the new coronavirus [ 10 , 11 , 108 - 114 ]. In addition, ECDC published two guidance documents about COVID-19 patient care and the management of persons having had contact with SARS-CoV-2 cases [ 12 , 13 ]. Chinese researches also published 14 rapid-advice guidance/guidelines documents on diagnosis, prevention and management of COVID-19, all of which were interim guidance/guidelines documents developed by hospitals [ 115 - 128 ].

Only eight of the guidance documents/guidelines formed a guideline development group (GDG) [ 129 ]; the recommendations of 15 guidance documents/guidelines, including six developed by the WHO, were difficult to distinguish. Only ten guidance/guidelines fulfilled the strict principles of evidence-based practice and cited reference documents, which were mainly epidemic reports, government documents, and indirect evidence related to SARS-CoV or MERS-CoV [ 6 , 7 , 105 , 116 - 118 , 120 , 122 , 125 , 126 ]. Only two guidelines, both developed by Chinese researchers, were graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [ 116 , 117 ]. Among the 35 guidance/guidelines, one [ 115 ] was completely on Traditional Chinese medicine and one [ 116 ] covered Chinese medicine. One Australian guideline [ 130 ] was adapted from SARS-CoV guidelines.

Our scoping review shows that while the number of articles on COVID-19 has been constantly increasing, as at 6 February, there were still clear gaps in several study types and research fields. We identified that some study types, in particular randomised controlled trials and cohort studies, were still non-existent before 6 February. According to a preliminary search of the Cochrane Network database up to 10 April 2020, the number of randomised controlled trials (RCTs) (n = 8) and observational studies (n = 42) still remains low [ 131 ].

We also found that there were only a few studies on clinical practice, making it difficult to develop clinical practice guidelines and health policies. The reason for the gaps in this area may be the rapid development of the outbreak and limited understanding of the new virus and the disease caused by it. Moreover, it takes time to conduct clinical research. When facing a public health emergency with a previously unknown cause, researchers should conduct studies on whether some clinical practice and public health interventions from other public health emergencies can be used as indirect evidence. However, we identified no such studies in our review.

We found that 14% of the studies related to COVID-19 were posted on preprint servers. This approach of sharing research as quickly as possible is very reasonable, especially in the case of such public health emergency. Previous studies have shown that preprints can accelerate progress in handling outbreaks of infectious disease [ 132 , 133 ].

The research topics in different types of articles/studies had both similarities and differences. Basic research was mostly focused on exploring the origin and reservoirs of the new virus, while epidemiological studies mainly focused on its transmissibility. Reviews and reports provided more general information of the virus and the outbreak, while guidance/guidelines included recommendations on how to prevent and control it.

Clinical practice guidelines are statements that include recommendations intended to optimise patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options [ 134 ]. Clinical practice guidelines can inform healthcare workers' actions [ 134 ], and, especially when public health emergencies occur, rapid advice guidelines can guide clinicians in terms of how to perform related work [ 135 ]. After the outbreak of COVID-19, the WHO, US CDC and ECDC released guidance/guidelines as soon as possible, as did several Chinese institutions. However, most of these documents did not establish formal guideline development groups, and they did not fulfil the strict principles of evidence-based practice. For example, most guidance/guidelines did not grade the quality of evidence and strength of recommendations, and thus owed to the emerging crisis, such guidance/guidelines need to be considered with these limitations in mind. In 2007, the WHO published guidance about the process of developing rapid advice guidelines [ 129 ], stating that when a public health emergency occurs, a rapid review is needed and the development time should not exceed 6 months [ 135 ]. However, considering the limited time to set up panels, this could be a challenge for guidance/guideline developers. Nonetheless, we still expect guidance/guideline developers to establish formal development groups and fulfil the evidence-based practice principles.

Our scoping review can help researchers identify research gaps so as to conduct research to fill these gaps. For example, in the current situation, a systematic review to estimate the incubation period or research on new drugs or treatments, would be of great importance. This scoping review has several strengths. We performed a systematic search of a comprehensive set of sources, including databases, preprint servers, and official websites of international organisations and associations at the early stage of the pandemic. Furthermore, our large sample size is sufficient to illustrate the state of research and identify research gaps related to COVID-19 at the onset of the pandemic.

This study also has some limitations. Because of the delay in indexing, some articles published as at 6 February 2020 may not have been identified. Also, because our retrieval time was only until this date, articles published or posted after this date, of which there have been many, have not been included in the analysis. As some preprints, guidance/guidelines and disease control plans are constantly updated, the publication date we extracted may not be the time of their first publication time. Also, we did not assess the quality of the included literature because of diversity of the types of included articles. Another limitation of our study was that it only included articles published in English and Chinese, which could introduce publication bias. However, as the epidemic was most heavily affecting China until early February, it is reasonable to expect that literature published in English and Chinese up until this point in time covered the majority of the available knowledge. Finally, we were unable to access the full texts of two articles despite contacting the authors. However, compared with the total number of articles included in the review, we anticipate that the exclusion of these two articles is unlikely to have a major impact.

This scoping review shows the state of literature published or posted online related to COVID-19 as at 6 February 2020. The number of articles in this field has steadily increased since the outbreak became evident. However, the types of studies lacked diversity, especially clinical studies. More clinical research is needed, but in the rapidly evolving global pandemic, we encourage researchers to continuously review the latest literature, to take into account the latest available evidence and avoid overlapping work, and to improve evidence for the development of clinical practice guidelines and public health policies.

Acknowledgements

Funding statement: 2020 Key R & D project of Gansu Province; Special funding for prevention and control of emergency of COVID-19 from Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province (No. GSEBMKT-2020YJ01).

The members of the COVID-19 evidence and recommendations working group: Xiao Liu (Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China); Nan Yang (Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China); Shuya Lu (Sichuan Provincial People’s hospital, Chengdu, China ); Peipei Du ( School of Public Health, Chengdu Medical College, Chengdu, China); Yanfang Ma (Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China); Zijun Wang (Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China); Qianling Shi (The First School of Clinical Medicine, Lanzhou University, Lanzhou, China); Hairong Zhang (Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China); Qiangqiang Guo (School of Public Health, ShanXi Medical University, Taiyuan,China); Yuting Yang (Children's Hospital of Chongqing Medical University, Chongqing, China); Bo Yang (Children's Hospital of Chongqing Medical University, Chongqing, China); Shouyuan Wu (School of Public Health, Lanzhou University, Lanzhou, China); Xiaoqin Wang (Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada).

Supplementary Data

Conflict of interest: None declared.

Authors’ contributions: All authors have read and agree to the published version of the manuscript. Conceptualisation, YC and XW; methodology, ML, XL and JE; software, YL, MR and JW; data extraction, QW, SZ, MR, XZ, LW, QZ and SY; formal analysis, XL and ML; resources, ML and WL; writing—original draft preparation, ML, XL, WM and XQ; writing—review and editing, YX, XY, YC, XW, SY, XF, WM, JE, EL and XQ; visualisation, ML and XL; supervision, YC and XW; project administration, YC; funding acquisition, YC.

Why the Pandemic Probably Started in a Lab, in 5 Key Points

By Alina Chan

Dr. Chan is a molecular biologist at the Broad Institute of M.I.T. and Harvard, and a co-author of “Viral: The Search for the Origin of Covid-19.”

This article has been updated to reflect news developments.

On Monday, Dr. Anthony Fauci returned to the halls of Congress and testified before the House subcommittee investigating the Covid-19 pandemic. He was questioned about several topics related to the government’s handling of Covid-19, including how the National Institute of Allergy and Infectious Diseases, which he directed until retiring in 2022, supported risky virus work at a Chinese institute whose research may have caused the pandemic.

For more than four years, reflexive partisan politics have derailed the search for the truth about a catastrophe that has touched us all. It has been estimated that at least 25 million people around the world have died because of Covid-19, with over a million of those deaths in the United States.

Although how the pandemic started has been hotly debated, a growing volume of evidence — gleaned from public records released under the Freedom of Information Act, digital sleuthing through online databases, scientific papers analyzing the virus and its spread, and leaks from within the U.S. government — suggests that the pandemic most likely occurred because a virus escaped from a research lab in Wuhan, China. If so, it would be the most costly accident in the history of science.

Here’s what we now know:

1 The SARS-like virus that caused the pandemic emerged in Wuhan, the city where the world’s foremost research lab for SARS-like viruses is located.

At the Wuhan Institute of Virology, a team of scientists had been hunting for SARS-like viruses for over a decade, led by Shi Zhengli.
Their research showed that the viruses most similar to SARS‑CoV‑2, the virus that caused the pandemic, circulate in bats that live r oughly 1,000 miles away from Wuhan. Scientists from Dr. Shi’s team traveled repeatedly to Yunnan province to collect these viruses and had expanded their search to Southeast Asia. Bats in other parts of China have not been found to carry viruses that are as closely related to SARS-CoV-2.

The closest known relatives to SARS-CoV-2 were found in southwestern China and in Laos.

Large cities

Mine in Yunnan province

Cave in Laos

South China Sea

The closest known relatives to SARS-CoV-2

were found in southwestern China and in Laos.

philippines

The closest known relatives to SARS-CoV-2 were found

in southwestern China and Laos.

Sources: Sarah Temmam et al., Nature; SimpleMaps

Note: Cities shown have a population of at least 200,000.

There are hundreds of large cities in China and Southeast Asia.

There are hundreds of large cities in China

and Southeast Asia.

The pandemic started roughly 1,000 miles away, in Wuhan, home to the world’s foremost SARS-like virus research lab.

The pandemic started roughly 1,000 miles away,

in Wuhan, home to the world’s foremost SARS-like virus research lab.

The pandemic started roughly 1,000 miles away, in Wuhan,

home to the world’s foremost SARS-like virus research lab.

Even at hot spots where these viruses exist naturally near the cave bats of southwestern China and Southeast Asia, the scientists argued, as recently as 2019 , that bat coronavirus spillover into humans is rare .
When the Covid-19 outbreak was detected, Dr. Shi initially wondered if the novel coronavirus had come from her laboratory , saying she had never expected such an outbreak to occur in Wuhan.
The SARS‑CoV‑2 virus is exceptionally contagious and can jump from species to species like wildfire . Yet it left no known trace of infection at its source or anywhere along what would have been a thousand-mile journey before emerging in Wuhan.

2 The year before the outbreak, the Wuhan institute, working with U.S. partners, had proposed creating viruses with SARS‑CoV‑2’s defining feature.

Dr. Shi’s group was fascinated by how coronaviruses jump from species to species. To find viruses, they took samples from bats and other animals , as well as from sick people living near animals carrying these viruses or associated with the wildlife trade. Much of this work was conducted in partnership with the EcoHealth Alliance, a U.S.-based scientific organization that, since 2002, has been awarded over $80 million in federal funding to research the risks of emerging infectious diseases.
The laboratory pursued risky research that resulted in viruses becoming more infectious : Coronaviruses were grown from samples from infected animals and genetically reconstructed and recombined to create new viruses unknown in nature. These new viruses were passed through cells from bats, pigs, primates and humans and were used to infect civets and humanized mice (mice modified with human genes). In essence, this process forced these viruses to adapt to new host species, and the viruses with mutations that allowed them to thrive emerged as victors.
By 2019, Dr. Shi’s group had published a database describing more than 22,000 collected wildlife samples. But external access was shut off in the fall of 2019, and the database was not shared with American collaborators even after the pandemic started , when such a rich virus collection would have been most useful in tracking the origin of SARS‑CoV‑2. It remains unclear whether the Wuhan institute possessed a precursor of the pandemic virus.
In 2021, The Intercept published a leaked 2018 grant proposal for a research project named Defuse , which had been written as a collaboration between EcoHealth, the Wuhan institute and Ralph Baric at the University of North Carolina, who had been on the cutting edge of coronavirus research for years. The proposal described plans to create viruses strikingly similar to SARS‑CoV‑2.
Coronaviruses bear their name because their surface is studded with protein spikes, like a spiky crown, which they use to enter animal cells. T he Defuse project proposed to search for and create SARS-like viruses carrying spikes with a unique feature: a furin cleavage site — the same feature that enhances SARS‑CoV‑2’s infectiousness in humans, making it capable of causing a pandemic. Defuse was never funded by the United States . However, in his testimony on Monday, Dr. Fauci explained that the Wuhan institute would not need to rely on U.S. funding to pursue research independently.

The Wuhan lab ran risky experiments to learn about how SARS-like viruses might infect humans.

1. Collect SARS-like viruses from bats and other wild animals, as well as from people exposed to them.

2. Identify high-risk viruses by screening for spike proteins that facilitate infection of human cells.

2. Identify high-risk viruses by screening for spike proteins that facilitate infection of

human cells.

In Defuse, the scientists proposed to add a furin cleavage site to the spike protein.

3. Create new coronaviruses by inserting spike proteins or other features that could make the viruses more infectious in humans.

4. Infect human cells, civets and humanized mice with the new coronaviruses, to determine how dangerous they might be.

While it’s possible that the furin cleavage site could have evolved naturally (as seen in some distantly related coronaviruses), out of the hundreds of SARS-like viruses cataloged by scientists, SARS‑CoV‑2 is the only one known to possess a furin cleavage site in its spike. And the genetic data suggest that the virus had only recently gained the furin cleavage site before it started the pandemic.
Ultimately, a never-before-seen SARS-like virus with a newly introduced furin cleavage site, matching the description in the Wuhan institute’s Defuse proposal, caused an outbreak in Wuhan less than two years after the proposal was drafted.
When the Wuhan scientists published their seminal paper about Covid-19 as the pandemic roared to life in 2020, they did not mention the virus’s furin cleavage site — a feature they should have been on the lookout for, according to their own grant proposal, and a feature quickly recognized by other scientists.
Worse still, as the pandemic raged, their American collaborators failed to publicly reveal the existence of the Defuse proposal. The president of EcoHealth, Peter Daszak, recently admitted to Congress that he doesn’t know about virus samples collected by the Wuhan institute after 2015 and never asked the lab’s scientists if they had started the work described in Defuse. In May, citing failures in EcoHealth’s monitoring of risky experiments conducted at the Wuhan lab, the Biden administration suspended all federal funding for the organization and Dr. Daszak, and initiated proceedings to bar them from receiving future grants. In his testimony on Monday, Dr. Fauci said that he supported the decision to suspend and bar EcoHealth.
Separately, Dr. Baric described the competitive dynamic between his research group and the institute when he told Congress that the Wuhan scientists would probably not have shared their most interesting newly discovered viruses with him . Documents and email correspondence between the institute and Dr. Baric are still being withheld from the public while their release is fiercely contested in litigation.
In the end, American partners very likely knew of only a fraction of the research done in Wuhan. According to U.S. intelligence sources, some of the institute’s virus research was classified or conducted with or on behalf of the Chinese military . In the congressional hearing on Monday, Dr. Fauci repeatedly acknowledged the lack of visibility into experiments conducted at the Wuhan institute, saying, “None of us can know everything that’s going on in China, or in Wuhan, or what have you. And that’s the reason why — I say today, and I’ve said at the T.I.,” referring to his transcribed interview with the subcommittee, “I keep an open mind as to what the origin is.”

3 The Wuhan lab pursued this type of work under low biosafety conditions that could not have contained an airborne virus as infectious as SARS‑CoV‑2.

Labs working with live viruses generally operate at one of four biosafety levels (known in ascending order of stringency as BSL-1, 2, 3 and 4) that describe the work practices that are considered sufficiently safe depending on the characteristics of each pathogen. The Wuhan institute’s scientists worked with SARS-like viruses under inappropriately low biosafety conditions .

In the United States, virologists generally use stricter Biosafety Level 3 protocols when working with SARS-like viruses.

Biosafety cabinets prevent

viral particles from escaping.

Viral particles

Personal respirators provide

a second layer of defense against breathing in the virus.

DIRECT CONTACT

Gloves prevent skin contact.

Disposable wraparound

gowns cover much of the rest of the body.

Personal respirators provide a second layer of defense against breathing in the virus.

Disposable wraparound gowns

cover much of the rest of the body.

Note: Biosafety levels are not internationally standardized, and some countries use more permissive protocols than others.

The Wuhan lab had been regularly working with SARS-like viruses under Biosafety Level 2 conditions, which could not prevent a highly infectious virus like SARS-CoV-2 from escaping.

Some work is done in the open air, and masks are not required.

Less protective equipment provides more opportunities

for contamination.

Some work is done in the open air,

and masks are not required.

Less protective equipment provides more opportunities for contamination.

In one experiment, Dr. Shi’s group genetically engineered an unexpectedly deadly SARS-like virus (not closely related to SARS‑CoV‑2) that exhibited a 10,000-fold increase in the quantity of virus in the lungs and brains of humanized mice . Wuhan institute scientists handled these live viruses at low biosafet y levels , including BSL-2.
Even the much more stringent containment at BSL-3 cannot fully prevent SARS‑CoV‑2 from escaping . Two years into the pandemic, the virus infected a scientist in a BSL-3 laboratory in Taiwan, which was, at the time, a zero-Covid country. The scientist had been vaccinated and was tested only after losing the sense of smell. By then, more than 100 close contacts had been exposed. Human error is a source of exposure even at the highest biosafety levels , and the risks are much greater for scientists working with infectious pathogens at low biosafety.
An early draft of the Defuse proposal stated that the Wuhan lab would do their virus work at BSL-2 to make it “highly cost-effective.” Dr. Baric added a note to the draft highlighting the importance of using BSL-3 to contain SARS-like viruses that could infect human cells, writing that “U.S. researchers will likely freak out.” Years later, after SARS‑CoV‑2 had killed millions, Dr. Baric wrote to Dr. Daszak : “I have no doubt that they followed state determined rules and did the work under BSL-2. Yes China has the right to set their own policy. You believe this was appropriate containment if you want but don’t expect me to believe it. Moreover, don’t insult my intelligence by trying to feed me this load of BS.”
SARS‑CoV‑2 is a stealthy virus that transmits effectively through the air, causes a range of symptoms similar to those of other common respiratory diseases and can be spread by infected people before symptoms even appear. If the virus had escaped from a BSL-2 laboratory in 2019, the leak most likely would have gone undetected until too late.
One alarming detail — leaked to The Wall Street Journal and confirmed by current and former U.S. government officials — is that scientists on Dr. Shi’s team fell ill with Covid-like symptoms in the fall of 2019 . One of the scientists had been named in the Defuse proposal as the person in charge of virus discovery work. The scientists denied having been sick .

4 The hypothesis that Covid-19 came from an animal at the Huanan Seafood Market in Wuhan is not supported by strong evidence.

In December 2019, Chinese investigators assumed the outbreak had started at a centrally located market frequented by thousands of visitors daily. This bias in their search for early cases meant that cases unlinked to or located far away from the market would very likely have been missed. To make things worse, the Chinese authorities blocked the reporting of early cases not linked to the market and, claiming biosafety precautions, ordered the destruction of patient samples on January 3, 2020, making it nearly impossible to see the complete picture of the earliest Covid-19 cases. Information about dozens of early cases from November and December 2019 remains inaccessible.
A pair of papers published in Science in 2022 made the best case for SARS‑CoV‑2 having emerged naturally from human-animal contact at the Wuhan market by focusing on a map of the early cases and asserting that the virus had jumped from animals into humans twice at the market in 2019. More recently, the two papers have been countered by other virologists and scientists who convincingly demonstrate that the available market evidence does not distinguish between a human superspreader event and a natural spillover at the market.
Furthermore, the existing genetic and early case data show that all known Covid-19 cases probably stem from a single introduction of SARS‑CoV‑2 into people, and the outbreak at the Wuhan market probably happened after the virus had already been circulating in humans.

An analysis of SARS-CoV-2’s evolutionary tree shows how the virus evolved as it started to spread through humans.

SARS-COV-2 Viruses closest

to bat coronaviruses

more mutations

Source: Lv et al., Virus Evolution (2024) , as reproduced by Jesse Bloom

The viruses that infected people linked to the market were most likely not the earliest form of the virus that started the pandemic.

Not a single infected animal has ever been confirmed at the market or in its supply chain. Without good evidence that the pandemic started at the Huanan Seafood Market, the fact that the virus emerged in Wuhan points squarely at its unique SARS-like virus laboratory.

5 Key evidence that would be expected if the virus had emerged from the wildlife trade is still missing.

In previous outbreaks of coronaviruses, scientists were able to demonstrate natural origin by collecting multiple pieces of evidence linking infected humans to infected animals.

Infected animals

Earliest known

cases exposed to

live animals

Antibody evidence

of animals and

animal traders having

been infected

Ancestral variants

of the virus found in

Documented trade

of host animals

between the area

where bats carry

closely related viruses

and the outbreak site

Infected animals found

Earliest known cases exposed to live animals

Antibody evidence of animals and animal

traders having been infected

Ancestral variants of the virus found in animals

Documented trade of host animals

between the area where bats carry closely

related viruses and the outbreak site

For SARS-CoV-2, these same key pieces of evidence are still missing , more than four years after the virus emerged.

For SARS-CoV-2, these same key pieces of evidence are still missing ,

more than four years after the virus emerged.

Despite the intense search trained on the animal trade and people linked to the market, investigators have not reported finding any animals infected with SARS‑CoV‑2 that had not been infected by humans. Yet, infected animal sources and other connective pieces of evidence were found for the earlier SARS and MERS outbreaks as quickly as within a few days, despite the less advanced viral forensic technologies of two decades ago.
Even though Wuhan is the home base of virus hunters with world-leading expertise in tracking novel SARS-like viruses, investigators have either failed to collect or report key evidence that would be expected if Covid-19 emerged from the wildlife trade . For example, investigators have not determined that the earliest known cases had exposure to intermediate host animals before falling ill. No antibody evidence shows that animal traders in Wuhan are regularly exposed to SARS-like viruses, as would be expected in such situations.
With today’s technology, scientists can detect how respiratory viruses — including SARS, MERS and the flu — circulate in animals while making repeated attempts to jump across species . Thankfully, these variants usually fail to transmit well after crossing over to a new species and tend to die off after a small number of infections. In contrast, virologists and other scientists agree that SARS‑CoV‑2 required little to no adaptation to spread rapidly in humans and other animals . The virus appears to have succeeded in causing a pandemic upon its only detected jump into humans.

The pandemic could have been caused by any of hundreds of virus species, at any of tens of thousands of wildlife markets, in any of thousands of cities, and in any year. But it was a SARS-like coronavirus with a unique furin cleavage site that emerged in Wuhan, less than two years after scientists, sometimes working under inadequate biosafety conditions, proposed collecting and creating viruses of that same design.

While several natural spillover scenarios remain plausible, and we still don’t know enough about the full extent of virus research conducted at the Wuhan institute by Dr. Shi’s team and other researchers, a laboratory accident is the most parsimonious explanation of how the pandemic began.

Given what we now know, investigators should follow their strongest leads and subpoena all exchanges between the Wuhan scientists and their international partners, including unpublished research proposals, manuscripts, data and commercial orders. In particular, exchanges from 2018 and 2019 — the critical two years before the emergence of Covid-19 — are very likely to be illuminating (and require no cooperation from the Chinese government to acquire), yet they remain beyond the public’s view more than four years after the pandemic began.

Whether the pandemic started on a lab bench or in a market stall, it is undeniable that U.S. federal funding helped to build an unprecedented collection of SARS-like viruses at the Wuhan institute, as well as contributing to research that enhanced them . Advocates and funders of the institute’s research, including Dr. Fauci, should cooperate with the investigation to help identify and close the loopholes that allowed such dangerous work to occur. The world must not continue to bear the intolerable risks of research with the potential to cause pandemics .

A successful investigation of the pandemic’s root cause would have the power to break a decades-long scientific impasse on pathogen research safety, determining how governments will spend billions of dollars to prevent future pandemics. A credible investigation would also deter future acts of negligence and deceit by demonstrating that it is indeed possible to be held accountable for causing a viral pandemic. Last but not least, people of all nations need to see their leaders — and especially, their scientists — heading the charge to find out what caused this world-shaking event. Restoring public trust in science and government leadership requires it.

A thorough investigation by the U.S. government could unearth more evidence while spurring whistleblowers to find their courage and seek their moment of opportunity. It would also show the world that U.S. leaders and scientists are not afraid of what the truth behind the pandemic may be.

More on how the pandemic may have started

Where Did the Coronavirus Come From? What We Already Know Is Troubling.

Even if the coronavirus did not emerge from a lab, the groundwork for a potential disaster had been laid for years, and learning its lessons is essential to preventing others.

By Zeynep Tufekci

Why Does Bad Science on Covid’s Origin Get Hyped?

If the raccoon dog was a smoking gun, it fired blanks.

By David Wallace-Wells

A Plea for Making Virus Research Safer

A way forward for lab safety.

By Jesse Bloom

The Times is committed to publishing a diversity of letters to the editor. We’d like to hear what you think about this or any of our articles. Here are some tips . And here’s our email: [email protected] .

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Alina Chan ( @ayjchan ) is a molecular biologist at the Broad Institute of M.I.T. and Harvard, and a co-author of “ Viral : The Search for the Origin of Covid-19.” She was a member of the Pathogens Project , which the Bulletin of the Atomic Scientists organized to generate new thinking on responsible, high-risk pathogen research.

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Orthostatic tachycardia after covid-19

Update to living WHO guideline on drugs for covid-19

Long covid—an update for primary care

Covid-19 vaccination in pregnancy

Diagnosis and management of covid-19 in pregnancy

From The BMJ

Efficacy and safety of an inactivated virus-particle vaccine for SARS-CoV-2, BIV1-CovIran: randomised, placebo controlled, double blind, multicentre, phase 3 clinical trial

Long term risk of death and readmission after hospital admission with covid-19 among older adults: retrospective cohort study

Safety of BA.4-5 or BA.1 bivalent mRNA booster vaccines: nationwide cohort study

Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study

From BMJ Journals