research on covid 19

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

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

PRISMA flow diagram

Characteristics of included reviews

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

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

Population and study designs

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

Systematic review findings

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

A meta-analysis of the prevalence of mortality

Clinical symptoms

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

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgments

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

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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Thilo Caspar von Groote

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Livia Puljak

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

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

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

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

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

Additional file 5: Appendix 5.

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

Additional file 6: Appendix 6.

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

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

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A Comprehensive Overview on COVID-19: Future Perspectives

The outbreak of COVID-19 has proven to be an unprecedented disaster for the whole world. The virus has inflicted billion of lives across the globe in all aspects—physically, psychologically, as well as socially. Compared to the previous strains of β-CoV genera- MERS and SARS, SARS-CoV-2 has significantly higher transmissibility and worst post-recovery implications. A frequent mutation in the initial SARS-CoV-2 strain has been a major cause of mortalities (approx. 3 million deaths) and uncontrolled virulence (approx. 1 billion positive cases). As far as clinical manifestations are concerned, this particular virus has exhibited deleterious impacts on systems other than the respiratory system (primary target organ), such as the brain, hematological system, liver, kidneys, endocrine system, etc. with no promising curatives to date. Lack of emergency treatments and shortage of life-saving drugs has promoted the repurposing of existing therapeutics along with the emergence of vaccines with the combined efforts of scientists and industrial experts in this short span. This review summarizes every detail on COVID-19 and emphasizes undermining the future approaches to minimize its prevalence to the remaining lives.

Introduction

The influence of viruses and viral infections on human history has been broadly described by the social history of viruses ever since the modifications in human behavior during the Neolithic period around 12,000 years ago ( Baranowski et al., 2001 ; Fuchs et al., 2019 ). This was the period when humans began to expand their agricultural communities and an exponential increase in the spread of viruses leading to becoming endemic was observed the most. With the rapid globalization and anthropogenic activities with time, pathogenic transmission has escalated across the globe and resulted in viral pandemics ( Fuchs et al., 2019 ). It was the mid-19th century that was remarkably known for pathogenic viral outbreaks and their multiplex associations with humans and animal species. This further leads to cross-species transmission, posing a high threat to human health and well-being  ( Ye et al., 2020 ).

Later at the beginning of the 21st century, it was observed that due to the rapid globalization and human activities, pathogenic transmission across continents has escalated and resulted in several pandemics, especially viral pandemics ( Ye et al., 2020 ). The pandemic caused by old diseases, namely plague, cholera, and yellow fever in addition to some emerging diseases such as Ebola, Zika, severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS), and COVID-19, makes it the most ferocious century in human history ( Ong et al., 2020 ). As per the reports, these viral pandemics have caused significant mortalities and majorly affected the international economy over the last three decades ( Ong et al., 2020 ). For example, the Ebola viral disease (EVD) identified in 1976 in Central Africa for the first time and its outbreak in 2014–2016 has resulted in more than 40% mortality in West Africa ( Control and Prevention, 2014 ). SARS-CoV infection was first identified in 2003 and has known to be originated from bats and transmitted to humans via palm civets (host) in Guangdong Province, China; there were 8422 reported cases including the mortality rate of 11% in 26 countries ( of the International, 2020 ). Similarly, MERS-CoV also originated in bats, transmitted through dromedary camels as an intermediate host reported in 2494 cases with 858 deaths (mortality rate 34%) in 27 countries  ( Omrani et al., 2015 ).

Now the biggest threat that the world is facing today is the outbreak of novel coronavirus (COVID-19) that originated in Wuhan, Hubei Province, China, in December 2019 and rapidly spread over the rest of the world in a short time ( Boni et al., 2020 ). It can best be characterized by pneumonia-like symptoms that may further extend up to major hypoxia and several cardiovascular complications ( Boni et al., 2020 ). Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses belonging to the Coronaviridae family and a leading cause of acute respiratory, hepatic, and neurological diseases with variable severities in vertebrates ( Wang et al., 2020 ). They are referred to be the common human pathogens with the tendencies of fleeting recombination and mutation ( Wang et al., 2020 ). It is due to the presence of crown-like spikes on the periphery of these viruses, popularly called coronaviruses ( Boni et al., 2020 ; Wang et al., 2020 ). These coronaviruses are segregated into four distinct genera based on phylogenetic clustering, namely alpha coronavirus (αCoV), beta coronavirus (βCoV), gamma coronavirus (γCoV), and delta coronavirus (δCoV) ( Huang et al., 2020 ). Among these, α and βCoVs (mainly found in bats and rodents) are known to infect humans; however, γ and δCoVs (found in birds) are known to infect mainly aves and mammals including pigs ( Paim et al., 2019 ). In addition to affecting a vast majority of humans by crossing the inter-species barrier, βCoVs (i.e., SARS-CoV and MERS-CoV) have been marked with the highest mortality rates among all the classes of coronaviruses ( Huang et al., 2020 ). Structurally they are composed of four major proteins: (a) the spike (S) protein, (b) the nucleocapsid (N) protein, (c) the membrane (M) protein, and (d) the envelope (E) protein, playing a pivotal role in mediating the attachment of the virus to the host receptor, its subsequent fusion, and accelerating virus assembly within the host system ( Samidurai and Das, 2020 ). Until 2003, barely two human CoV (HCoV) strains, HcoV-OC43 and HcoV-229E, were recognized, but from 2003 to 2021, the world has experienced havoc and an exponential increase in mortality rates due to the emergence of 5 other deadly strains of coronaviruses: HcoV-NL63, HcoV-HKU1, severe acute respiratory syndrome corononavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, which may cause fatal respiratory infections in humans ( Ivanov and Ziebuhr, 2004 ; Ye et al., 2020 ). Due to the rapid spread of the disease and its manifestations (i.e., enhanced mortality rate) caused by the newest corona strain viz. SARS-CoV-2 originated from Wuhan, China, in December 2019 has raised the concerns of researchers and clinicians concerns across the world ( Long et al., 2020 ). As a result, the World Health Organization (WHO) in February 2020 has named it coronavirus disease 2019, abbreviated as COVID-19, and on March 11, 2020, the situation was declared a pandemic ( Long et al., 2020 ).

The statistical data on COVID-19 has reported around 4,995,996 confirmed cases of SARS-CoV-2 infection along with 327,821 deaths in 216 countries, and the number is increasing exponentially daily ( Nižetić, 2020 ; Sharma et al., 2020 ). China, which is an epicenter of SARS-COV-2, has reported 84,520 confirmed cases with 4645 deaths, the United States of America (USA) has 1,528,186 confirmed cases including 92,000 deaths, and India has a maximum number of confirmed cases at 22,362,920 and 242,000 deaths ( Sharma et al., 2020 ). To control COVID-19’s superspread event and its impact on global health care infrastructure, the WHO has substantiated on early diagnosis, prevention, social distancing, proper sanitization, and complete lockdown-like strategies. Additionally, the guidelines approved by various national and international authorities about the dos and don’ts have been made available to national and international platforms ( Saadat et al., 2020 ). Apart from this, rigorous efforts being made by our researchers and medical practitioners to disseminate accurate details mimetic to etiology, pathogenesis, clinical course, and protective measures for the widespread COVID-19 disease across the communities, one of the fastest and reliable sources is real-time counts infected cases worldwide ( Nižetić, 2020 ).

In corroboration with the recent editorial in Lancet prioritizing the spread of reliable, adequate, and independently scrutinized data and information related to COVID-19 disease among the general audience, the present review abridges all the scientific findings related to the COVID-19 outbreak in one place and thereby minimizes the effort of readers in going through the enormous studies available online.

Emergence and Evolution of SARS-CoV-2

Since the outbreak of COVID-19 disease in December 2019 in Wuhan, China, the interest of epidemiologists has piqued in assessing the rationale behind the eruption of SARS-CoV-2 in humans, including the involvement of animal reservoir, endemic circulation, co-infection, recombination events within RNA segments, and its time of divergence from animal species ( Decaro et al., 2021 ).

In December 2019, when the cases of pneumonia were epidemiologically related to the open-air seafood market in Wuhan, China, the local authorities in China provisioned an epidemiological alert and issued a complete lockdown for a couple of weeks ( Decaro et al., 2021 ). After rigorous research and clinical implications, in January 2020, the scientists at Wuhan obtained a complete genome sequence from the infected people and obtained around 80% sequence similarity with SARS-CoV, confirming pneumonia to be a SARS-induced condition ( Zhou et al., 2020 ). Initially, this novel human pathogen was placed in the Sarbecovirus subgenus of the Coronaviridae family, the family in which SARS falls ( Boni et al., 2020 ). The virus is responsible for more than 8,200 cases from 2002–2003. Later, by mid-January 2020, the virus did super-spread within China, and by mid-March 2020 was labeled as pandemic status ( Cucinotta and Vanelli, 2020 ). This, in turn, enhanced the concern of the medical fraternity to prevent its spread and, at the same time, the researchers across the world were busy identifying the strain affecting millions of lives ( Cucinotta and Vanelli, 2020 ). With the subsequent studies and ongoing reports the virus was named SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) study group and also named hCoV-19 by Wu et al. ( Wu et al., 2020a ).

For the first time in a consortium on virological.org led by Zhang on January 10, 2020 (GMT), the advent of the first genome sequence of SARS-CoV-2, Wuhan-Hu-1 assisted the researchers to understand the ancestry of this novel coronavirus (SARS-CoV-2) ( Boni et al., 2020 ; Wu et al., 2020b ). Later the data from the bioinformatics analysis has evidenced the homology between SARS-CoV-2 and other members of the coronavirus family, especially with the betacoronavirus 2B ( Boni et al., 2020 ). Thus further studies have been undertaken on SARS-CoV-2 by considering it to be a new member of betacoronavirus 2B lineage infecting humans ( Boni et al., 2020 ). Upon aligning the full-length genome sequence of SARS-CoV-2 and obtainable genomes of beta coronaviruses, scientists observed around 96% of sequence identity within the genomes of SARS-CoV-2 and SARS-like BatCov and RaTG13 coronaviruses. This indicates the bat origin of SARS-CoV-2 or, in other words, SARS-CoV-2 has been naturally evolved from bats ( Boni et al., 2020 ; Naqvi et al., 2020 ; Xiao et al., 2020 ; Zhou et al., 2020 ).

Concurrently, studies have also suggested Malayan pangolins ( Manis javanica ) to be the possible host in the emergence of SARS-CoV-2 infection in humans ( Xiao et al., 2020 ). Pangolins, the scaly ant-eaters belonging to the mammalian order Pholidota, are among the illegally trafficked mammalian species used for food and medicine purposes ( Lam et al., 2020 ). Due to the extensive manhandling of these pangolins, researchers have decided to conduct a study on frozen tissue samples (blood, lungs, and intestine) obtained from 18 Malayan pangolins during an anti-smuggling task by Guangxi Customs officers ( Lam et al., 2020 ). In particular, data from high through-put RNA sequencing has confirmed the Malayan pangolins to be the intermediate host of coronaviruses to humans, and later the readouts from sequence similarity search have demonstrated nearly 85.5–93% identity in the sequences of pangolin coronavirus genome and SARS-CoV-2 ( Lam et al., 2020 ). Hence, the local authorities in China have decided to remove pangolins from wet markets to avoid further zoonotic transmissions ( Boni et al., 2020 ; Lam et al., 2020 ).

Portal of SARS-CoV-2 Entry in the Host Cell

The respiratory tract is considered to be the prominent portal for the ingression of viruses into the mammalian system, due to its direct contact with the external environment ( Matrosovich et al., 2004 ). Therefore, the principal symptoms and complications of SARS-CoV-2 are observed in the respiratory tract at its primary stage ( Belser et al., 2013 ). The viral particles encapsulated in the droplets or aerosols are released from a COVID positive individual when inhaled by a healthy and uninfected person, and the SARS-CoV-2 adheres to the specific cell-surface receptor for the viral protein. In due course it enters into the endosomes and, finally, the viral and lysosomal membranes fusion occurs ( Peiris et al., 2003 ; Belser et al., 2013 ).

The process of SARS-CoV and SARS-CoV-2 coronaviruses entrance into the host is facilitated by the host cells Transmembrane protease serine 2 (TMPRSS2) and lysosomal proteases (especially cathepsins) through two independent mechanisms: proteolytic cleavage of ACE2 receptor which stimulates viral uptake and cleavage of coronavirus spike glycoproteins which turns on the glycoprotein for host cell entry ( Zhang et al., 2021 ). The host cell entry mechanism of these coronaviruses has been extensively studied and found to be almost similar in the case of both SARS-CoV and SARS-CoV-2 ( Zou et al., 2020 ). The virus entry into the cell is mediated by the spike proteins anchored onto the virus surfaces. The spike protein on a mature virus consists of three receptor-binding S1 heads existing on top of trimeric membrane fusion S2 stalk. Once the virus is inhaled by the healthy individual and enters into the respiratory tract, it is the S1 subunit of spike protein with receptor-binding domain (RBD) which first recognizes the human angiotensin-converting enzyme-2 (hACE-2) as its receptor ( Zheng, 2020 ; Zou et al., 2020 ). In general, hACE-2 is a membrane-bound protein expressing in several human cells, namely respiratory tract (abundant in the lower respiratory tract), vascular endothelium, cardiovascular tissue, renal tissue, and intestinal epithelia ( Wang et al., 2020 ). After the recognition of hACE-2 by S1, the proteolytic activation of SARS spike protein at S1/S2 boundary is triggered by the activity of cell surface protease TMPRSS2 and lysosomal proteases (cathepsins) ( Wang et al., 2020 ). Their activity causes the dissociation of S1 from S2, and the segregated S2 molecule further undergoes dramatic conformational changes. This in turn activates the glycoprotein for host cell entry, causing ingression or release of viral RNA into the host cytoplasm, followed by a translation of new viral proteins and affecting nearby cells in the vicinity ( Walls et al., 2020 ; Wang et al., 2020 ).

The cellular entry mechanism for SARS-CoV and SARS-CoV-2 are reported to be almost similar, with a difference in receptor (hACE-2) recognition and binding potential of RBD units in S1 glycoproteins on the surface of SARS-CoV and SARS-CoV-2. The binding affinity of SARS-CoV-2 with hACE-2 is known to be comparatively higher than that of SARS-CoV. Apart from this, the presence of an extra proprotein convertase (PPC) motif in the spike protein of SARS-CoV-2 also distinguishes it from SARS-CoV ( Berry et al., 2004 ; Wang et al., 2020 ).

Epidemiological Traits of SARS-CoV-2

As per the literature, bats and pangolins are reported to be the primary and intermediate reservoirs for the SARS-CoV-2 strain of coronavirus infecting humans ( Zheng, 2020 ). Apart from this, the animals residing in proximity with humans, especially cats, ferrets, and even golden hamsters, are at high risk of SARS-CoV-2 transmissions ( Sharun et al., 2021 ). Initially, it was reported that the expected roots of transmission for SARS-CoV-2 are mainly droplets and fomites exchange between a nCoV infected and an uninfected, healthy individual ( Jayaweera et al., 2020 ). Later a study has also stipulated the emergence of virus from the surrounding environment (air-borne), potentially affecting an uninfected person upon inhaling the aerosols emitted by an infected person while exhaling, sneezing, shouting, coughing, etc. ( Gralton et al., 2011 ; Liu et al., 2017 ). The authors have also quoted that SARS-CoV-2 could remain stable in the aerosols for 3 h ( van Doremalen et al., 2020 ). This report on the airborne transmission of respiratory viruses has been considered as the dominant mode of spread, as it was even difficult to demonstrate on ground levels compared to those of droplets and ferrets mediated transmission ( van Doremalen et al., 2020 ).

As per the recent reports, this new human pathogen (SARS-CoV-2) can continue to stabilize in the digestive tract for a longer duration than in the respiratory tract ( Xu et al., 2020 ). Studies on humans have noted the presence of viral RNAs in the excreta of infected people for more than 33 days after they have been detected as COVID negative ( Arslan et al., 2020 ; Wu et al., 2020d ). This particular finding substantiates another unprecedented mode of viral transmission, i.e., fecal-oral route of viral distribution in the environment ( Wu et al., 2020d ). The viral transmission through the fecal-oral route was further confirmed when children with COVID-19 positive tests have reported negative results in nasopharyngeal swabs while their rectal swabs indicated a consistently positive result for COVID-19 infection ( Yeo et al., 2020 ; Wu et al., 2020d ). Noteworthy, the discharge of COVID-19 patients’ fecal matter may increase the potential risk for wastewater treatment plants (WWTPs), as the virus could embed into the fecal matter and settle in WWTPs ( Arslan et al., 2020 ). Studies have indicated the presence of SARS-CoV-2 in sewage samples in seven cities of Netherlands and Schipol airport at Amsterdam between February and March 2020 ( Arslan et al., 2020 ).

Initially, it was known that SARS-CoV-2 cannot be distributed through intra-uterine vertical transmission from a pregnant woman to an infant, but later the studies have changed the notion by demonstrating the possibility of vertical transmission of the virus in a newborn with few neurological disorganizations whose mother tested positive with SARS-CoV-2 during the last trimester of her pregnancy ( Chen et al., 2020 ; Wang et al., 2020 ). Likewise, a case was reported wherein anti-SARS-CoV-2 IgM antibodies and IL-6 levels were noted to be comparatively higher than the normal neonates indicating the likelihood of transplacental transmigration of virus from COVID-19 positive mother to the neonate ( Dong et al., 2020 ). There is an availability of a relatively good amount of data stating the perinatal transmission of SARS-CoV-2 in pregnant women, but the chances are quite low as compared to SARS-CoV-1 and MERS ( Fan et al., 2020 ; Parazzini et al., 2020 ; Wang et al., 2020 ).

Among all the common and major spread routes for the SARS-CoV-2 virus is direct contact, i.e., person to person contact, public gatherings, and/or crowding at one place as compared to the fecal-oral transmissions, vertical transmissions, and aerosol-mediated spread of virus among the community ( Ghinai et al., 2020b ; Ghinai et al., 2020a ). This viral transmittance is not only limited to human-to-human transmissions but also the pattern of animal to human, human to animal, and animal to animal transmissions being frequently observed in recent days. The best-known instances for animal to human transmission of the primary and intermediate reservoir of SARS-CoV-2 for humans is bats and Malayan pangolins as discussed above. However, transmissions from humans to animals was confirmed when a study indicated the resemblance in viral genetic sequences of SARS-CoV-2 diagnosed in two dogs with that of human SARS-CoV-2 virus ( Sit et al., 2020 ). Hence it was discovered later that animals like tigers, cats, and dogs are on the higher edge of getting infected with the SARS-CoV-2 virus when residing in contact with an infected person for longer ( Singla et al., 2020 ). As the virus can be transmitted from one infected person to another, a similar trend has been observed in the case of animals when for the first time a SARS-CoV-2 positive cat has affected the naïve cat with the same virus and an adult SARS-CoV-2 positive ferret affected a naïve ferret via close contact ( Wang et al., 2020 ). See Figure 1 .

The potential hosts and possible routes of SARS-CoV-2 dissemination.

Variants of Coronavirus

There is a general tendency of viruses including COVID-19 causing SARS-CoV-2 to evolve and gradually change over time ( Abdool Karim and de Oliveira, 2021 ). During the replication process, these viruses every-so-often undergo changes in the genetic code termed as “mutation,” giving rise to a new strain of virus called “variant” ( Abdool Karim and de Oliveira, 2021 ). Mutation in viruses is neither new nor unprecedented, it is a commonly occurring phenomenon in almost all viruses having RNA as a genetic material ( Manrubia and Lázaro, 2006 ). It is mostly the geographic separation events that may result in genetically different variants ( Manrubia and Lázaro, 2006 ).

The data from high throughput sequencing analysis has confirmed around 20 mutation events in the genome of SARS-CoV-2 collected in October 2020 over the first strain sequenced in January 2020 (Wuhan-Hu-1) ( Fang et al., 2021 ). The virus has been reported evolving at a rate of ∼1.1 × 10 −3 substitutions per site per year, corresponding to one substitution every 11 days approximately ( Martin et al., 2021 ). This contrasts with the mutations in the HIV occurring at a rate of ∼4 × 10 −3 substitutions per site per year ( Andrews and Rowland-Jones, 2017 ). Based on the aforementioned details, the US government interagency established a variant classification scheme that classifies SARS-CoV-2 variants into three distinct groups:

(A). Variants of Interest (VOI): It can best be defined as an isolate of SARS-CoV-2 with genotypic and/or phenotypic changes compared to the reference genome. It is a variant with discrete genetic markers associated with inducing alterations in receptor binding, minimized neutralization by antibodies generated against previous exposure of viruses, affecting diagnostics and treatment strategies ( Covid, 2021 ). The threshold for defining a VOI is quite low, to support surveillance efforts.

To date, eight different VOIs for nCoV-2 have been reported in the literature. These variants are an outcome of a common mutation, i.e., D614G, first documented in the United States of America (USA) during the initial phase of the pandemic ( Control and Prevention, 2021 ). The variant with D614G mutation in SARS-CoV-2 spike glycoprotein curtails S1 shedding and enhances viral infectivity compared to the viruses without this mutation or with different mutations ( Control and Prevention, 2021 ). Following is the list of VOIs known till date:

(i). B.1.526: This variant of SARS-CoV-2 was first identified in November 2020 and reported to spread at an alarming rate in New York. DNA sequencing analysis has confirmed the presence of B.1.526 sequence in approximately 27% of the total populatiobn of New York City ( Annavajhala et al., 2021 ). The variant arose due to E484K and S477N mutations in the receptor-binding domain upraising complications associated with resistance to vaccine-elicited and therapeutics ( Annavajhala et al., 2021 ).

(ii). B.1.526.1: The variant for the first time was identified in New York City (October 2020). It is a sub lineage of B1.526.1 with T95I and D253G spike mutation in nCoV-2 original strain ( Wang et al., 2021 ). Like the parent strain (B.1.526), this variant also imparts potential resistance against monoclonal antibodies and reduction in neutralization by post-vaccination sera ( Wang et al., 2021 ).

(iii). B.1.525: This variant was identified in December 2020 for the first time in Nigeria mainly and the sequence analysis studies later have confirmed its appearance in UK and France as well. It is also called the Nigerian strain of SARS-CoV-2. The variant is thought to be an outcome of E484K with H69–V70 deletion and Q677H mutation in the S1 domain of viral spike protein. The B1.525 mutant strains are attributed to increased transmissibility, virulence, and immune escape ( Ozer et al., 2021 ).

(iv). P.2: The whole-genome sequencing studies have reported their occurrences in Brazil mainly and in some regions of Manaus since April 2020. This variant is a sublineage of B.1.128 lineage with E484K point mutation in the receptor-binding domain of SARS-CoV-2 S1 glycoprotein. Presence of E484K mutation in the virus-induced reduced neutralization by polyclonal antibodies in convalescent sera ( Naveca et al., 2021b ; Nonaka et al., 2021 ; Resende et al., 2021 ).

(v). B.1.617: It is the most prominent mutation in India now, which was detected for the first time in Maharashtra, India, in February 2021. It is often called a double mutant of novel coronavirus due to two prominent mutations: E484Q and L452R ( Challen et al., 2021 ). The presence of this variant has triggered the transmittance and drug or vaccine resistance capacity of SARS-CoV-2 in infected people. Later on, UK detected three different but genetically resembling variants of COVID-19 that emerged in Indian: B.1.617.1, B1.617.2, and B.1.617.3 found to be adversely affecting the U.K., U.S., and Israel health sector ( Challen et al., 2021 ; Ferreira et al., 2021 ).

(B). Variants of concern (VOC) or emerging variants: As per the document issued by WHO on February 25, 2021, outlining the description of VOCs and VOIs, VOC can be expounded as a VOI with a noticeable increase in spread, virulence, and demonstrable impacts on diagnosis/treatment/vaccines ( Harper et al., 2021 ). The mounting data on the initial variant of concerns have identified some of them, and the research is still underway to identify the presence of other unknown VOCs:

(i). B.1.1.7: It was first identified as VOC in December 2020 by COVID-19 Genomics (COG)-U.K. consortium, i.e., COG-UK. B.1.1.7 was recognized as the most frequently spreading variant across the UK during the nationwide lockdown; however, other strains usually demonstrate a significant reduction in their transmission by lockdown or social distancing ( Frampton et al., 2021 ). Thus with a rigorous evaluation of retroactive data, the researcher has confirmed the existence of the variant in circulation since September 2020. The variant is also known as 20I/501Y.V1. Studies on B.1.1.7 stipulate that it is one of the well-versed and highly sequenced VOCs with the highest transmissibility (at a rate of between 40% to 70%), infectivity (30% to 50% higher than other strains), and demonstrable mortality rates (61% to 67%) due to mutation in the Y501 region of S1 protein of the virus ( Galloway et al., 2021 ).

(ii). P.1: This particular variant has been detected in Japan by their surveillance system in 4 travelers who had returned from Brazil ( Naveca et al., 2021a ). The variant was noted to be emerged due to N501Y mutation associated with higher binding affinity to hACE receptor, E484 mutation linked to drug/monoclonal antibodies/vaccine resistance, and K417N/T mutation responsible for imparting higher receptor binding affinity to virus in combination with N501Y mutation in the spike protein of the virus ( Naveca et al., 2021a ).

(iii). B.1.1351: The variant is popularly known as “ 20H/501Y.V2” or “ South African variant.” It was first identified in Nelson Mandela Bay, South Africa, in October 2020, after frontline clinicians were notified about the increased frequency of cases to the Network for Genomic Surveillance in South Africa (NGS-SA), which in turn promoted genomic investigations and analysis ( Ellis, 2021 ). The variant is known to have multiple mutations in spike protein, especially the K417N, E484K , and N501Y mutations. These mutations make it a variant of concern as it exhibits enhanced transmissibility and resistance to vaccines ( Ellis, 2021 ).

(iv). Cluster 5: Danish public health authorities first identified this variant on mink farms in Denmark and Netherlands on November 5, 2020 ( Larsen and Paludan, 2020 ). After this, Denmark decided to halt all farmed mink in Denmark ( Larsen and Paludan, 2020 ). The emergence of the Cluster 5 variant is due to the notable Y453 F mutation in the SARS-CoV-2 S1 domain, imparting resistance against neutralizing antibodies ( Larsen and Paludan, 2020 ).

(C). Variants of high consequences: The presence of such variants ensures a considerable reduction in the effectiveness of preventive measures or medical countermeasures (MCMs) as compared to the variants in circulation. The relieving part is that currently there is no trace of the presence of such threatening variants reported or that has come forward from any region of the world ( Control and Prevention, 2021 ).

It is very important to keep an eye on the circulation of these variants and to work efficiently on their preventive measures and vaccine suppression strategies. Moreover, it is equally important to keep track of any further mutation in the nCoV-2 genome by genomic surveillances and sequencing methodologies.

Clinical Manifestations

Patients with COVID-19 may have an extensive range of clinical manifestations. The clinical attributes of COVID-19 may vary from patient to patient ranging from asymptomatic to acute respiratory distress syndrome (ARDS) ( Nepal et al., 2020 ). In general, the disease manifestations of nCoV-2 are dominated by a respiratory condition known as interstitial pneumonia ( Nepal et al., 2020 ). A person infected with SARS-CoV-2 will initially experience fever, sore throat, dry cough, headache, fatigue, restlessness, myalgia, anosmia, and dysgeusia ( Nepal et al., 2020 ). Later it may progress to mild to moderate pneumonia followed by hypoxia, and if left undiagnosed and untreated, then it may further lead to severe complications such as acute respiratory disease syndrome (ARDS) and systemic inflammatory response syndrome (SIRS), and multiorgan failure (MOF) and/or shock ( Nepal et al., 2020 ).

Regardless of respiratory symptoms, unrestricted SARS-CoV-2 infection may stimulate a severe immune reaction called a “Cytokine storm,” in which a body dissipates too many cytokines in the blood very quickly and uncontrollably ( Zhai et al., 2020 ). As a result, the production of neutrophils, proinflammatory cytokines (IL-1β, IL-6, TNF-α, etc.), and chemokines (Ccl1, CXCl10, Ccl3, etc.) exceeds the levels of anti-inflammatory cytokines in the body, which in turn leads to multiorgan damages ( Fu et al., 2021 ). The majority of patients together with the asymptomatic ones are reported to exhibit diffused bilateral pneumonia surrounded with ground-glassy opacity either progressing or coexisting with consolidation ( Cui et al., 2020 ). Histological examinations have also evidenced that the lower respiratory tract holds a higher overall viral load than the upper respiratory tract ( Wölfel et al., 2020 ). Besides this, pathological findings in the infected lungs have also clearly indicated the appearance of proteinaceous exudates in lung tissues as well as in BALF, development of pulmonary edema, bilateral diffuse alveolar damage (DAD), interstitial thickening, infiltration of T cells or inflammatory monocytes, etc. compared to a healthy lung ( Wölfel et al., 2020 ). Moreover, COVID-19 patients have also been marked with relatively low levels of lymphocytic T cells (CD4 +  and CD8 + ) and natural killer (NK) cells, i.e., overall low levels of lymphocyte counts in the blood profile ( Varchetta et al., 2021 ). Two of the most prominent reasons for low lymphocytes are hypokalemia (low potassium levels) and hypophosphatemia (low sodium levels), induced due to the impact of SARS-CoV-2 on patients ACE-Angiotensin-II (ACE-Ang-II) that prevents the degradation of intact Ang-II within the system. As a result, aldosterone production triggers promoting to frequent vomiting, diarrhea, and urination. This in turn affects lymphocyte production in the infected person ( Kordzadeh-Kermani et al., 2020 ). In addition to this, people with co-morbidities like diabetes, hypertension, hypothyroidism, chronic lung diseases (COPD, ALI, etc.), any malignancies, even obesity are at high risk of severe COVID-19 infection ( Chen et al., 2020 ). In conformation with retrospective studies during the first wave of COVID-19 (i.e., unmutated strain), aged people (>50 years) were known to be at high risk, but the variant of SARS-CoV-2 as a leading cause for the second wave has affected youngsters mainly as compared to children and the aged once ( Ioannidis et al., 2021 ). Hence aging cannot be precisely considered a factor for COVID-19 infection ( Ioannidis et al., 2021 ).

Besides the involvement of the respiratory tract, the involvement of other vital organs has also been reported in the literature during infection either directly or indirectly ( Catapano et al., 2021 ). According to the literature emergence of interstitial pneumonia in COVID-19 patients is an additive effect of respiratory complications and GI tract symptoms ( Su et al., 2020 ). The presence of dense hACE-2 receptors on the epithelial cells of the GI tract promotes the viral ingression into the GI tract and causes GI associated abnormalities, namely vomiting, diarrhea, nausea, abdominal pain, etc. ( Su et al., 2020 ). Data from the recent retrospective studies on COVID-19 has indicated that around 10% of the mortalities occurred because of low cardiac reserves, especially coronary artery disease and heart failure ( Guzik et al., 2020 ). The laboratory findings suggest the spike in hs-Troponin-I levels and significant abnormalities in electrocardiogram (ECG) are the leading factors of nCoV-2 associated cardiac injuries, namely acute coronary syndrome (ACS), myocarditis, arrhythmias, venous thromboembolic episodes, and pericarditis ( Guzik et al., 2020 ). Several case reports and series of surveys on hospitalized COVID-19 patients so far evidenced the acute kidney injury (AKI) to be a pivotal reason for COVID-19 related deaths ( Lee et al., 2021 ). Similar to the lungs, kidneys are also the potential site of action for SARS-CoV-2 viruses due to the presence of enriched ACE-2 receptors ( Lee et al., 2021 ). The clarity came after pathological examinations which demonstrated the dramatically higher counts of D-dimer, hematuria, proteinuria, serum creatinine, and microalbumin in the blood and urine samples of SARS-CoV-2 affected patients ( Kordzadeh-Kermani et al., 2020 ). However, the effect of nCoV-2 infection on mammalian hematologic mechanism came into existence after autopsy reports obtained from six COVID-19 patients unveiled the SARS-CoV-2- mediated deterioration of spleen and lymph nodes, implicating the abnormal hematopoiesis, coagulopathy, and clear sign of thrombocytopenia to be the major cause of death ( Connors and Levy, 2020 ; Fox et al., 2020 ; Qu et al., 2020 ).

According to Cai and Huang et al. (April 2020), more than 40% of COVID-19 patients have exhibited abnormal liver functioning and liver injuries due to increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ( Cai et al., 2020 ). Recently there have been some insights pointing towards the higher affinity of SARS-CoV-2 towards hACE-2 receptors present on cholangiocytes, leading to cholangiocytes deregulation followed by the induction of systemic inflammatory response, a major factor responsible for liver injury in the majority of cases ( Kordzadeh-Kermani et al., 2020 ). Besides this elevated alkaline phosphatases, higher Gamma-glutamyltransferase (γ-GT) and lactate dehydrogenase (LDH) levels in the hospitalized COVID-19 patients have confirmed the impact of COVID-19 on the patient’s liver ( Cai et al., 2020 ; Kordzadeh-Kermani et al., 2020 ). The list of organs and vital parameters getting affected by COVID-19 hasn’t been terminated here. The breakthrough occurred when the findings from Hamburg, Germany, confirmed the deleterious effects of SARS-CoV-2 on the mammalian endocrine system, by putting forward a report stating around 68% of the severe COVID-19 cases have presented critically low levels of testosterone and dihydrotestosterone along with elevated levels of estradiol in the males mimetic to higher IL-6 counts. Females with COVID-19 disease demonstrated higher testosterone levels correlated with IL-6 increase ( Schroeder et al., 2020 ). Researchers from the retrospective cohort have already declared the direct impact of nCoV-2 on Leydig cells, a leading cause of testosterone secretions during stress or infection ( Zou et al., 2020 ).

Later, as the knowledge on COVID-19 and its clinical features continued to expand, the observational studies came forward with shreds of evidence on neurological symptoms in the patients infected with COVID-19 ( Kordzadeh-Kermani et al., 2020 ). The clinical implications of COVID-19 on the neurological system have been evidenced for the first time in a clinical report from Wuhan, China, when a 62-year-old severe COVID-19 patient admitted to a local hospital was shown to develop intracerebral hemorrhage which later progressed to intracranial hemorrhage, and the patient died finally ( Li et al., 2020b ). In corroboration to this was a clinical investigation of a 79-year-old male without any medical background of hypertension and a 54-year-old woman with a medical history of hypertension suffering from COVID-19 and admitted to a local hospital in Iran, presented with fever, dry cough, and acute loss of consciousness in initial stages of infection. With the progression in severity of infection, the CT brain examinations unveiled an immense intracerebral hemorrhage in the right hemisphere along with intraventricular and subarachnoid hemorrhage in the former case and bilateral sub-acute basal ganglia hemorrhage in the latter case ( Nepal et al., 2020 ). Subsequently, many other studies and case reports have confirmed the invasion of SARS-CoV-2 through the hACE-2 receptors on nasal and oral cavities leading to impaired functioning of sensory neurons, exhibiting neuromuscular symptoms, confirming the involvement of all three nervous systems (CNS, ANS, and PNS) in COVID-19 mediated mortalities ( Mao et al., 2020 ). The nCoV-2 induced complications in CNS are confirmed by the commonly observed symptoms like headache, dizziness, ataxia, epilepsy, and impaired consciousness in COVID-19 patients ( Mao et al., 2020 ). Intense nerve pain, skeletal muscle injury, cranial polyneuritis, neurosensory hearing loss, dysautonomia, neuro-ophthalmological disorders, Guillain-Barré syndrome, and similar signs represent PNS manifestation in COVID-19 infected patients ( Andalib et al., 2021 ). However, the effect of COVID-19 on ANS is linked to cytokine storm as a response to viral ingression within the system. This exceedingly higher level of proinflammatory cytokines due to activation of the sympathetic system leads to vagal stimulation in order to produce anti-inflammatory cytokines to counter the higher levels of proinflammatory cytokines. As a result, symptoms like orthostasis hypotension, postural orthostatic tachycardia condition, and vasovagal syncope have been observed, which confirms the abnormal ANS ( Dani et al., 2021 ).

Under mild COVID-19 conditions, the home-quarantined patients have also experienced erythema, papules, rashes, abnormal scaling patterns, the appearance of chicken-pox like vesicles followed by itching, and burning symptoms on the dermal tissues infrequently ( Tsankov and Darlenski, 2020 ). Of note, references have also indicated the ocular manifestations in the patients with SARS-CoV-2 characterized with lacrimal infection, epiphora, chemosis, and conjunctival hyperemia ( Recalcati, 2020 ). COVID-19 patients have shown interestingly higher levels of LDH, leukocytosis, CRP, and prolactin, which have been considered to be pivotal factors for ocular manifestations of COVID-19 ( Wu et al., 2020c ) ( Figure 2 ).

Systematic overview of the complete article.

Post-COVID-19 Complications

The majority of COVID-19 patients recover within a week or two after infection; on the other hand, some of them have been noticed to experience moderate to severe post-COVID conditions ( Silva Andrade et al., 2021 ). The data from COVID-19 hospitals from different nations suggest multiple health issues extending from a week to a month, even in people who did not have symptoms during COVID-19 infection ( Silva Andrade et al., 2021 ). Predominantly it is the fatigue, muscle ache, headache, chest pain, cough, reduced performance, anxiety, lack of concentration, and depression-like symptoms being experienced in the patients with the “Long COVID-19” condition ( Silva Andrade et al., 2021 ).

After diving deep into the health status of patients diagnosed with negative COVID-19, symptoms such as acute disseminated encephalomyelitis, Guillain-barre syndrome (GBS), acute necrotizing hemorrhagic encephalopathy (ANHE), acute neuropathy, etc. arising due to deregulated immune response, cranial involvement, and impaired central and peripheral nervous system are seen nowadays as a post-COVID condition and have become a matter of concern Montalvan et al., 2020 ; ( Sedaghat and Karimi, 2020 ; Shahmirzaei and Moghadasi, 2021 ). Apart from these multiorgan effects, especially autoimmune conditions and multisystem inflammatory syndrome (MIS), i.e., a clinical condition in which edema occurs in different regions of the body due to elevated proinflammatory cytokines production have also been reported by the patients after a week of recovering from COVID-19 ( Ramos-Casals et al., 2021 ). Further progress in scientific and clinical investigations, pieces of evidence related to the post-COVID multiorgan condition with an extensive spectrum of manifestations of the disease, is brought into the knowledge. Examples of these multiorgan systems include rapid hair loss, feces with viral load for longer times, persistent palpitation, dyspnea, bone demineralization, uncontrolled diabetes, restrictive pulmonary physiology, elevated D-dimer, and COVID-19-associated nephropathy (COVAN) condition (a foremost pattern of renal injury in the majority of the African population) ( Mokhtari et al., 2020 ; Velez et al., 2020 ).

Our local health sectors and doctors are required to provide maximum attention to the COVID-19 patients who were on ventilators and hospitalized for longer durations as they are the ones who have consistently been reported to present the most complicated manifestations of the disease such as severe weakness, post-intensive care syndrome (PICS), post-traumatic stress disorder (PTSD), and the most deadly “mucormycosis” infection ( Garg et al., 2021 ; Smith and Rahman, 2020 ).

Mucormycosis is one of the devastating but rare fungal infections caused by exposure to a group of mucor moulds named mucormycetes. These mucormycetes, members of Mucorales order, are the cluster of fungi existing throughout the environment predominantly in soil rich in decaying organic matter such as animal drugs, composite piles, dead leaves, etc. ( Lehrer et al., 1980 ). These fungi are more common in soil than in the air; similarly, they are noted to be more active in summers than winters or springs ( Richardson and Rautemaa-Richardson, 2020 ). Among these mucormycetes, it is the Rhizopus and Mucor species that are commonly known to cause mucormycosis ( Richardson and Rautemaa-Richardson, 2020 ). As per the literature, the majority of us are encountered with microscopic fungal spores on a regular basis, as it is almost impossible to 100% circumvent the contact with mucormycetes. Although it is not really harmful to most people, for those with a weak immune system and recovering from some critical pathologies and still breathing in mucormycetes spores, then the possibility of infection in the sinuses, brain, lungs, and to other body parts may occur ( Spellberg et al., 2005 ). This particular fungal infection is noted to be life-threatening in severely immunocompromised individuals or patients with diabetes mellitus ( Spellberg et al., 2005 ).

Depending on its clinical features and anatomical localization, mucormycosis is broadly classified into six distinct classes: (1) Rhinocerebral or rhino-orbitocerebral mucormycosis, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations ( Spellberg et al., 2005 ). People infected with mucormycosis exhibit the presence of substantial angioinvasion followed by blood vessel thrombosis and tissue necrosis ( Ibrahim et al., 2012 ). As a result, penetration through endothelial cells lining blood vessels and their deterioration is observed commonly ( Ibrahim et al., 2012 ). Based on a retrospective cohort study on the mucormycosis, involvement of some predisposition conditions has been noted and reported in the present review; rhinocerebral, pulmonary, and disseminated muccormycosis are commonly known to affect those with uncontrolled diabetes mellitus (specifically in those with ketoacidosis), extensive burns, iron overload, solid malignancies, treatment with glucocorticosteroids, or patients with neutropenia ( Skiada et al., 2020 ). GI mucormycosis may arise due to malnutrition ( Skiada et al., 2020 ). However, cutaneous/subcutaneous mucormycosis may affect the patients who underwent prolonged hospitalization and have been in touch with catheters and ventilators ( Castrejón-Pérez et al., 2017 ).

The massive upsurge or according to local news “Tsunami of black fungus” has been observed in India in the wake of a spike in COVID-19 cases. Patients infected with this black fungus are presenting with nasal congestion, headache, and facial swelling ( Serris et al., 2019 ). In the worst scenario, fever, cough, and dyspnea are also reported when the infection reaches the lungs ( Serris et al., 2019 ). As per the reports, more than 10,000 patients have been known to be infected with black fungus (mucormycosis) in different parts of India ( Bhuyan, 2021 ; Moona and Islam, 2021 ). Statisticians have claimed that steroids useful in curtailing the mortality rate in COVID-19 patients are potential factors for mucormycosis infection ( Mehta and Pandey, 2020 ). At the same time, the shortage of oxygen tanks and delivery devices due to fulfilling the demands of exceedingly high COVID-19 cases in India has compelled the local authorities to gather oxygen cylinders without keeping an eye on their sources, resulting in the use of outdated oxygen delivery devices and cylinders contaminated with black fungus colonies delivered to the local hospital authorities ( Carter and Notter, 2021 ; Feinmann, 2021 ). Other possible risk factors could be steam inhalation abuse, genetic pre-disposition, higher use of antibiotics, poor oral-nasal hygiene, repeated use of the same mask, etc. ( Spellberg et al., 2012 ).

There are not much data available on the treatment and preventive measures for black fungus so far; however, experts are only left with either advising the use of Amphotericin B and posaconazole, or isavuconazole, or mostly the employment of surgical procedures to remove infected or dead tissue ( Ochi et al., 1988 ).

Impacts of COVID-19

COVID-19 has frequently affected day-to-day life and decelerated the global economy by freezing world trade and moments in multiple ways ( Chakraborty and Maity, 2020 ). Despite these, the biggest threat that the world is facing today is to slow down the mortality rates due to the rapid spread of SARS-CoV-2 and its associated manifestations. The complications of modern medicine and research have been aggravated by the emerging variants of nCoV-2, influencing the responses of the drugs and vaccines designed so far ( Munzig, 2019 ). There are reports available that evidence the long-term psychological impact of COVID-19 on people even after being cured of it ( Saladino et al., 2020 ).

The havoc caused by the COVID-19 pandemic has pushed the world into prolonged exposure to stress due to a sense of helplessness, lack of freedom, and separation from our dear ones ( Saladino et al., 2020 ). As an aftermath, psychological disturbances, depression, anxiety, and inability to tackle negative emotions leading to suicidal attempts have become a subject of concern ( Saladino et al., 2020 ). The group which is majorly affected due to this is school-going children, college students, earning youngsters, and the health professionals ( Saladino et al., 2020 ). As per a recent survey on 1143 parents and children aged between 3–18 years in Italy and Spain, parents experienced drastic emotional and behavioral changes in their children during lockdown ( Orgilés et al., 2020 ). Parents reported that their children have difficulty in concentrating, few of them have expressed consistent irritability, complaining of boredom, sensing uneasiness, and loneliness throughout the quarantine ( Orgilés et al., 2020 ). On contrary, the observations in the parents have exhibited some worrying responses, including: most of the parents have undergone depression due to loss of their wages and earning resources, in some cases relationships among the couples have also been compromised, and staying disconnected for longer ( Orgilés et al., 2020 ). In corroboration to this, the data collected from a small survey in China during the initial stages of quarantine due to COVID-19 also demonstrated its worsening impact on the socio-behavioral and psychological tendencies of college-going students and earning individuals especially ( Li et al., 2020a ).

Apart from this, literature has also emphasized the mental state of healthcare workers (HCWs) and health professionals, who have equally been affected and registered with a high level of stress due to soaring COVID-19 cases ( Garcia-Castrillo et al., 2020 ; Saladino et al., 2020 ). Ever since the emergence of SARS-CoV-2, this particular segment of people is engrossed with direct contact of the COVID-19 patients and loaded with enormous responsibilities, making them suffer from a high level of psycho-physical stress ( Mohindra et al., 2020 ). This causes them to enter into secondary traumatic stress disorders, emotional and physical exhaustion, and sometimes a sense of helplessness is observed when sufficient resources and treatments lack to save lives ( Mohindra et al., 2020 ; Saladino et al., 2020 ).

Therefore, to combat these alterations in the socio-psychological behavior of the majority of the population across the globe, World Health Organization (WHO) and Centers for Disease Control and Prevention (CDCP) have advocated specific conventions on the correct usage of health protection to curtail the distress and anxiety in the communities getting affected during the pandemic ( Saladino et al., 2020 ). Besides this, local governments have also decided to avail psychotherapists to provide psychological support online and help the youngsters and HCWs to deal with their challenges ( Saladino et al., 2020 ).

Treatments Available

The global threat that prevailed due to this emerging SARS-CoV-2 virus has been a challenge to the health sector and medicine due to lack of information on specific anti-viral therapies or pharmacological entities to prevent nCoV-2 infection. As emergency medicine, doctors are relying on oxygen therapy, extracorporeal membrane oxygenation (ECMO), glucocorticoid supplementation (Dexamethasone), a common antibiotic, and antifungal treatments ( van Paassen et al., 2020 ). Refer to Table 1 ( Han et al., 2020 ; Madjid et al., 2020 ; Zheng, 2020 ; Ardestani and Azizi, 2021 ; Malgotra and Sharma, 2021 ; Shamsi et al., 2021 ).

Table 1

The list of potential therapeutics against clinical manifestations of COVID-19 in use and their side effects.

The increasing number of cases and deaths due to COVID-19 has raised the concerns of local governments in all the nations across the globe. This has further created immense pressure on researchers and clinicians to expand trials on unknown or new drug moieties. According to the undergoing clinical trials the Food and Drug Administration (FDA) has recommended and allotted “emergency use authorization (EAU)” certification only to the three types of vaccines:

• 1. mRNA-based vaccines: exhibit an encouraging alternative to conventional vaccine approaches with their expeditious development capacities, low manufacturing investments, high potency, and secure administration ( Verbeke et al., 2021 ). mRNA vaccines carry material from the COVID-19 causing virus that instructs our cells to synthesize a harmless protein that is unusual to the virus. Once the copies of such proteins are prepared by the cells, the genetic material from the vaccine is destroyed. Immediately after this body recognizes no more need for those proteins, so it starts generating relevant T- and B- lymphocytes to store the memory of how to combat the encounter of the body with the same virus for the next time ( Verbeke et al., 2021 ).
• 2. Subunit vaccines: Protein subunit vaccines also called “A cellular vaccines” are considered to be the safest vaccine types over other categories. Instead of injecting a whole pathogen to trigger an immune response, they include purified, harmless protein fragments of the viral or bacterial pathogen selected especially for stimulating immune cells. After having sufficient copies of the desirable protein, our body cells then promotes the production of T- and B-lymphocytes for the memory to protect the body from future attack of the same virus ( Kaur and Gupta, 2020 ).

Table 2

Update on FDA authorized COVID-19 vaccines for emergency use.

Almost a year after the start of the COVID-19 pandemic, the U.S. Food and Drug Administration authorized the emergency use of the first nCoV-2 vaccine ( Quinn et al., 2020 ). Raising vaccines and conducting vaccination drives has been realized to be the foremost requisite of public health intervention. Indeed, it is the only way to stay protected during the pandemic. Again, this incredible and prolific outcome of researchers’ great input has been found to be associated with a limitation, known as “vaccine hesitancy” ( Sallam, 2021 ). According to the World Health Organization (WHO), vaccine hesitancy is a retarded acceptance or rejection of vaccine despite the ongoing vaccination drives; it has been labeled as among the top-10 global threats of 2019 ( Recio-Román et al., 2021 ). A significant proportion of the U.S. population has experienced a pattern of hesitancy against this first COVID-19 vaccine ( Coustasse et al., 2021 ). This skeptical attitude of individuals against the non-authorized SARS-CoV-2 vaccine has been more aggravated by the previous experience from the approved flu A and B vaccine reported with minimal acceptance and in turn introduced an anonymous distrust among the community ( Razai et al., 2021 ). Additionally the political influence and fake media announcements have also played a considerable role in manipulating the notions of the general public on available COVID-19 vaccine ( Mills et al., 2020 ; Razai et al., 2021 ). As per a small survey conducted on 10-item vaccine hesitancy scale developed by WHO SAGE working group in Canada, China, Ethiopia, and Guatemala, maximum hesitancy towards any novel vaccine is expressed by parents of the middle age group ( Wagner et al., 2021 ). Around 19% of the total parents within any country have expressed their distrust against un-authorized or non-FDA approved vaccines, making the vaccination drive challenging ( Wagner et al., 2021 ).

Indeed the rationale behind vaccine hesitancy has been categorized into three categories: (1) lack of trust on the efficacy and safety profile of the vaccine, (2) missing complacency, i.e., confidence on not perceiving vaccine preventable diseases (VPDs) in the future, and (3) inconvenience due to managing authorities responsible for vaccination in terms of accessibility and unavailability of vaccine, unorganized vaccination pattern, inequitable distribution of vaccine, appeal of immunization services such as time, place, language, and cultural contexts ( Razai et al., 2021 ).

Therefore, to overcome this COVID-19 induced catastrophic moral failure of the world, first we need to untidily work on pushing the equitable production and equitable distribution of vaccine to every single individual across the globe at our earliest convenience. Second, we need to keep on track on boosting our testing and tracing, oxygen supplies, and therapeutic and public health measures approaches.

Concluding Remarks and Future Perspective

As the COVID-19 pandemic continues to unfurl, the complications of the general public and health sector crisis are presumed to continue. A subsequent increase in cases and flaring death cases due to the outbreak of this disease created unprecedented havoc initially in most afflicted nations such as China, Italy, the United States, and Iran, and eventually to the entire world. Earlier the WHO and local governments of all the countries decided to impose global lockdown to minimize social gatherings and in-person contact with the thought of preventing SARS-CoV-2 distribution. Later it was reported that the virus can spread even through the aerosols in the atmosphere and can be transmitted from pets to humans and vice versa. This has further compounded an inevitable stress on researchers and doctors and poses a serious threat to public health.

Henceforth, the need for enormous research and meta-analysis was realized and the significant findings from those studies to justify the reason for viral spread, possible preventive measures, and future approaches to be adopted made available to the general audience in the form of distinguished articles in pieces. Therefore, to save the precious time and effort of our readers, the authors in the present review have strived to gather, compile, and place every possible detail on COVID-19 disease from different sources and available literature in one place. By diving deep into the details shared in retrospective cohort studies and considering the present scenario, the current review has intensively discussed the origin of COVID-19, its pathogenesis, epidemiology, possible routes of SARS-CoV-2 invasion and zoonotic dissemination, virus variants, its implications on mental as well as on physical health, post-COVID-19 side-effects, and details on pros and cons of available curatives (therapeutics and vaccines) across the globe.

Depending on the rate of mortalities and the catastrophe caused by nCoV-2 infection, the production and administration of vaccines should be prioritized by limiting the usage of corticosteroids to COVID-19 patients to prevent the ferocious side effects, especially mucormycosis infection. We should also speed our trials on ongoing therapeutics with a special emphasis on some minimally studied nanoparticles, bio-flavonoids, nano-nutraceuticals, etc., with reported antiviral attributes to obtain certain novel and efficient pharmacological moieties to combat COVID-19 and post-COVID-19 clinical manifestations with minimal or no side effects.

Author Contributions

RR contributed to the study design and concept. RR, AT, NK and NG were involved in the study organization. RR and AT wrote the manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest

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

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

RR is thankful to Sir Ganga Ram Hospital, Delhi, India, for providing the necessary support.

Abbreviations

ACE, Angiotensin-converting enzyme; β-CoV, Betacoronavirus; BatCov, Bat coronavirus (HKU3); CoV, Coronavirus; COVID-19, Coronavirus disease 2019; FDA, Food and Drug Administration; GMT, Greenwich Mean Time; HCoV, Human coronavirus; hACE, Human Angiotensin-converting enzyme; HIV, Human Immunodeficiency Virus; ILs, Interleukins; IFN, Interferon; WHO, World Health Organization; MERS, Middle East respiratory syndrome; SARS, Severe Acute Respiratory Syndrome; TMPRSS2, Transmembrane protease, serine 2.

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Coronavirus (COVID-19)

How americans view the coronavirus, covid-19 vaccines amid declining levels of concern.

Just 20% of the public views the coronavirus as a major threat to the health of the U.S. population and only 10% are very concerned about getting a serious case themselves. In addition, a relatively small share of U.S. adults (28%) say they’ve received an updated COVID-19 vaccine since last fall.

How the Pandemic Has Affected Attendance at U.S. Religious Services

During the pandemic, a stable share of U.S. adults have been participating in religious services in some way – either virtually or in person – but in-person attendance is slightly lower than it was before COVID-19. Among Americans surveyed across several years, the vast majority described their attendance habits in roughly the same way in both 2019 and 2022.

Mental health and the pandemic: What U.S. surveys have found

Here’s a look at what surveys by Pew Research Center and other organizations have found about Americans’ mental health during the pandemic.

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Just 20% of the public views the coronavirus as a major threat to the health of the U.S. population and only 10% are very concerned about getting a serious case themselves. In addition, a relatively small share of U.S. adults (28%) say they’ve received an updated COVID-19 vaccine since last fall.

Online Religious Services Appeal to Many Americans, but Going in Person Remains More Popular

About a quarter of U.S. adults regularly watch religious services online or on TV, and most of them are highly satisfied with the experience. About two-in-ten Americans (21%) use apps or websites to help with reading scripture.

About a third of U.S. workers who can work from home now do so all the time

About a third of workers with jobs that can be done remotely are working from home all the time, according to a new Pew Research Center survey.

Economy Remains the Public’s Top Policy Priority; COVID-19 Concerns Decline Again

Americans now see reducing the budget deficit as a higher priority for the president and Congress to address than in recent years. But strengthening the economy continues to be the public’s top policy priority.

At least four-in-ten U.S. adults have faced high levels of psychological distress during COVID-19 pandemic

58% of those ages 18 to 29 have experienced high levels of psychological distress at least once between March 2020 and September 2022.

Key findings about COVID-19 restrictions that affected religious groups around the world in 2020

Our study analyzes 198 countries and territories and is based on policies and events in 2020, the most recent year for which data is available.

How COVID-19 Restrictions Affected Religious Groups Around the World in 2020

Nearly a quarter of countries used force to prevent religious gatherings during the pandemic; other government restrictions and social hostilities related to religion remained fairly stable.

What Makes Someone a Good Member of Society?

Most in advanced economies say voting, taking steps to reduce climate change and getting a COVID-19 vaccine are ways to be a good member of society; fewer say this about attending religious services.

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COVID-19 Research

EPA researchers are building on an expansive body of world-class research by applying knowledge to reduce the risk of exposure to SARS-CoV-2, the virus that causes COVID-19. Read an overview of EPA research efforts related to COVID-19 is below, or learn more about EPA's COVID-19 research efforts, including data and results.  

• Community Exposure
• Masks and PPE

Research on Covid-19 in the Air

Common modes of transmission of Covid-19 include aerosols or respiratory droplets that are produced when a person coughs, sneezes, sings or talks, particularly in indoor environments with limited ventilation. Aerosols are very tiny particles that linger in the air and move with air currents like smoke or dust. Respiratory droplets are larger and fall, landing on surfaces where they can linger hours to days.

To learn more about how the virus moves in the air, researchers modeled viral aerosols in an office environment. The focus of this research was an “open office” such as a cubicle work environment where there is concern about how aerosols from an infected person, though likely asymptomatic, might affect other workers in other locations in an office. This research will first determine potential levels of exposure and then look at practical office modifications that might reduce exposure to the virus.

Researchers are also looking at technologies that are safe to operate in spaces where there will be people, like offices, subways, restaurants, etc, to reduce the amount of SARS-CoV-2 in the air. These technologies include devices and products like UV-C devices, chemical-based devices, and physical removal devices like filters.

• Read more about EPA's research related to SARS-CoV-2 aerosols.

Research on COVID-19 on Surfaces

Respiratory droplets, which are larger, and fall quickly, can still be a mode of transmission for SARS-CoV-2, the virus that causes Covid-19. First, researchers had to develop a way to quickly detect live virus in surface samples because current testing takes a few days to get results, which would be too late to worry about surface contamination. Researchers developed a rapid analytical method so that they could understand potential surface transmission in a short time.

Areas that are frequently touched by many different people can pose a public health risk during the pandemic, so researchers evaluated commercially available antimicrobial products for potential long-lasting effectiveness against the virus. Currently, EPA-registered products with long-lasting effectiveness claims are limited to those that control odor-causing bacteria on hard, non-porous surfaces; there are no EPA registered products with public health claims that provide long-lasting (e.g., weeks to months) disinfection. The benefits of having a longer-lasting antimicrobial product are important, especially when cleaning and disinfecting a surface or object cannot be accomplished every time someone new touches it.

In addition, ways to apply disinfectants to many different, large surface areas quickly and effectively were needed to reduce the risk of exposure to the virus. Researchers evaluated electrostatic sprayers and foggers to rapidly apply disinfectants over large, complex surface areas. 

At the request of some of the countries largest transit agencies, EPA researchers also studied whether UV-C could inactivate the SARS-CoV-2 virus on subways and buses. This results from this research are useful for business owners, school administrators, and others.

Overall, this research will help decision makers determine the best ways to help reduce the risk of exposure to COVID-19 from potential surface transmission.

• Learn more about EPA's research related to COVID-19 and surfaces.  
• Review information from CDC about Cleaning and Disinfecting Your Home, workplace and other Facilities.

Determining Community Exposure

With an infectious disease like COVID-19, people may be contagious before they show any symptoms. Some may never show symptoms. To determine the true rate of community infection and to provide information to help public health departments around the country to make the best decisions on directing resources, EPA researchers have developed several ways to monitor exposure.

EPA researchers are analyzing wastewater samples from communities in southwestern Ohio using a molecular approach to look for the genetic marker of SARS-CoV-2. This approach acts as an early warning system to alert public health officials about increasing infection in a community. It can also serve to let the officials know when cases are dropping.

Researchers are also working on a standardized method that could quantify the level of live, or infectious, SARS-CoV-2 detected in raw sewage at wastewater treatment plants.

• Learn more about EPA's research efforts related to COVID-19 and sewage.

EPA researchers have also developed a salivary antibody test that is simple, easy-to-collect, low-cost, and noninvasive. Antibody testing helps identify people who have been exposed to SARS-CoV-2 and have developed an immune response, but who might not have ever developed symptoms. This test can help public health officials determine the rate of infection and provide insights on the true impact of the pandemic in communities across the country.

• Read a summary of EPA's research results related to the creation of SARS-CoV-2 salivary antibody test.

Research on Masks and PPE

Masks and social distancing have been important to reduce the risk of exposure to COVID-19. Researchers studied the effectiveness of different kinds of masks and facial coverings to help people decide which kind of masks to buy and wear to protect themselves and others.

• Learn more about EPA's research related to the effectiveness of masks and facial coverings against COVID-19.

Researchers also evaluated methods to disinfect used PPE and evaluated whether any of the disinfection methods causes damage to the PPE or limited its performance in reducing exposure to COVID-19. This information helps frontline workers such as healthcare staff and emergency responders when PPE are in limited supply. Proper cleaning and disinfection for PPE ensures continued protection from exposure to the disease.

• Read a summary of EPA's research efforts related to proper disinfection of PPE.
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BMJ's Coronavirus (covid-19) Hub

BMJ's covid-19 hub supports health professionals and researchers with practical guidance and online CPD courses, as well as free access to the latest news, comment, and research from The BMJ. Covid-related research content from the rest of our portfolio of journals is also freely available for a year.

BMJ is committed to providing access to covid-related materials to those who need them. If you require access to an article that is no longer freely available, please contact [email protected] with the subject line "Covid Article Request".

What you need to know

Highlights from the bmj, what do we know about covid-19’s effects on the gut.

01 May 2024

NHS hospital capacity during covid-19: overstretched staff, space, systems, and stuff

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UK workers during the pandemic: inadequate protection and, consequently, increased risk

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US public health after covid-19: learning from the failures of the hollow state and racial capitalism

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Essential workers during covid-19: how quickly we forget

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Covid-19 has cut UK life expectancy by around half a year, data suggest

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Learning to live with covid-19: testing, vaccination, and mask wearing still play a key part in managing the pandemic

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Embedding implementation research to cross the quality of care chasm during the covid-19 pandemic and beyond

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Communicating scientific advice: lessons from the UK covid-19 inquiry

07 December 2023

Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: population based cohort study

22 November 2023

Equity and technology in the pandemic treaty

03 November 2023

Clinical guidance

A living who guideline on drugs to prevent covid-19.

24 March 2023

A living WHO guideline on drugs for covid-19

14 July 2022

Covid-19 diagnosis and management

BMJ Best Practice provides regularly updated information on prevention, diagnosis, management, follow up

Work and vocational rehabilitation for people living with long covid

10 May 2024

Cognitive dysfunction after covid-19

01 February 2024

Diagnosis of venous thromboembolic diseases in people with covid-19: summary of updated NICE guidance

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Pathophysiology, diagnosis, and management of neuroinflammation in covid-19

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Breathing difficulties after covid-19: a guide for primary care

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Orthostatic tachycardia after covid-19

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Update to living WHO guideline on drugs for covid-19

12 January 2023

Long covid—an update for primary care

22 September 2022

Covid-19 vaccination in pregnancy

10 August 2022

Diagnosis and management of covid-19 in pregnancy

26 April 2022

From The BMJ

Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (regain study): multicentre randomised controlled trial.

07 February 2024

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

21 September 2023

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

09 August 2023

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

25 July 2023

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

Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in nordic countries: population based cohort analyses.

24 July 2023

From BMJ Journals

Lessons from covid-19 syndromic surveillance through emergency department activity: a prospective time series study from western switzerland, covid-19, body weight and the neighbourhood: food system dimensions and consumption associated with changes in body weight of peruvian adults during first wave lockdowns, impact of physical activity on covid-19-related symptoms and perception of physical performance, fatigue and exhaustion during stay-at-home orders, effectiveness of ehteraz digital contact tracing app versus conventional contact tracing in managing the outbreak of covid-19 in the state of qatar, vaccine rollout.

Protecting infants through covid-19 vaccination during pregnancy

Maternal mrna covid-19 vaccination during pregnancy and delta or omicron infection or hospital admission in infants: test negative design study, investing in robust surveillance of the effects of covid-19 and future emerging infections in pregnancy should be prioritised, epidural analgesia during labour and severe maternal morbidity: population based study, effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials, ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses, advances in the management of chronic kidney disease, association of ultra-processed food consumption with all cause and cause specific mortality: population based cohort study, association between exposure to antibiotics during pregnancy or early infancy and risk of autism spectrum disorder, intellectual disorder, language disorder, and epilepsy in children: population based cohort study, pandemic treaty: panel calls for “reset” to talks as negotiators miss deadline.

30 May 2024

Covid-19: South African disclosures reveal secretive world of nations’ vaccine contracts

28 May 2024

Covid inquiry: What have we learnt about Northern Ireland’s response?

24 May 2024

Covid-19: Charities question inquiry’s “refusal” to fully examine mental health impact

12 April 2024

Covid inquiry: What we have learnt about Wales’s response?

11 March 2024

Covid-19 taskforce called for a new national vaccine agency to prepare for future pandemics

29 February 2024

Covid inquiry: What did we learn this week?

26 January 2024

Covid-19: Doctors instruct law firm in bid for compensation after developing long covid

Covid-19: vaccines have saved at least 1.4 million lives in europe, who reports.

17 January 2024

Covid-19: Undervaccination was associated with higher risk of hospital admission or death, study finds

16 January 2024

Covid-19: NICE plans to expand Paxlovid eligibility to 1.4 million more people

11 January 2024

Covid-19: Some US states and hospitals recommend masks again

05 January 2024

Covid-19: WHO adds JN.1 as new variant of interest

21 December 2023

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15 December 2023

Covid inquiry: Sunak defends his pandemic policies made as chancellor

13 December 2023

Covid-19: Preliminary figures show 1.2% of people in England had infection at end of November

Pfizer sues poland over unclaimed covid vaccines.

28 November 2023

Covid inquiry: The week that science became both bamboozling and a millstone

27 November 2023

Clinicians with long covid must get financial support, say unions

17 November 2023

Covid-19: Whitehall chaos and misplaced confidence undermined UK’s response, inquiry hears

Prisons and pandemic preparedness.

24 April 2023

How pandemic publishing struck a blow to the visibility of women’s expertise

06 April 2023

Closing the gap in childhood immunisation after the pandemic

21 March 2023

WHO keeps covid-19 a public health emergency of international concern

06 March 2023

Financing covid-19 mRNA vaccines

01 March 2023

08 February 2023

Labour’s proposed covid corruption commissioner: an important signal, but it won’t be easy to get the money back

25 October 2023

Hancock’s covid inquiry evidence offers few clues as to why long covid was sidelined

Helen salisbury: covid booster chaos.

05 September 2023

Outsourcing covid-19 vaccination to the private sector will increase health inequalities

04 September 2023

Why older adults can continue to benefit from covid-19 boosters

Weakened by a decade of austerity: why the uk’s covid-19 inquiry is right to look at policies since 2010.

06 June 2023

The covid public health emergency is ending: it now joins the ordinary emergency that is American health

26 April 2023

Employers must provide better support to workers with long covid

Helen salisbury: unexplained symptoms aren’t always long covid, latest covid-19 blogs from bmj journals.

A centralised hub of all the latest covid-19 blogs and podcasts posts from BMJ's 70 specialty journals. All posts are freely available and you can search by subject area or journal.

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Information

COVID-19 Research

Stanford Medicine scientists have launched dozens of research projects as part of the global response to COVID-19. Some aim to prevent, diagnose and treat the disease; others aim to understand how it spreads and how people’s immune systems respond to it.

Below is a curated selection, including summaries, of the projects.

To  participate in research ,  browse COVID-19 studies . Our  research registry  also connects people like you with teams conducting  research to make advances in health care. If you are eligible for a study, researchers may contact you to provide additional details on how to participate.

By participating in clinical research, you help accelerate medical science by providing valuable insights into potential treatments and methons of prevention.

Stanford COVID-19 Study Directory Stanford Medicine Research Registry   

To improve our ability to determine who has COVID-19 and treat those infected.

Transmission

To better prevent and understand the transmission of the coronavirus.

Vaccination and Treatment

To improve our ability to prevent COVID-19 and treat those infected.

Epidemiology

To better understand how the coronavirus is spreading.

Data Science and Modeling

To better predict medical, fiscal and resource-related outcomes of the COVID-19 pandemic.

To better understand immune responses to the coronavirus.

Cardiovascular

To better understand the way the virus affects the cardiovascular system.

To better enable the workforce to achieve its goals during the COVID-19 pandemic.

Miscellaneous

A variety of other research projects related to the COVID-19 pandemic.

The list isn’t comprehensive and instead represents a portion of Stanford Medicine research on COVID-19. If you are a Stanford Medicine scientist and would like to see your research included here, please send a note to: [email protected].

The Stanford Institute for Human-Centered Artificial Intelligence has also created a  webpage  for COVID-19 research collaborations and other opportunities, such as research positions, internships and funding. If you would like to submit an opening please use the following  form  and they will post it on their website.

Support Stanford Medicine’s response to COVID-19 by  making a gift .

COVID-19 Research Projects

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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.

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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Risk of death from COVID-19 lessens, but infection still can cause issues 3 years later

Study also shows that patients hospitalized within 30 days after infection face 29% higher death risk in 3rd year compared with those not infected

by Kristina Sauerwein • May 30, 2024

New findings on long COVID by Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care system reveal that COVID-19 patients who were hospitalized within the first 30 days after infection face a 29% higher risk of death in the third year post-infection compared with people who have not had the virus. However, the three-year death risk marks a significant decline compared with such risk at previous time points post-infection. The study also shows that even people with mild COVID-19 still experienced new health problems related to the infection three years later.

New findings on long COVID — long-term effects on health experienced by many who have had COVID-19 — present a good-news, bad-news situation, according to a study at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care system.

The bad news: COVID-19 patients who were hospitalized within the first 30 days after infection face a 29% higher risk of death in the third year compared with people who have not had the virus. However, the three-year death risk still marks a significant decline compared with such risk at the one- and two-year marks post-infection. The findings also show that even people with mild COVID-19 were still experiencing new health problems related to the infection three years later.

The good news: The increased risk of death diminishes significantly one year after a SARS-CoV-2 infection among people who were not hospitalized for the virus. This demographic accounts for most people who have had COVID-19.

The new research, published May 30 in Nature Medicine, tracked the virus’s health effects in people three years after being infected with the original strain of COVID-19 in 2020. That year, about 20 million people tested positive for the virus in the U.S. The new study assessed the risk of death and 80 adverse health conditions in people three years after being diagnosed with COVID-19.

“We aren’t sure why the virus’s effects linger for so long,” said senior author Ziyad Al-Aly, MD, a Washington University clinical epidemiologist and a global leader in long COVID research. “Possibly it has to do with viral persistence, chronic inflammation, immune dysfunction or all the above. We tend to think of infections as mostly short-term illnesses with health effects that manifest around the time of infection. Our data challenges this notion. I feel COVID-19 continues to teach us — and this is an important new lesson — that a brief, seemingly innocuous or benign encounter with the virus can still lead to health problems years later.”

Up to 10% of people infected with the virus experience long COVID, according to federal data.

Al-Aly’s prior research has documented COVID-19’s damage to nearly every human organ, contributing to diseases and conditions affecting the lungs, heart, brain, and the body’s blood, musculoskeletal and gastrointestinal (GI) systems.

Such studies with longer follow-up are limited, said Al-Aly, a nephrologist who treats patients at the Washington University-affiliated John J. Cochran Veterans Hospital in midtown St. Louis. “Addressing this knowledge gap is critical to enhance our understanding of long COVID and will help inform care for people suffering from long COVID.”

Al-Aly and his team analyzed millions of de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation’s largest integrated health-care system. The study included more than 114,000 veterans with mild COVID-19 who did not require hospitalization; more than 20,000 hospitalized COVID-19 patients; and 5.2 million veterans with no COVID-19 diagnosis. Patients were enrolled in the study from March 1, 2020, to Dec. 31, 2020, and followed for at least three years, until Dec. 31, 2023. Patients included people of diverse ages, races and sexes; statistical modeling ensured parity in representation.

In the third year after infection, COVID-19 patients who had been hospitalized experienced a 34% elevated health risk across all organ systems compared with people who did not have COVID. That number is down from a 182% increased risk one year after a COVID infection and a 57% risk two years after.

Among nonhospitalized patients, researchers found a 5% increased risk in suffering from long COVID in the third year after infection. This translates into 41 more health problems per 1,000 persons – a small but not trivial burden. The long-term health effects in the third year primarily affected the GI, pulmonary and neurological systems. By comparison, the risk was increased by 23% one year after infection and increased by 16% two years after.

In the analysis, researchers also measured and compared the number of healthy life-years lost due to COVID-19. They found that among the nonhospitalized, at three years after infection, COVID-19 had contributed to 10 lost years of healthy life per 1,000 persons. By comparison, three years post-infection, those hospitalized for COVID-19 had experienced 90 lost years of healthy life per 1,000 persons.

For context, in the U.S., heart disease and cancer each cause about 50 lost years of healthy life per 1,000 persons, while stroke contributes to 10 lost years of healthy life per 1,000 persons.

“That a mild SARS-CoV-2 infection can lead to new health problems three years down the road is a sobering finding,” said Al-Aly, who is also director of the Clinical Epidemiology Center at the VA St. Louis Health Care System, and head of the research and development service. “The problem is even worse for people with severe SARS-CoV-2 infection. It is very concerning that the burden of disease among hospitalized individuals is astronomically higher.”

“COVID-19 is a serious threat to the long-term health and well-being of people and it should not be trivialized,” he said.

The extended trajectory for long COVID may change as researchers incorporate data from years beyond 2020. At that time, vaccines and antivirals had not been developed. Similarly, Al-Aly’s analysis does not consider subsequent variants such as omicron or delta.

“Even three years out, you might have forgotten about COVID-19, but COVID hasn’t forgotten about you,” Al-Aly said. “People might think they’re out of the woods, because they had the virus and did not experience health problems. But three years after infection, the virus could still be wreaking havoc and causing disease or illness in the gut, lungs or brain.”

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Mounting research shows that COVID-19 leaves its mark on the brain, including with significant drops in IQ scores

Chief of Research and Development, VA St. Louis Health Care System. Clinical Epidemiologist, Washington University in St. Louis

Disclosure statement

Ziyad Al-Aly receives funding from the U.S. Department of Veterans Affairs.

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From the very early days of the pandemic, brain fog emerged as a significant health condition that many experience after COVID-19.

Brain fog is a colloquial term that describes a state of mental sluggishness or lack of clarity and haziness that makes it difficult to concentrate, remember things and think clearly.

Fast-forward four years and there is now abundant evidence that being infected with SARS-CoV-2 – the virus that causes COVID-19 – can affect brain health in many ways .

In addition to brain fog, COVID-19 can lead to an array of problems , including headaches, seizure disorders, strokes, sleep problems, and tingling and paralysis of the nerves, as well as several mental health disorders .

A large and growing body of evidence amassed throughout the pandemic details the many ways that COVID-19 leaves an indelible mark on the brain. But the specific pathways by which the virus does so are still being elucidated, and curative treatments are nonexistent.

Now, two new studies published in the New England Journal of Medicine shed further light on the profound toll of COVID-19 on cognitive health .

I am a physician scientist , and I have been devoted to studying long COVID since early patient reports about this condition – even before the term “long COVID” was coined. I have testified before the U.S. Senate as an expert witness on long COVID and have published extensively on this topic.

How COVID-19 leaves its mark on the brain

Here are some of the most important studies to date documenting how COVID-19 affects brain health:

Large epidemiological analyses showed that people who had COVID-19 were at an increased risk of cognitive deficits , such as memory problems.

Imaging studies done in people before and after their COVID-19 infections show shrinkage of brain volume and altered brain structure after infection .

A study of people with mild to moderate COVID-19 showed significant prolonged inflammation of the brain and changes that are commensurate with seven years of brain aging .

Severe COVID-19 that requires hospitalization or intensive care may result in cognitive deficits and other brain damage that are equivalent to 20 years of aging .

Laboratory experiments in human and mouse brain organoids designed to emulate changes in the human brain showed that SARS-CoV-2 infection triggers the fusion of brain cells . This effectively short-circuits brain electrical activity and compromises function.

Autopsy studies of people who had severe COVID-19 but died months later from other causes showed that the virus was still present in brain tissue . This provides evidence that contrary to its name, SARS-CoV-2 is not only a respiratory virus, but it can also enter the brain in some individuals. But whether the persistence of the virus in brain tissue is driving some of the brain problems seen in people who have had COVID-19 is not yet clear.

Studies show that even when the virus is mild and exclusively confined to the lungs, it can still provoke inflammation in the brain and impair brain cells’ ability to regenerate .

COVID-19 can also disrupt the blood brain barrier , the shield that protects the nervous system – which is the control and command center of our bodies – making it “leaky.” Studies using imaging to assess the brains of people hospitalized with COVID-19 showed disrupted or leaky blood brain barriers in those who experienced brain fog.

A large preliminary analysis pooling together data from 11 studies encompassing almost 1 million people with COVID-19 and more than 6 million uninfected individuals showed that COVID-19 increased the risk of development of new-onset dementia in people older than 60 years of age.

Drops in IQ

Most recently, a new study published in the New England Journal of Medicine assessed cognitive abilities such as memory, planning and spatial reasoning in nearly 113,000 people who had previously had COVID-19. The researchers found that those who had been infected had significant deficits in memory and executive task performance.

This decline was evident among those infected in the early phase of the pandemic and those infected when the delta and omicron variants were dominant. These findings show that the risk of cognitive decline did not abate as the pandemic virus evolved from the ancestral strain to omicron.

In the same study, those who had mild and resolved COVID-19 showed cognitive decline equivalent to a three-point loss of IQ. In comparison, those with unresolved persistent symptoms, such as people with persistent shortness of breath or fatigue, had a six-point loss in IQ. Those who had been admitted to the intensive care unit for COVID-19 had a nine-point loss in IQ. Reinfection with the virus contributed an additional two-point loss in IQ, as compared with no reinfection.

Generally the average IQ is about 100. An IQ above 130 indicates a highly gifted individual, while an IQ below 70 generally indicates a level of intellectual disability that may require significant societal support.

To put the finding of the New England Journal of Medicine study into perspective, I estimate that a three-point downward shift in IQ would increase the number of U.S. adults with an IQ less than 70 from 4.7 million to 7.5 million – an increase of 2.8 million adults with a level of cognitive impairment that requires significant societal support.

Another study in the same issue of the New England Journal of Medicine involved more than 100,000 Norwegians between March 2020 and April 2023. It documented worse memory function at several time points up to 36 months following a positive SARS-CoV-2 test.

Parsing the implications

Taken together, these studies show that COVID-19 poses a serious risk to brain health, even in mild cases, and the effects are now being revealed at the population level.

A recent analysis of the U.S. Current Population Survey showed that after the start of the COVID-19 pandemic, an additional 1 million working-age Americans reported having “serious difficulty” remembering, concentrating or making decisions than at any time in the preceding 15 years. Most disconcertingly, this was mostly driven by younger adults between the ages of 18 to 44.

Data from the European Union shows a similar trend – in 2022, 15% of people in the EU reported memory and concentration issues .

Looking ahead, it will be critical to identify who is most at risk. A better understanding is also needed of how these trends might affect the educational attainment of children and young adults and the economic productivity of working-age adults. And the extent to which these shifts will influence the epidemiology of dementia and Alzheimer’s disease is also not clear.

The growing body of research now confirms that COVID-19 should be considered a virus with a significant impact on the brain. The implications are far-reaching, from individuals experiencing cognitive struggles to the potential impact on populations and the economy.

Lifting the fog on the true causes behind these cognitive impairments, including brain fog, will require years if not decades of concerted efforts by researchers across the globe. And unfortunately, nearly everyone is a test case in this unprecedented global undertaking.

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Fauci testifies about Covid-19

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Fauci testifies on the origins of Covid-19

By Antoinette Radford, Maureen Chowdhury, Elise Hammond, Carma Hassan and Jen Christensen

Fauci says he supports suspending funding to EcoHealth Alliance

CNN's Jen Christensen

Dr. Anthony Fauci said on Monday he supports suspending US grant funding to EcoHealth Alliance , a New York-based virus research organization that has been tied to question and controversy around the origins of the virus that causes Covid-19.

The US Department of Health and Human Services in May suspended funding to EcoHealth Alliance and proposed the group be blocked from receiving federal funds in the future, possibly for years.

Asked on Monday if he supposed the suspension and debarment of EcoHealth Alliance, Fauci responded “yes.” 

Before the pandemic, the US gave a $120,000 grant to EcoHealth Alliance with a subaward that funded work at the Wuhan Institute of Virology. In April 2020, the National Institutes of Health terminated the grant.

Fauci said that he later learned that the White House had called to tell the NIH to cancel the grant. Asked Monday if he agreed or disagreed with the decision at the time, he said that wasn’t his problem with the request.

“It wasn’t a question of agreeing or disagreeing. It was like, ‘Can we really do that? I don’t think that you can do that.’ And as it turned out I was right, because the general counsel of HHS said, 'By the way, you can’t do that. You’ve got to restore the grant,' ” Fauci testified.

The grant was reinstated, then suspended pending a compliance review.

Fauci said once he learned that there were compliance issues with the grant, the National Institute of Allergy and Infectious Diseases was told to stay out of it.

Since that time, NIH found numerous violations of grant policies by EcoHealth and has since blocked funding to the Wuhan Institute of Virology and suspended and proposed blocking NIH funding to EcoHealth as an institution and Dr. Peter Daszak individually.

In a May letter to EcoHealth Alliance and its president, Dr. Peter Daszak, HHS lists 30 pieces of evidence some dating back to 2013 to support its decision. HHS said in a memo that EcoHealth failed to “adequately monitor” virus growth experiments at the Wuhan Institute of Virology, notify the NIH that viruses studied there “appeared to grow beyond permissible thresholds” laid out in a grant or provide requested information in a timely manner.

In a statement last month, a spokeperson for EcoHealth Alliance said the organization was “disappointed by HHS’ decision" and that it would contest the decision.

GOP subcommittee chair and ranking member wrap up hearing with closing statements

From CNN's Maureen Chowdhury

In his closing statement, Ranking Member Raul Ruiz thanked Dr. Anthony Fauci for his testimony and for his decades of service to the nation in dealing with various epidemics and pandemics.

He also blasted Republicans for pushing extreme narratives for political gain.

"Over the past four years you have been personally targeted by extreme narratives of the origins of the Covid-19 pandemic and the US governments response to it," Ruiz said. "These extreme narratives have been the bedrock of this subcommittees Republican-led probe and have been undermined by what's been found through interviews and by thousands of documents that have been reviewed."

Ruiz added that the evidence found that "Dr. Fauci did not fund research through the EcoHealth Alliance Grant that caused the Covid-19 pandemic, Dr. Fauci did not lie about gain of function research in Wuhan China, Dr. Fauci did not orchestrate a campaign to suppress the lab-leak theory."

Subcommittee Chair Brad Wenstrup also thanked Fauci for coming voluntarily to testify.

He went on to say that the hearing was an opportunity to learn more about the government's Covid-19 response and how the government can improve and do better. He said that while there some things that were done well, there were some wrongdoings in the office where Fauci served.

Wenstrup highlighted that moving forward, clarity is important in order to improve messaging.

"I think what I'm most concerned about as we go forward as a country and from our agencies is that we an be trusted and that we are better in our messaging and talk about clarity," Wenstrup said.

Officials will evaluate "cost-benefit ratio" of vaccine mandates in analysis of pandemic response, Fauci says

From CNN's Elise Hammond

When evaluating the United States’ handling of the Covid-19 pandemic, public health officials will take a closer look at “the cost-benefit ratio” of things like vaccine mandates, Dr. Anthony Fauci said.

Fauci was answering a question about whether issuing mandates could have led to vaccine hesitancy.

“That’s something that I think we need to go back now, when we do an after-the-event evaluation about whether or not given the psyche of the country and the pushback that you get from those types of things — we need to reevaluate the cost-benefit ratio of those types of things,” Fauci said.

Earlier in the hearing, Fauci defended the government’s use of vaccines as saving “hundreds of thousands of lives in the United States and millions of lives throughout the world.

US still needs to close communication gaps to be better prepared for next pandemic, Fauci says

Dr. Anthony Fauci said there are still some things the United States needs to work on to be more prepared for another pandemic in the aftermath of Covid-19.

The former director of the National Institute of Allergy and Infectious Diseases (NIAID) said in “some respects” the country is better prepared to deal with a health crisis than in 2020, “but in others, I am still disappointed.”

Fauci was answering a question from Florida Democratic Rep. Jared Moskowitz, who served as the Director of the Florida Division of Emergency Management during the pandemic. The lawmaker said he felt that states were not ready to deal with Covid-19.

“I think one of the things that was really a problem with the response was the degree of divisiveness that we had in the country about a lack of a coherent response where we were having people, for reasons that had nothing to do with public health or science, refusing to adhere to public health intervention measures,” Fauci said.

One thing that he hopes the US will do better moving forward is tightening communication between the federal response and local public health officials.

He said there was a “disconnect between the healthcare system and the public health system” during Covid-19 in the US. Specifically, the Centers for Disease Control (CDC) could not demand information from local agencies, which caused a lag in sharing data.

“We were at a disadvantage,” Fauci said, adding that the CDC is working on ways to fix this pain point.

California lawmaker whose parents died of Covid-19 thanks Fauci for life-saving policies

California Democratic Rep. Robert Garcia, who said both of his parents died from Covid-19, thanked Dr. Anthony Fauci for putting in policies that saved lives during the pandemic.

Garcia said his mother was a health care worker and she and his step-father both died from Covid-19.

“I lost both of my parents during the pandemic, so I take this very personally," he said, condemning other lawmakers “who are tasked to be responsible and actually help the American people” attack medical professionals, Garcia said.

The comments came after heated remarks from Republican Rep. Marjorie Taylor Greene who criticized mask mandates and called for Fauci to be put in prison.

“Your quote-unquote so-called science that the gentlewoman is referring to has saved millions of lives in this country and around the world,” Garcia said. “It’s important to note that my opinion is that you are an American hero and your team has done more to save lives than all 435 members of this body on both sides of the aisle.”

GOP chairman has to remind Marjorie Taylor Greene to be respectful as she refuses to call Fauci a doctor

CNN's Haley Talbot

GOP Chairman Brad Wenstrup had to remind Georgia Republican Rep. Marjorie Taylor Greene to be respectful after she insisted that she would not refer to Dr. Anthony Fauci by the title of doctor and would only refer to him as "Mr. Fauci."

"You're not doctor, you're Mr. Fauci in my few minutes," Greene said.

In response, Wenstrup ordered Greene to address Fauci as a doctor. “I have instructed her to address him as doctor,” Wenstrup said. 

“I’m not addressing him as doctor,” she shot back.  

Several Democratic lawmakers jumped in to criticize Greene over her refusal to address Fauci as a doctor.

Wenstrup then asked members to “afford all other members the respect they are entitled” and to “refrain from using rhetoric that could be construed as an attack on the motives or character of another member or the witness.”

Fauci: NIH official using unofficial email is an "aberrancy and an outlier"

Dr. Anthony Fauci testified Monday that he has not used his personal email to conduct business, and he was not aware before a congressional investigation that a former senior adviser at the National Institutes of Health had used unofficial email.

“What you saw, I believe, with Dr. Morens was aberrancy and an outlier,” Fauci testified on Monday, referring to a former senior adviser at NIH. “The individuals at the NIH and NIAID are a very committed group of individuals and this one instance that you point out is an aberrancy and an outlier.”

The House Oversight Select Subcommittee on the Coronavirus Pandemic previously released a series of  private emails  that Republican members of the committee argue show that some NIH officials deleted emails and tried to get around requirements to disclose information through public records laws.

In a memo  published at the end of May , committee members said Dr. David Morens, a former senior adviser to Fauci, engaged in “nefarious behavior.” The committee points to email that Morens sent another colleague that suggests he would send email to Fauci’s private account and “there is no worry about FOIAs.” FOIA is the Freedom of Information Act, the law that gives the public the right to obtain federal records, including emails sent within government agencies. Morens’ email goes on to say that he can also hand information to Fauci to avoid it being a part of the public record.

“He is too smart to let colleagues send him stuff that could cause trouble,” Morens said in a 2021 email to Peter Daszak, the president of EcoHealth Alliance, a nonprofit virus research organization linked to controversy about the origins of the virus that causes Covid-19. The US Department of Health and Human Services suspended funding to the group in May.

Fauci details threats he and his family have received

From CNN's Antoinette Radford

Anthony Fauci detailed the threats he received during his time as the director of the National Institute of Allergy and Infectious Diseases, describing death threats against him and threats against his wife and daughters.

Democratic Rep. Debbie Dingell asked Fauci to explain what some of the threats were, where he replied:

“Everything from harassments from emails, texts, letters of myself, my wife, my three daughters. There have been credible death threats leading to the arrest of two individuals – and credible death threats means someone who clearly was on their way to kill me. And it’s required my having protective services essentially all the time," Fauci said.

Fauci said he feared that the threats against public health workers during the Covid-19 pandemic would serve as a “powerful disincentive” for the best and brightest candidates to take up the profession.

“They say to themselves, 'I don’t want to go there. Why should I get involved in that?'” he said.

“They’re reluctant to put themselves and their family through what they see their colleagues being put through,” he testified.

The 6-foot social distance guideline came from the CDC, Fauci clarifies

Dr. Anthony Fauci clarified that the 6-foot guidance for social distancing given during the beginnings for the Covid-19 pandemic did not come from him, but from the Centers for Disease Control (CDC).

"It actually came from the CDC. The CDC was responsible for those kinds of guidelines to schools, not me," Fauci said.

Fauci, who repeated the guidance during the pandemic, once said that there was no science behind it — but he meant that there were no clinical trials to back it up.

"It had little to do with me since I didn't make the recommendation and my saying 'there was no science behind it' meant there was no clinical trial behind that," Fauci said.

He added that he believed the CDC used studies about droplets years ago as reasoning for the 6-foot guidelines.

More background: When the CDC first promoted the idea of 6-foot “ social distancing ” for people who had to be around others during the pandemic, scientists thought that larger contaminated droplets would fall out of the air quickly and couldn’t travel farther than 6 feet. At the time, the World Health Organization recommended that people keep a meter, or 3.3 feet, between them. But even as early as  2021,  scientists were starting to understand that the coronavirus is airborne.

CNN's Jen Christensen contributed to this report.

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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] .

Follow the New York Times Opinion section on Facebook , Instagram , TikTok , WhatsApp , X and Threads .

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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Misleading COVID-19 headlines from mainstream sources did more harm on Facebook than fake news, study finds

S ince the rollout of the COVID-19 vaccine in 2021, fake news on social media has been widely blamed for low vaccine uptake in the United States—but research by MIT Sloan School of Management Ph.D. candidate Jennifer Allen and Professor David Rand finds that the blame lies elsewhere.

In a new paper published in Science and co-authored by Duncan J. Watts of the University of Pennsylvania, the researchers introduce a new methodology for measuring social media content's causal impact at scale. They show that misleading content from mainstream news sources—rather than outright misinformation or "fake news"—was the primary driver of vaccine hesitancy on Facebook.

A new approach to estimating impact

"Misinformation has been correlated with many societal challenges, but there's not a lot of research showing that exposure to misinformation actually causes harm," explained Allen.

During the COVID-19 pandemic, for example, the spread of misinformation related to the virus and vaccine received significant public attention. However, existing research has, for the most part, only established correlations between vaccine refusal and factors such as sharing misinformation online—and largely overlooked the role of "vaccine-skeptical" content, which was potentially misleading but not flagged as misinformation by Facebook fact-checkers.

To address that gap, the researchers first asked a key question: What would be necessary for misinformation or any other type of content to have far-reaching impacts?

"To change behavior at scale, content has to not only be persuasive enough to convince people not to get the vaccine, but also widely seen," Allen said. "Potential harm results from the combination of persuasion and exposure."

To quantify content's persuasive ability, the researchers conducted randomized experiments in which they showed thousands of survey participants the headlines from 130 vaccine-related stories—including both mainstream content and known misinformation—and tested how those headlines impacted their intentions to get vaccinated against COVID-19.

Researchers also asked a separate group of respondents to rate the headlines across various attributes, including plausibility and political leaning. One factor reliably predicted impacts on vaccination intentions: the extent to which a headline suggested that the vaccine was harmful to a person's health.

Using the "wisdom of crowds" and natural language processing AI tools, Allen and her co-authors extrapolated those survey results to predict the persuasive power of all 13,206 vaccine-related URLs that were widely viewed on Facebook in the first three months of the vaccine rollout.

By combining these predictions with data from Facebook showing the number of users who viewed each URL, the researchers could predict each headline's overall impact—the number of people it might have persuaded not to get the vaccine. The results were surprising.

The underestimated power of exposure

Contrary to popular perceptions, the researchers estimated that vaccine-skeptical content reduced vaccination intentions 46 times more than misinformation flagged by fact-checkers.

The reason? Even though flagged misinformation was more harmful when seen, it had relatively low reach. In total, the vaccine-related headlines in the Facebook data set received 2.7 billion views—but content flagged as misinformation received just 0.3% of those views, and content from domains rated as low-credibility received 5.1%.

"Even though the outright false content reduced vaccination intentions the most when viewed, comparatively few people saw it," explained Rand. "Essentially, that means there's this class of gray-area content that is less harmful per exposure but is seen far more often —and thus more impactful overall—that has been largely overlooked by both academics and social media companies."

Notably, several of the most impactful URLs within the data set were articles from mainstream sources that cast doubt on the vaccine's safety. For instance, the most-viewed was an article—from a well-regarded mainstream news source—suggesting that a medical doctor died two weeks after receiving the COVID-19 vaccine. This single headline received 54.9 million views—more than six times the combined views of all flagged misinformation.

While the body of this article did acknowledge the uncertainty of the doctor's cause of death, its "clickbait" headline was highly suggestive and implied that the vaccine was likely responsible. That's significant since the vast majority of viewers on social media likely never click out to read past the headline.

How journalists and social media platforms can help

According to Rand, one implication of this work is that media outlets need to take more care with their headlines, even if that means they aren't as attention-grabbing.

"When you are writing a headline, you should not just be asking yourself if it's false or not," he said. "You should be asking yourself if the headline is likely to cause inaccurate perceptions."

For platforms, added Allen, the research also points to the need for more nuanced moderation—across all subjects, not just public health.

"Content moderation focuses on identifying the most egregiously false information—but that may not be an effective way of identifying the most overall harmful content," she says. "Platforms should also prioritize reviewing content from the people or organizations with the largest numbers of followers while balancing freedom of expression. We need to invest in more research and creative solutions in this space—for example, crowdsourced moderation tools like X's Community Notes."

"Content moderation decisions can be really difficult because of the inherent tension between wanting to mitigate harm and allowing people to express themselves," Rand said. "Our paper introduces a framework to help balance that trade-off by allowing tech companies to actually quantify potential harm."

And the trade-offs could be large. An exploratory analysis by the authors found that if Facebook users hadn't been exposed to this vaccine-skeptical content, as many as 3 million more Americans could have been vaccinated.

"We can't just ignore this gray area-content," Allen concluded. "Lives could have been saved."

More information: Jennifer Allen, Quantifying the impact of misinformation and vaccine-skeptical content on Facebook, Science (2024). DOI: 10.1126/science.adk3451 . www.science.org/doi/10.1126/science.adk3451

Provided by MIT Sloan School of Management

Anthony Fauci faces questions during contentious COVID-19 hearing in the House

In partisan hearing, fauci defends himself against republican accusations, as democrats shower him with praise..

During a contentious hearing Monday on Capitol Hill, Dr. Anthony Fauci defended himself against vague accusations of helping fund Chinese government efforts to create the COVID-19 virus, hiding medical data about the pandemic and making up U.S. guidelines that kept people 6 feet apart during the height of the pandemic.

Fauci, who said none of that was true, has become a focus of anger and frustration for his stands on vaccination, science and social distancing – the same qualities that make him highly admired by others.

He remained calm during the more than three-hour hearing, outlining the threats that he, his wife and his three daughters have received over the course of the pandemic, including death threats.

"There have been credible death threats leading to the arrests of two individuals and credible death threats means someone who clearly was on their way to kill me," Fauci said.

He appeared voluntarily at Monday's hearing of the House Committee on Oversight and Accountability, as he has a number of other times he has been called before Congress to discuss COVID-19.

Fauci said widespread threats against public health workers during and after the pandemic have robbed America of some “very good talent,” young people who might have gone into public health but now chose not to. “They’re reluctant to put themselves and their families through what they see us going through,” he said.

Several Republican representatives questioned Fauci about the $120,000 grant his agency provided through another organization to China’s Wuhan Institute of Virology. If the virus that causes COVID-19 originated in a lab, that lab was most likely at the Wuhan Institute, which had an annual budget of $6 billion. "If they were going to do something on the side, then they would have had plenty of money to do it," Fauci said.

But it is not biologically possible for the money his agency provided to have led to the creation of the SARS-CoV-2 virus, Fauci testified. Even if the virus came out of the Wuhan lab, it had to have come from a different virus than the one the U.S. money supported, he said.

“The viruses were phylogenetically so far removed from SARS‑CoV‑2 virus that it’s molecularly impossible for those viruses to have evolved into SARS-CoV-2 virus,” he said. “It’s just a biological fact.”

He also vigorously denied that he had somehow “bribed” scientists to change their stance on the origins of the virus by offering millions of dollars in grant money, calling the accusation “simply preposterous.”

The Republicans on the committee have spent 15 months looking for information suggesting Fauci behaved improperly during the COVID-19 pandemic, which Democrats on the committee said they had failed to find.

“We haven’t seen a damned thing to suggest that these accusations are accurate,” said Rep. Kweisi Mfume, R-Md.

Another topic was the Committee's release on Friday of information about two of Fauci's former employees,  Dr. David Morens and Greg Folkers, whose emails during the pandemic appear to show they were trying to avoid federal transparency laws and also circumvent Freedom of Information Act requests, in part by using personal email.

Fauci said multiple times that he "knew nothing" of these attempts and that he had never knowingly used his personal email for his official position. "I knew nothing of Dr. Morens' actions," he said.

A number of Republicans mentioned COVID-19 guidelines meant to slow the spread of the virus and the ways in which they disrupted life ‒ and were rejected by and infuriated many Americans. Fauci said the guidelines represented the best-known information at a time when faced with a virus no one had ever seen before.

But the American public didn’t get to see the scientific data to support the guidelines, said Dr. Richard McCormick, R-Ga.

“Americans were aggressively bullied, shamed and silenced for debating issues such as social distancing, masks, vaccines or the origins of COVID,” he said. “Americans do not hate science, but Americans know hypocrisy when they see it.”

On the topic of whether the 6-foot social distancing guidelines were scientifically valid, several committee members questioned Fauci on his statement during a closed-door hearing in January in which he said, “It sort of just appeared that 6 feet was going to be the distance” and that it was not based in science.

Fauci clarified first that the 6-foot requirement came from the Centers for Disease Control and Prevention, not the National Institute of Allergy and Infectious Diseases. He also said that his testimony spoke to the measure of feet, not to the scientific veracity of the guidelines, given what was known about COVD-19 at the time.

There were no specific clinical trials that tested whether 3 feet, 6 feet or more were the best, he said. But given the CDC's knowledge at the time, that droplets were a main route of transmission for the COVID-19 virus, the guidelines fit well with known research on the safest distances.

The hearing took a loud turn about two hours in when Rep. Marjorie Taylor Greene, R-Ga., began a line of questioning in which she pointedly used the honorific Mister rather than Doctor for Fauci, who served as director of the National Institute of Allergy and Infectious Diseases from 1984 to 2022 and was chief medical adviser to the president from 2021 to 2022. 

When other Representatives objected, Green said, “That man does not deserve to have a license and in fact he deserves to be in prison.”

(Though vilified by AIDS activists early in that epidemic, Fauci was later credited with promoting research into drugs that have saved millions of lives worldwide and transformed the disease from a death sentence to a chronic illness. He also helped oversee the U.S. response to other health crises, including Ebola, Zika, and swine flu.)

A few minutes later Greene attempted to speak further and the head of the committee, Rep. James Comer, R-Ky., instructed Capitol Police to escort her out of the chamber.

Later, Rep. Robert Garcia, D-Calif., said "This might be the most insane hearing I've actually attended.”

COVID Select Subcommittee Releases Dr. Fauci’s Transcript, Highlights Key Takeaways in New Memo

WASHINGTON — Today, Select Subcommittee on the Coronavirus Pandemic Chairman Brad Wenstrup (R-Ohio) released the transcript from Dr. Anthony Fauci’s transcribed interview. Dr. Fauci served as the Director of the National Institute of Allergy and Infectious Diseases (NIAID) and was the face of America’s public health response during the COVID-19 pandemic. His closed door, 14-hour, two-day testimony in January 2024 has served as a critical component of the Select Subcommittee’s investigations into the origins of COVID-19, pandemic-era domestic policy failures, and improvements to the United States’ public health system. In conjunction with the transcript, the Select Subcommittee also released a new staff memo that highlights the key takeaways from Dr. Fauci’s transcribed interview. The memo can be found here .

The Select Subcommittee also released four additional transcripts from senior public health officials. These transcripts, as well as Dr. Fauci’s transcript, can be found below:

• Dr. Anthony Fauci Part 1
• Dr. Anthony Fauci Part 2
• Dr. Hugh Auchincloss
• Dr. Cliff Lane
• Greg Folkers
• Gray Handley

Below are important exchanges from Dr. Fauci’s transcribed interview:

SOCIAL DISTANCING : The “6 feet apart” social distancing recommendation forced on Americans by federal health officials was arbitrary and not based on science. Dr. Fauci testified that this guidance — which shut down schools and small businesses nationwide — “sort of just appeared” and was not based on any scientific studies.

Majority Counsel: “ Do you recall when discussions regarding, kind of, the at least a 6 foot threshold began? ”

Dr. Fauci: “The 6 foot in the school?”

Majority Counsel: “Six foot overall.  I mean, 6-foot was applied at businesse s—”

Dr. Fauci: “Yeah.”

Majority Counsel: “ —it was applied in schools, it was applied here.  At least how the messaging was applied was that 6-foot distancing was the distance that needed to be— “

Dr. Fauci: “ You know, I don’t recall.  It sort of just appeared.  I don’t recall, like, a discussion of whether it should be 5 or 6 or whatever.  It was just that 6 foot is— ”   

Majority Counsel: “ Did you see any studies that supported 6 feet? ”

Dr. Fauci: “ I was not aware of studies that in fact, that would be a very difficult study to do. ”

MASKING : Dr. Fauci testified that he did not recall any supporting evidence for masking children. Concerningly, mask-wearing has been associated with learning loss and severe speech development issues in America’s children.

Majority Counsel: “ Do you recall reviewing any studies or data supporting masking for children? ”

Dr. Fauci: “ You know, I might have, Mitch, but I don’t recall specifically that I did. I might have. ”

Majority Counsel: “ Since the — there’s been a lot of studies that have come out since the pandemic started, but specifically on this there have been significant on kind of like the learning loss and speech and development issues that have been associated with particularly young children wearing masks while they’re growing up. They can’t see their teacher talk and can’t learn how to form words. Have you followed any of those studies? ”

Dr. Fauci: “ No. But I believe that there are a lot of conflicting studies too, that there are those that say, yes, there is an impact, and there are those that say there’s not. I still think that’s up in the air. ”

TRAVEL RESTRICTIONS : Dr. Fauci unequivocally agreed with EVERY travel restriction issued by the Trump Administration at the height of the COVID-19 pandemic. This testimony runs counter to the public narrative that the Trump Administration’s travel restrictions were xenophobic. During his transcribed interview, the Biden Administration’s counsel curiously prohibited Dr. Fauci from answering questions on whether he recommended the travel restrictions.

Majority Counsel: “ Did you agree with President Trump’s decision to restrict travel from China? ”                             

Dr. Fauci: “ I did , and I said there were caveats to restrictions. I agreed with it, but I said we have to be careful because sometimes when you do restrictions they have negative consequences in that you don’t have open access to help or even information. But fundamentally, I agreed at that time, since we had almost no infections that we knew of in our country, that at least a temporary restriction would be important. ”

Majority Counsel: “ Did you also agree with the EU travel restriction? ”

Dr. Fauci: “ I agreed with the suggestion that that be done, yes. ”

Majority Counsel: “ Did you agree with the U.K. travel restriction? ”

Dr. Fauci: “ Yes, I did. ”

Majority Counsel: “ Did you recommend instituting travel restrictions in response to the pandemic? ”

Biden Administration Official: “ I’m going to step in here .”

VACCINE MANDATES: Dr. Fauci admitted that vaccine mandates during the COVID-19 pandemic could increase vaccine hesitancy in the future. He also claimed that these mandates were not sufficiently studied ahead of the pandemic. Previously, Dr. Fauci advocated “that when you make it difficult for people in their lives, they lose their ideological bullshit, and they get vaccinated.”

Majority Counsel: “ Do you think mandating vaccines can result in some hesitancy? ” 

Dr. Fauci: “ I think one of the things that we really need to do after the fact, now, to — you know, after-the-game, after-the-event  evaluation of things that need to be done, we really need to take a look at the psyche of  the country, have maybe some social-type studies to figure out, does the mandating of vaccines in the way the country’s mental framework is right now, does that actually cause more people to not want to get vaccinated, or not? I don’t know. But I think that’s something we need to know. ”

LAB LEAK THEORY : Dr. Fauci acknowledged that the lab leak hypothesis is not a conspiracy theory. This comes nearly four years after prompting the publication of the now infamous “Proximal Origin” paper that attempted to vilify and disprove the lab leak hypothesis.

Majority Counsel: “ Just you sitting here today, do you think the possibility or the hypothesis that the coronavirus emerged from a laboratory accident is a conspiracy theory? ”

Dr. Fauci: “ Well, it’s a possibility. I think people have made conspiracy aspects from it.  And I think you have to separate the two when you keep an open mind, that it could be a lab leak or it could be a natural occurrence. I’ve mentioned in this committee that I believe the evidence that I’ve seen weighs my opinion towards one, which is a natural occurrence, but I still leave an open mind. So I think that in and of itself isn’t inherently a conspiracy theory, but some people spin off things from that that are kind of crazy .”

GAIN-OF-FUNCTION RESEARCH : Dr. Fauci repeatedly played semantics with the definition of “gain-of-function” research in an effort to avoid conceding that the NIH’s funded this dangerous research in China . As the head of NIAID and the face of America’s response to the pandemic, Dr. Fauci certainly understood the common definition of “gain-of-function.” Yet, he repeatedly refused — both behind closed doors and to Sen. Rand Paul during a 2021 hearing — to clarify a general understanding of the term and instead only referred to his own “operative definition.

Dr. Fauci: “ So, when I, to repeat, when I’m asked is something gain of function, I’m referring to the operative definition of gain of function according to the framework of the 3PCO…That’s my definition. That is the regulatory operational definition. And as we were talking about before, other people use the word “gain of function” this, “gain of function” that, and everybody’s got their own interpretation of it.  But when you’re deciding whether a grant should be funded, this is the operational definition. And when I was asked anywhere by the Congress, by the Senate, by Senator Paul this is what I was referring to .” 

CONFLICTS OF INTEREST : Dr. Fauci claimed that his staff had no conflicts of interest regarding the origins of COVID-19, yet his Senior Advisor — Dr. David Morens — was “best-friends” with disgraced and soon-to-be debarred EcoHealth Alliance President Dr. Peter Daszak . Considering Dr. Morens worked under Dr. Fauci’s leadership for more than 20 years, it seems highly unlikely that Dr. Fauci was genuinely unaware of this relationship.

Majority Counsel: “ I was wondering if you had thoughts on whether Dr. Daszak should have filed competing interest statements when he was weighing in on these issues, whether through the National Academies or other venues. ”

Dr. Fauci: “ You know, I hesitate to speculate about what someone else should do. The only people that I am involved with is my own staff, who we’ve mentioned many times in this discussion, who don’t have a conflict of interest. ”

GRANT APPROVAL : Dr. Fauci testified that he signed off on every foreign and domestic NIAID grant without reviewing the proposals. He was also unable to confirm if NIAID has ANY mechanisms to conduct oversight of the foreign laboratories they fund . NIAID’s flawed grant process — which relies heavily on trusting its grantees without verifying — leaves opportunities  for adversaries to exploit.

Majority Counsel: “ Who gives the final approval? ”

Dr. Fauci: “ You know, technically, I sign off on each council, but I don’t see the grants and what they are.  I never look at what grants are there.  It’s just somebody at the end of the council where they’re all finished and they go, ‘Here,’ and you sign it .”  

Majority Counsel: “ Okay. So to your knowledge, NIAID wouldn’t kind of independently verify the biosafety of a foreign lab? ”

Dr. Fauci: “ Again, I’d have to say I’m not sure.  To my knowledge, I wouldn’t be able to make a statement that I would be confident it would be. ”

Majority Counsel: “ Do you know if NIAID grants go through any type of national security review as part of the process? ”

Dr. Fauci: “ National security review? ”

Majority Counsel: “ So, like, through the National Security Council or— “

Dr. Fauci: “ No. ”

Majority Counsel: “ —or anyone in the [intelligence community]— “

Dr. Fauci: “ Not to my knowledge .”

Majority Counsel: “ I guess what we’re trying to learn going forward is, obviously, U.S. labs are vetted, certified, and there’s a standard of how U.S. labs operate. Are foreign labs held to the same standard as U.S. labs when they receive U.S. money, or are they the standards of the country in which they operate? ” 

Dr. Fauci: “ I am not certain. I have heard again, I think it was subsequent to of course, that was never brought up. ”

Majority Counsel: “ Uh huh. ”

Dr. Fauci: “ When I was the director, no one ever asked me, you know, who determines, you know, what the standards of a foreign lab are. But so the answer to your question is I don’t know, okay? ”

FEIGNED IGNORANCE : Dr. Fauci claimed he “did not recall” numerous issues and events surrounding the pandemic more than 100 times . Specifically, Dr. Fauci testified that despite the fact EcoHealth Alliance was conducting risky gain-of-function research in China, he did not know any details about the grant, nor did he maintain a relationship with its President, Dr. Peter Daszak.

Majority Counsel: “ Do you recall when you first found out that the year 5 progress report was missing from the EcoHealth grant? ”

Dr. Fauci: “ I don’t recall precisely.  It was somewhere on a briefing that the staff gave to me.  I don’t know exactly when that was.  It could have been later.  I don’t know. ”

Majority Counsel: “ Okay.  Do you think, just to the best of your recollection, whether it was before you were aware that the year 5 progress report was late before May 2021 or it would have been after? ”

Dr. Fauci: “ I don’t recall. ”