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

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

PRISMA flow diagram

Characteristics of included reviews

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

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

Population and study designs

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

Systematic review findings

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

A meta-analysis of the prevalence of mortality

Clinical symptoms

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

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgments

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

This research received no external funding.

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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

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

Thilo Caspar von Groote

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

Hebatullah Mohamed Abdulazeem

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

Ishanka Weerasekara

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

Cochrane Croatia, University of Split, School of Medicine, Split, Croatia

Ana Marusic, Irena Zakarija-Grkovic & Tina Poklepovic Pericic

Center for Evidence-Based Medicine and Health Care, Catholic University of Croatia, Ilica 242, 10000, Zagreb, Croatia

Livia Puljak

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

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

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

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

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

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

Additional file 5: Appendix 5.

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

Additional file 6: Appendix 6.

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

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

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

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January 12, 2021

Experimental coronavirus vaccine highly effective

At a glance.

• Clinical trial results showed that the investigational vaccine known as mRNA-1273 is 94.1% effective in preventing symptomatic COVID-19.
• The findings suggest that the vaccine, which has now been FDA-approved for emergency use, is safe and effective.

Researchers have been working to develop a safe and effective vaccine against SARS-CoV-2, the coronavirus that causes COVID-19. One vaccine candidate, called mRNA-1273, is being developed by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the biotech company Moderna, Inc. Early results showed it can trigger an immune response against the virus without serious side effects.

To further investigate the safety and efficacy of this vaccine, a research team led by Dr. Lindsey R. Baden of Brigham and Women’s Hospital in Boston, Dr. Hana M. El-Sahly of Baylor College of Medicine, and Dr. Brandon Essink of Meridian Clinical Research carried out a clinical trial with more than 30,000 adult volunteers nationwide. Participants were 18 years of age or older with no known previous SARS-CoV-2 infection. Results were published on December 30, 2020 in the New England Journal of Medicine.

Volunteers were randomly assigned to receive either two doses of the investigational vaccine (100 micrograms each) or two shots of a saline placebo. They received the first injection between July 27 and October 23, 2020. The second shot was given 28 days after.

The investigators recorded 196 cases of symptomatic COVID-19 among participants at least 14 days after they received their second shot. Only 11 of these cases were in the group that received the vaccine, with none severe. In contrast, 185 of the cases occurred in the placebo group, 30 of which were severe. The incidence of symptomatic COVID-19 was thus 94.1% lower in participants who received mRNA-1273 compared to those receiving placebo. For participants 65 years or older, the efficacy was 86.4%.

There were no concerning safety issues with vaccination. Local reactions to the vaccine were generally mild. About half the participants receiving mRNA-1273 experienced moderate to severe side effects—such as fatigue, muscle aches, joint pain and headache—after the second dose. In most volunteers, these resolved within two days.

One potential concern about COVID-19 vaccines is an unusual phenomenon called vaccine-associated enhanced respiratory disease, or VAERD. VAERD can occur when a vaccine induces an immune response that causes the disease the vaccine is supposed to protect against to be more severe if you’re exposed to the virus. However, the team found no evidence of VAERD among those who received mRNA-1273.

“There is much we still do not know about SARS-CoV-2 and COVID-19. However, we do know that this vaccine is safe and can prevent symptomatic COVID-19 and severe disease,” says NIAID Director Dr. Anthony S. Fauci. “It is my hope that all Americans will protect themselves by getting vaccinated when the vaccine becomes available to them. That is how our country will begin to heal and move forward.”

The FDA issued an Emergency Use Authorization for Moderna to make the vaccine available for the prevention of COVID-19 in adults on December 18, 2020.

Although mRNA-1273 can prevent symptomatic COVID-19, more study is needed to determine whether it protects against SARS-CoV-2 transmission. Additional analyses are also underway to understand the vaccine’s impact on asymptomatic infections.

Related Links

• Experimental Coronavirus Vaccine is Safe and Produces Immune Response
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References:  Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine . Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Kehtan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. N Engl J Med . 2020 Dec 30. doi: 10.1056/NEJMoa2035389. Online ahead of print. PMID: 33378609.

Funding:  NIH’S National Institute of Allergy and Infectious Diseases (NIAID); Office of the Assistant Secretary for Preparedness and Response.

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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.

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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.

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

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

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To better understand how the coronavirus is spreading.

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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.

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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.

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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.

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NIH's Strategic Response

In late 2019, NIH worked quickly to create and act on a plan to address the COVID-19 pandemic. We prioritized research to study SARS-CoV-2, the virus that causes COVID-19, and developed tests, treatments, and vaccines to detect, treat, and prevent the disease, including support for communities that were hardest hit by the pandemic.

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Covid-19 research priorities.

NIH’s response plan includes five strategic priorities to guide COVID-19 programs and research. Each priority fueled the creation of one or more initiatives, which harness NIH’s infrastructure to speed up research and foster collaboration with academic and private institutions.

We lead and support research to better understand SARS-CoV-2 and the short- and long-term health effects of COVID-19.

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Researchers Identify Four Long COVID Categories

A study classifying Long COVID into four types can help health care providers better target treatments for a patient’s specific symptoms.

MORE INFORMATION: Long COVID and common symptoms

We support the development of new COVID-19 testing technology and develop strategies to quickly deliver tests to communities around the country.

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The RADx initiative speeds innovation in the development, commercialization, and implementation of COVID-19 testing technology.

NIH Launches Telehealth COVID-19 Testing and Treatment Program

The Home Test to Treat initiative partners with health departments in high-risk communities to provide free COVID-19 testing and access to antiviral treatments.

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Our research identifies and tests new and existing treatments for COVID-19 and Long COVID.

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The ACTIV public-private partnership evaluates the most promising potential treatments for COVID-19.

Antiviral Treatment Reduces Likelihood of Severe Illness From Omicron

Researchers have found that Paxlovid is effective at preventing severe COVID-19 resulting from infection by the Omicron variant of SARS-CoV-2.

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We played an important role in the early testing and development of several vaccines, including the Moderna mRNA vaccine, and we continue to support research to prevent the spread of infection.

ACTIV has accelerated the clinical testing and evaluation of the most promising COVID-19 vaccines for approval.

mRNA Vaccine Technology: A Promising Idea for Fighting HIV

Scientists are studying the potential of mRNA vaccines to fight other diseases, including other coronaviruses, malaria, influenza, and cancer.

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How COVID-19 and Community Violence Affect Mothers and Babies

A study supported by NIH investigates the toll of COVID-19 and police violence on pregnant people and babies in Black communities.

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FDA Approves and Authorizes Updated mRNA COVID-19 Vaccines to Better Protect Against Currently Circulating Variants

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Today, the U.S. Food and Drug Administration approved and granted emergency use authorization (EUA) for updated mRNA COVID-19 vaccines (2024-2025 formula) to include a monovalent (single) component that corresponds to the Omicron variant KP.2 strain of SARS-CoV-2. The mRNA COVID-19 vaccines have been updated with this formula to more closely target currently circulating variants and provide better protection against serious consequences of COVID-19, including hospitalization and death. Today’s actions relate to updated mRNA COVID-19 vaccines manufactured by ModernaTX Inc. and Pfizer Inc.

In early June, the FDA advised manufacturers of licensed and authorized COVID-19 vaccines that the COVID-19 vaccines (2024-2025 formula) should be monovalent JN.1 vaccines. Based on the further evolution of SARS-CoV-2 and a rise in cases of COVID-19, the agency subsequently determined and advised manufacturers that the preferred JN.1-lineage for the COVID-19 vaccines (2024-2025 formula) is the KP.2 strain, if feasible.

“Vaccination continues to be the cornerstone of COVID-19 prevention,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “These updated vaccines meet the agency’s rigorous, scientific standards for safety, effectiveness, and manufacturing quality. Given waning immunity of the population from previous exposure to the virus and from prior vaccination, we strongly encourage those who are eligible to consider receiving an updated COVID-19 vaccine to provide better protection against currently circulating variants.”

The updated mRNA COVID-19 vaccines include Comirnaty and Spikevax, both of which are approved for individuals 12 years of age and older, and the Moderna COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine, both of which are authorized for emergency use for individuals 6 months through 11 years of age.

What You Need to Know

• Unvaccinated individuals 6 months through 4 years of age are eligible to receive three doses of the updated, authorized Pfizer-BioNTech COVID-19 Vaccine or two doses of the updated, authorized Moderna COVID-19 Vaccine.
• Individuals 6 months through 4 years of age who have previously been vaccinated against COVID-19 are eligible to receive one or two doses of the updated, authorized Moderna or Pfizer-BioNTech COVID-19 vaccines (timing and number of doses to administer depends on the previous COVID-19 vaccine received).
• Individuals 5 years through 11 years of age regardless of previous vaccination are eligible to receive a single dose of the updated, authorized Moderna or Pfizer-BioNTech COVID-19 vaccines; if previously vaccinated, the dose is administered at least 2 months after the last dose of any COVID-19 vaccine.
• Individuals 12 years of age and older are eligible to receive a single dose of the updated, approved Comirnaty or the updated, approved Spikevax; if previously vaccinated, the dose is administered at least 2 months since the last dose of any COVID-19 vaccine.
• Additional doses are authorized for certain immunocompromised individuals ages 6 months through 11 years of age as described in the Moderna COVID-19 Vaccine and Pfizer-BioNTech COVID-19 Vaccine fact sheets.

Individuals who receive an updated mRNA COVID-19 vaccine may experience similar side effects as those reported by individuals who previously received mRNA COVID-19 vaccines and as described in the respective prescribing information or fact sheets. The updated vaccines are expected to provide protection against COVID-19 caused by the currently circulating variants. Barring the emergence of a markedly more infectious variant of SARS-CoV-2, the FDA anticipates that the composition of COVID-19 vaccines will need to be assessed annually, as occurs for seasonal influenza vaccines.

For today’s approvals and authorizations of the mRNA COVID-19 vaccines, the FDA assessed manufacturing and nonclinical data to support the change to include the 2024-2025 formula in the mRNA COVID-19 vaccines. The updated mRNA vaccines are manufactured using a similar process as previous formulas of these vaccines. The mRNA COVID-19 vaccines have been administered to hundreds of millions of people in the U.S., and the benefits of these vaccines continue to outweigh their risks.

On an ongoing basis, the FDA will review any additional COVID-19 vaccine applications submitted to the agency and take appropriate regulatory action.

The approval of Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to BioNTech Manufacturing GmbH. The EUA amendment for the Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula) was issued to Pfizer Inc.

The approval of Spikevax (COVID-19 Vaccine, mRNA) (2024-2025 Formula) was granted to ModernaTX Inc. and the EUA amendment for the Moderna COVID-19 Vaccine (2024-2025 Formula) was issued to ModernaTX Inc.

Related Information

• Comirnaty (COVID-19 Vaccine, mRNA) (2024-2025 Formula)
• Spikevax (COVID-19 Vaccine, mRNA) (2024-2025 Formula)
• Moderna COVID-19 Vaccine (2024-2025 Formula)
• Pfizer-BioNTech COVID-19 Vaccine (2024-2025 Formula)
• FDA Resources for the Fall Respiratory Illness Season
• Updated COVID-19 Vaccines for Use in the United States Beginning in Fall 2024
• June 5, 2024, Meeting of the Vaccines and Related Biological Products Advisory Committee

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Shots - Health News

The new covid shot is now available. here's what you need to know.

New COVID Vaccines

A new round of COVID-19 vaccines will be rolled out soon. Scott Olson/Getty Images hide caption

It’s that time of year again.

New COVID-19 shots are now available all over the country.

That comes after the Food and Drug Administration last week greenlighted the two updated vaccines, which are aimed at helping protect people from the latest strains of the virus.

The arrival of the new shots may come as a relief to those who’ve tried to dodge a summer surge in cases, fueled by the FLiRT variants.

Whether or not you decide to rush out and get the vaccine could depend on a few factors, including when you last had COVID-19 and your underlying risk of getting seriously ill.

Here’s what you need to know:

Is COVID endemic yet? Yep, says the CDC. Here's what that means

What exactly are these new shots.

The Pfizer-BioNTech and Moderna vaccines rely on the same mRNA technology as the earlier versions of the vaccine, but they now target the KP.2 variant – a member of the omicron family that rose to prominence over the summer.

As many of us know by now, the virus continues evolving to better evade our immune defense, which means regularly updating the vaccines to keep up with the latest strain.

It turns out the KP.2 variant has already been overtaken by newer variants. Because those are also descendants of omicron, the hope is that the new vaccines are close enough matches that they can still boost immunity and protect people in the coming months – ideally reducing the chances of a big winter wave.

“The vaccine is not intended to be perfect. It’s not going to absolutely prevent COVID-19," Dr. Peter Marks from the FDA told NPR in an interview.

"But if we can prevent people from getting serious cases that end up in emergency rooms, hospitals or worse — dead — that’s what we’re trying to do with these vaccines.”

On average across all age groups, the new vaccines should cut the risk of having COVID-19 by 60% to 70% and reduce the risk of getting seriously ill by 80% to 90% during the three to four months after receiving the shot, Marks says.

A third vaccine is also expected to get the FDA’s stamp of approval soon.

That one, made by Novavax, is based on older technology (not mRNA), and targets an earlier strain of the virus, called JN.1.

Who should get them?

The FDA gave the OK for anyone ages 6 months and older to get one of the new shots. The Centers for Disease Control and Prevention is recommending the vaccines for those age groups.

“In my opinion, everyone should get one of the new vaccines,” says Dr. George Diaz , chief of medicine at Providence Regional Medical Center Everett and a spokesperson for the Infectious Disease Society of America.

That said, it’s most important for those at high risk of becoming seriously ill from COVID-19, namely those over the age of 65 or who have other underlying health problems like a weakened immune system.

Studies suggest getting vaccinated can also reduce the risk of long COVID, Diaz adds.

While anyone can get a shot, Dr. Paul Offit says not everyone necessarily needs another one.

“Anyone who wants to get this vaccine should get it,” says Offit, a vaccine expert at the University of Pennsylvania and Children's Hospital of Philadelphia who advises the FDA.

The vaccine does lessen your chance of getting a mild or moderate infection for about four to six months and to “some extent lessens your chances of spreading the virus,” he says.

But the calculation could be different for younger people who may have enough immunity from previous COVID shots and infections that they’re already protected from getting very sick.

“Were I a 35-year-old healthy adult who’d already had several doses of vaccine and one or two natural infections, I wouldn’t feel compelled to get it,” he says.

And regardless of the public health advice, it’s far from clear how many people will want one of the new shots. Only about 22% of eligible adults got one of the last ones.

Should I get the shot now? Or wait?

That’s a personal judgment call.

Marks suggests most people get vaccinated sooner rather than later because there’s an ongoing surge in COVID cases and the current vaccine is a “reasonably close match” to the current strain that’s circulating.

“Right now we’re in a wave, so you’d like to get protection against what’s going on right now,” Marks says. “You’re probably going to get the most benefit.”

However, it would be wise to hold off if you had COVID-19 over the summer.

People should wait at least two or three months since their last bout, or their last shot, in order to maximize the chances of getting the best protection from this new vaccine, says Marks.

Some people may want to get vaccinated later in September or October if they are primarily concerned about fending off COVID during a potential winter surge and staying healthy over the holiday season.

“This [protection] is not like something that suddenly cuts off at three or four months,” says Marks, “It’s just that the immunity will decrease with time.”

Where can I find the shots? Do I have to pay?

All the major pharmacy chains, including CVS, Rite Aid and Walmart, say the shots should be available at all their stores this week.

Insured people can get vaccinated for free if they get their shot from an in-network provider. But it won’t necessarily be free for those without health coverage.

A federal program that paid for the vaccines for uninsured adults expired. The uninsured may be able to still get the shots for free at some places, such as federally-funded health clinics.

“In the public health community we’re very concerned about how they will access protection,” says Dr. Kelly Moore , who runs Immunize.org , an advocacy group.

“We know that the people who are uninsured are the least likely to be able to afford becoming ill – missing work, staying home from school.”

Can I double up and get the COVID and flu shots at the same time?

Yes, health officials say it’s perfectly safe to get both shots at the same time. In fact, officials are recommending that, especially if that makes it more likely that people will get vaccinated because it’s more convenient.

What about kids? Can they get the same shots?

Yes, children can get the same vaccines that adults receive. But kids get different doses and may need more than one dose, depending on their age and whether they’ve been vaccinated before. They may also need to get their shots from a pediatrician.

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• Review Article
• Published: 13 January 2023

Long COVID: major findings, mechanisms and recommendations

• Hannah E. Davis   ORCID: orcid.org/0000-0002-1245-2034 1 ,
• Lisa McCorkell   ORCID: orcid.org/0000-0002-3261-6737 2 ,
• Julia Moore Vogel   ORCID: orcid.org/0000-0002-4902-3540 3 &
• Eric J. Topol   ORCID: orcid.org/0000-0002-1478-4729 3  

Nature Reviews Microbiology volume  21 ,  pages 133–146 ( 2023 ) Cite this article

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An Author Correction to this article was published on 17 April 2023

This article has been updated

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

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The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID

Epidemiology, clinical presentation, pathophysiology, and management of long COVID: an update

Long-COVID in children and adolescents: a systematic review and meta-analyses

Introduction.

Long COVID (sometimes referred to as ‘post-acute sequelae of COVID-19’) is a multisystemic condition comprising often severe symptoms that follow a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. At least 65 million individuals around the world have long COVID, based on a conservative estimated incidence of 10% of infected people and more than 651 million documented COVID-19 cases worldwide 1 ; the number is likely much higher due to many undocumented cases. The incidence is estimated at 10–30% of non-hospitalized cases, 50–70% of hospitalized cases 2 , 3 and 10–12% of vaccinated cases 4 , 5 . Long COVID is associated with all ages and acute phase disease severities, with the highest percentage of diagnoses between the ages of 36 and 50 years, and most long COVID cases are in non-hospitalized patients with a mild acute illness 6 , as this population represents the majority of overall COVID-19 cases. There are many research challenges, as outlined in this Review, and many open questions, particularly relating to pathophysiology, effective treatments and risk factors.

Hundreds of biomedical findings have been documented, with many patients experiencing dozens of symptoms across multiple organ systems 7 (Fig.  1 ). Long COVID encompasses multiple adverse outcomes, with common new-onset conditions including cardiovascular, thrombotic and cerebrovascular disease 8 , type 2 diabetes 9 , myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) 10 , 11 and dysautonomia, especially postural orthostatic tachycardia syndrome (POTS) 12 (Fig.  2 ). Symptoms can last for years 13 , and particularly in cases of new-onset ME/CFS and dysautonomia are expected to be lifelong 14 . With significant proportions of individuals with long COVID unable to return to work 7 , the scale of newly disabled individuals is contributing to labour shortages 15 . There are currently no validated effective treatments.

The impacts of long COVID on numerous organs with a wide variety of pathology are shown. The presentation of pathologies is often overlapping, which can exacerbate management challenges. MCAS, mast cell activation syndrome; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; POTS, postural orthostatic tachycardia syndrome.

Because diagnosis-specific data on large populations with long COVID are sparse, outcomes from general infections are included and a large proportion of medical conditions are expected to result from long COVID, although the precise proportion cannot be determined. One year after the initial infection, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections increased the risk of cardiac arrest, death, diabetes, heart failure, pulmonary embolism and stroke, as studied with use of US Department of Veterans Affairs databases. Additionally, there is clear increased risk of developing myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia. Six months after breakthrough infection, increased risks were observed for cardiovascular conditions, coagulation and haematological conditions, death, fatigue, neurological conditions and pulmonary conditions in the same cohort. The hazard ratio is the ratio of how often an event occurs in one group relative to another; in this case people who have had COVID-19 compared with those who have not. Data sources are as follows: diabetes 9 , cardiovascular outcomes 8 , dysautonomia 12 , 201 , ME/CFS 10 , 202 and breakthrough infections 4 .

There are likely multiple, potentially overlapping, causes of long COVID. Several hypotheses for its pathogenesis have been suggested, including persisting reservoirs of SARS-CoV-2 in tissues 16 , 17 ; immune dysregulation 17 , 18 , 19 , 20 with or without reactivation of underlying pathogens, including herpesviruses such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others 17 , 18 , 21 , 22 ; impacts of SARS-CoV-2 on the microbiota, including the virome 17 , 23 , 24 , 25 ; autoimmunity 17 , 26 , 27 , 28 and priming of the immune system from molecular mimicry 17 ; microvascular blood clotting with endothelial dysfunction 17 , 29 , 30 , 31 ; and dysfunctional signalling in the brainstem and/or vagus nerve 17 , 32 (Fig.  3 ). Mechanistic studies are generally at an early stage, and although work that builds on existing research from postviral illnesses such as ME/CFS has advanced some theories, many questions remain and are a priority to address. Risk factors potentially include female sex, type 2 diabetes, EBV reactivation, the presence of specific autoantibodies 27 , connective tissue disorders 33 , attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis 34 , although a third of people with long COVID have no identified pre-existing conditions 6 . A higher prevalence of long Covid has been reported in certain ethnicities, including people with Hispanic or Latino heritage 35 . Socio-economic risk factors include lower income and an inability to adequately rest in the early weeks after developing COVID-19 (refs. 36 , 37 ). Before the emergence of SARS-CoV-2, multiple viral and bacterial infections were known to cause postinfectious illnesses such as ME/CFS 17 , 38 , and there are indications that long COVID shares their mechanistic and phenotypic characteristics 17 , 39 . Further, dysautonomia has been observed in other postviral illnesses and is frequently observed in long COVID 7 .

There are several hypothesized mechanisms for long COVID pathogenesis, including immune dysregulation, microbiota disruption, autoimmunity, clotting and endothelial abnormality, and dysfunctional neurological signalling. EBV, Epstein–Barr virus; HHV-6, human herpesvirus 6; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

In this Review, we explore the current knowledge base of long COVID as well as misconceptions surrounding long COVID and areas where additional research is needed. Because most patients with long COVID were not hospitalized for their initial SARS-CoV-2 infection 6 , we focus on research that includes patients with mild acute COVID-19 (meaning not hospitalized and without evidence of respiratory disease). Most of the studies we discuss refer to adults, except for those in Box  1 .

Box 1 Long COVID in children

Long COVID impacts children of all ages. One study found that fatigue, headache, dizziness, dyspnoea, chest pain, dysosmia, dysgeusia, reduced appetite, concentration difficulties, memory issues, mental exhaustion, physical exhaustion and sleep issues were more common in individuals with long COVID aged 15–19 years compared with controls of the same age 203 . A nationwide study in Denmark comparing children with a positive PCR test result with control individuals found that the former had a higher chance of reporting at least one symptom lasting more than 2 months 204 . Similarly to adults with long COVID, children with long COVID experience fatigue, postexertional malaise, cognitive dysfunction, memory loss, headaches, orthostatic intolerance, sleep difficulty and shortness of breath 204 , 205 . Liver injury has been recorded in children who were not hospitalized during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections 206 , and although rare, children who had COVID-19 have increased risks of acute pulmonary embolism, myocarditis and cardiomyopathy, venous thromboembolic events, acute and unspecified renal failure, and type 1 diabetes 207 . Infants born to women who had COVID-19 during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first year after delivery 208 . A paediatric long COVID centre’s experience treating patients suggests that adolescents with a moderate to severe form of long COVID have features consistent with myalgic encephalomyelitis/chronic fatigue syndrome 205 . Children experiencing long COVID have hypometabolism in the brain similar to the patterns found in adults with long COVID 209 . Long-term pulmonary dysfunction is found in children with long COVID and those who have recovered from COVID-19 (ref. 210 ). Children with long COVID were more likely to have had attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis before being infected 34 .

More research on long COVID in children is needed, although there are difficulties in ensuring a proper control group due to testing issues. Several studies have found that children infected with SARS-CoV-2 are considerably less likely to have a positive PCR test result than adults despite seroconverting weeks later, with up to 90% of cases being missed 189 , 190 . Additionally, children are much less likely to seroconvert and, if they develop antibodies, are more likely to have a waning response months after infection compared with adults 193 .

Major findings

Immunology and virology.

Studies looking at immune dysregulation in individuals with long COVID who had mild acute COVID-19 have found T cell alterations, including exhausted T cells 18 , reduced CD4 + and CD8 + effector memory cell numbers 18 , 19 and elevated PD1 expression on central memory cells, persisting for at least 13 months 19 . Studies have also reported highly activated innate immune cells, a lack of naive T and B cells and elevated expression of type I and type III interferons (interferon-β (IFNβ) and IFNλ1), persisting for at least 8 months 20 . A comprehensive study comparing patients with long COVID with uninfected individuals and infected individuals without long COVID found increases in the numbers of non-classical monocytes, activated B cells, double-negative B cells, and IL-4- and IL-6-secreting CD4 + T cells and decreases in the numbers of conventional dendritic cells and exhausted T cells and low cortisol levels in individuals with long COVID at a median of 14 months after infection 18 . The expansion of cytotoxic T cells has been found to be associated with the gastrointestinal presentation of long COVID 27 . Additional studies have found elevated levels of cytokines, particularly IL-1β, IL-6, TNF and IP10 (refs. 40 , 41 ), and a recent preprint has reported persistent elevation of the level of CCL11, which is associated with cognitive dysfunction 42 . It remains to be seen whether the pattern of cytokines in ME/CFS, where the levels of certain cytokines are elevated in the first 2–3 years of illness but decrease over time without a corresponding decrease in symptoms 43 , is similar in long COVID.

Multiple studies have found elevated levels of autoantibodies in long COVID 27 , including autoantibodies to ACE2 (ref. 28 ) (the receptor for SARS-CoV-2 entry), β 2 -adrenoceptor, muscarinic M2 receptor, angiotensin II AT 1 receptor and the angiotensin 1–7 MAS receptor 26 . High levels of other autoantibodies have been found in some patients with COVID-19 more generally, including autoantibodies that target the tissue (such as connective tissue, extracellular matrix components, vascular endothelium, coagulation factors and platelets), organ systems (including the lung, central nervous system, skin and gastrointestinal tract), immunomodulatory proteins (cytokines, chemokines, complement components and cell-surface proteins) 44 . A major comprehensive study, however, did not find autoantibodies to be a major component of long COVID 18 .

Reactivated viruses, including EBV and HHV-6, have been found in patients with long COVID 18 , 21 , 22 , 27 (and have been identified in ME/CFS 45 ), and lead to mitochondrial fragmentation and severely affect energy metabolism 46 . A recent preprint has reported that EBV reactivation is associated with fatigue and neurocognitive dysfunction in patients with long COVID 22 .

Several studies have shown low or no SARS-CoV-2 antibody production and other insufficient immune responses in the acute stage of COVID-19 to be predictive of long COVID at 6–7 months, in both hospitalized patients and non-hospitalized patients 47 , 48 . These insufficient immune responses include a low baseline level of IgG 48 , low levels of receptor-binding domain and spike-specific memory B cells, low levels of nucleocapsid IgG 49 and low peaks of spike-specific IgG 47 . In a recent preprint, low or absent CD4 + T cell and CD8 + T cell responses were noted in patients with severe long COVID 49 , and a separate study found lower levels of CD8 + T cells expressing CD107a and a decline in nucleocapsid-specific interferon-γ-producing CD8 + T cells in patients with long COVID compared with infected controls without long COVID 50 . High levels of autoantibodies in long COVID have been found to be inversely correlated with protective COVID-19 antibodies, suggesting that patients with high autoantibody levels may be more likely to have breakthrough infections 27 . SARS-CoV-2 viral rebound in the gut, possibly resulting from viral persistence, has also been associated with lower levels and slower production of receptor-binding domain IgA and IgG antibodies 51 . There are major differences in antibody creation, seroreversion and antibody titre levels across the sexes, with women being less likely to seroconvert, being more likely to serorevert and having lower antibody levels overall 52 , 53 , even affecting antibody waning after vaccination 54 .

Several reports have pointed towards possible viral persistence as a driver of long COVID symptoms; viral proteins and/or RNA has been found in the reproductive system, cardiovascular system, brain, muscles, eyes, lymph nodes, appendix, breast tissue, hepatic tissue, lung tissue, plasma, stool and urine 55 , 56 , 57 , 58 , 59 , 60 . In one study, circulating SARS-CoV-2 spike antigen was found in 60% of a cohort of 37 patients with long COVID up to 12 months after diagnosis compared with 0% of 26 SARS-CoV-2-infected individuals, likely implying a reservoir of active virus or components of the virus 16 . Indeed, multiple reports following gastrointestinal biopsies have indicated the presence of virus, suggestive of a persistent reservoir in some patients 58 , 61 .

Vascular issues and organ damage

Although COVID-19 was initially recognized as a respiratory illness, SARS-CoV-2 has capability to damage many organ systems. The damage that has been demonstrated across diverse tissues has predominantly been attributed to immune-mediated response and inflammation, rather than direct infection of cells by the virus. Circulatory system disruption includes endothelial dysfunction and subsequent downstream effects, and increased risks of deep vein thrombosis, pulmonary embolism and bleeding events 29 , 30 , 62 . Microclots detected in both acute COVID-19 and long COVID contribute to thrombosis 63 and are an attractive diagnostic and therapeutic target. Long-term changes to the size and stiffness of blood cells have also been found in long COVID, with the potential to affect oxygen delivery 64 . A long-lasting reduction in vascular density, specifically affecting small capillaries, was found in patients with long COVID compared with controls, 18 months after infection 65 . A study finding elevated levels of vascular transformation blood biomarkers in long COVID also found that the angiogenesis markers ANG1 and P-selectin both had high sensitivity and specificity for predicting long COVID status 66 .

An analysis of the US Department of Veterans Affairs databases (VA data) including more than 150,000 individuals 1 year after SARS-CoV-2 infection indicated a significantly increased risk of a variety of cardiovascular diseases, including heart failure, dysrhythmias and stroke, independent of the severity of initial COVID-19 presentation 8 (Fig.  2 ). Cardiac MRI studies revealed cardiac impairment in 78% of 100 individuals who had a prior COVID-19 episode (investigated an average of 71 days after infection 67 ) and in 58% of participants with long COVID (studied 12 months after infection 68 ), reinforcing the durability of cardiac abnormalities.

Multiple studies have revealed multi-organ damage associated with COVID-19. One prospective study of low-risk individuals, looking at the heart, lungs, liver, kidneys, pancreas and spleen, noted that 70% of 201 patients had damage to at least one organ and 29% had multi-organ damage 69 . In a 1-year follow-up study, conducted by the same research group with 536 participants, the study authors found that 59% had single-organ damage and 27% multi-organ damage 70 . A dedicated kidney study of VA data including more than 89,000 individuals who had COVID-19 noted an increased risk of numerous adverse kidney outcomes 71 . Another VA data analysis, including more than 181,000 individuals who had COVID-19, found that infection also increases the risk of type 2 diabetes 9 (Fig.  2 ). The organ damage experienced by patients with long COVID appears durable, and long-term effects remain unknown.

Neurological and cognitive systems

Neurological and cognitive symptoms are a major feature of long COVID, including sensorimotor symptoms, memory loss, cognitive impairment, paresthesia, dizziness and balance issues, sensitivity to light and noise, loss of (or phantom) smell or taste, and autonomic dysfunction, often impacting activities of daily living 7 , 32 . Audiovestibular manifestations of long COVID include tinnitus, hearing loss and vertigo 7 , 72 .

In a meta-analysis, fatigue was found in 32% and cognitive impairment was found in 22% of patients with COVID-19 at 12 weeks after infection 3 . Cognitive impairments in long COVID are debilitating, at the same magnitude as intoxication at the UK drink driving limit or 10 years of cognitive ageing 73 , and may increase over time, with one study finding occurrence in 16% of patients at 2 months after infection and 26% of patients at 12 months after infection 74 . Activation of the kynurenine pathway, particularly the presence of the metabolites quinolinic acid, 3-hydroxyanthranilic acid and kynurenine, has been identified in long COVID, and is associated with cognitive impairment 74 . Cognitive impairment has also been found in individuals who recovered from COVID-19 (ref.  75 ), and at higher rates when objective versus subjective measures were used 3 , suggesting that a subset of those with cognitive impairment may not recognize and/or report their impairment. Cognitive impairment is a feature that manifests itself independently of mental health conditions such as anxiety and depression 74 , 76 , and occurs at similar rates in hospitalized and non-hospitalized patients 74 , 76 . A report of more than 1.3 million people who had COVID-19 showed mental health conditions such as anxiety and depression returned to normal over time, but increased risks of cognitive impairment (brain fog), seizures, dementia, psychosis and other neurocognitive conditions persisted for at least 2 years 77 .

Possible mechanisms for these neuropathologies include neuroinflammation, damage to blood vessels by coagulopathy and endothelial dysfunction, and injury to neurons 32 . Studies have found Alzheimer disease-like signalling in patients with long COVID 78 , peptides that self-assemble into amyloid clumps which are toxic to neurons 79 , widespread neuroinflammation 80 , brain and brainstem hypometabolism correlated with specific symptoms 81 , 82 and abnormal cerebrospinal fluid findings in non-hospitalized individuals with long COVID along with an association between younger age and a delayed onset of neurological symptoms 83 . Multilineage cellular dysregulation and myelin loss were reported in a recent preprint in patients with long COVID who had mild infections, with microglial reactivity similar to that seen in chemotherapy, known as ‘chemo-brain’ 42 . A study from the UK Biobank, including brain imaging in the same patients before and after COVID-19 as well as control individuals, showed a reduction in grey matter thickness in the orbitofrontal cortex and parahippocampal gyrus (markers of tissue damage in areas connected to the primary olfactory cortex), an overall reduction in brain size and greater cognitive decline in patients after COVID-19 compared with controls, even in non-hospitalized patients. Although that study looked at individuals with COVID-19 compared with controls, not specifically long COVID, it may have an implication for the cognitive component of long COVID 84 . Abnormal levels of mitochondrial proteins as well as SARS-CoV-2 spike and nucleocapsid proteins have been found in the central nervous system 85 . Tetrahydrobiopterin deficiencies and oxidative stress are found in long COVID as well 86 .

In the eyes, corneal small nerve fibre loss and increased dendritic cell density have been found in long COVID 87 , 88 , as well as significantly altered pupillary light responses 89 and impaired retinal microcirculation 90 . SARS-CoV-2 can infect and replicate in retinal 59 and brain 91 organoids. Other manifestations of long COVID include retinal haemorrhages, cotton wool spots and retinal vein occlusion 92 .

Mouse models of mild SARS-CoV-2 infection demonstrated microglial reactivity and elevated levels of CCL11, which is associated with cognitive dysfunction and impaired neurogenesis 42 . Hamster models exhibited an ongoing inflammatory state, involving T cell and myeloid activation, production of pro-inflammatory cytokines and an interferon response that was correlated with anxiety and depression-like behaviours in the hamsters, with similar transcriptional signatures found in the tissue of humans who had recovered from COVID-19 (ref. 93 ). Infected non-human primates with mild illness showed neuroinflammation, neuronal injury and apoptosis, brain microhaemorrhages, and chronic hypoxaemia and brain hypoxia 94 .

Recent reports indicate low blood cortisol levels in patients with long COVID as compared with control individuals, more than 1 year into symptom duration 18 , 27 . Low cortisol production by the adrenal gland should be compensated by an increase in adrenocorticotropic hormone (ACTH) production by the pituitary gland, but this was not the case, supporting hypothalamus–pituitary–adrenal axis dysfunction 18 . This may also reflect an underlying neuroinflammatory process. Low cortisol levels have previously been documented in individuals with ME/CFS.

ME/CFS, dysautonomia and related conditions

ME/CFS is a multisystem neuroimmune illness with onset often following a viral or bacterial infection. Criteria include a “substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities” for at least 6 months, accompanied by a profound fatigue that is not alleviated by rest, along with postexertional malaise, unrefreshing sleep and cognitive impairment or orthostatic intolerance (or both) 95 . Up to 75% of people with ME/CFS cannot work full-time and 25% have severe ME/CFS, which often means they are bed-bound, have extreme sensitivity to sensory input and are dependent on others for care 96 . There is a vast collection of biomedical findings in ME/CFS 97 , 98 , although these are not well known to researchers and clinicians in other fields.

Many researchers have commented on the similarity between ME/CFS and long COVID 99 ; around half of individuals with long COVID are estimated to meet the criteria for ME/CFS 10 , 11 , 29 , 100 , and in studies where the cardinal ME/CFS symptom of postexertional malaise is measured, a majority of individuals with long COVID report experiencing postexertional malaise 7 , 100 . A study of orthostatic stress in individuals with long COVID and individuals with ME/CFS found similar haemodynamic, symptomatic and cognitive abnormalities in both groups compared with healthy individuals 101 . Importantly, it is not surprising that ME/CFS should stem from SARS-CoV-2 infection as 27.1% of SARS-CoV infection survivors in one study met the criteria for ME/CFS diagnosis 4 years after onset 102 . A wide range of pathogens cause ME/CFS onset, including EBV, Coxiella burnetii (which causes Q fever), Ross River virus and West Nile virus 38 .

Consistent abnormal findings in ME/CFS include diminished natural killer cell function, T cell exhaustion and other T cell abnormalities, mitochondrial dysfunction, and vascular and endothelial abnormalities, including deformed red blood cells and reduced blood volume. Other abnormalities include exercise intolerance, impaired oxygen consumption and a reduced anaerobic threshold, and abnormal metabolic profiles, including altered usage of fatty acids and amino acids. Altered neurological functions have also been observed, including neuroinflammation, reduced cerebral blood flow, brainstem abnormalities and elevated ventricular lactate level, as well as abnormal eye and vision findings. Reactivated herpesviruses (including EBV, HHV-6, HHV-7 and human cytomegalovirus) are also associated with ME/CFS 97 , 98 , 103 , 104 .

Many of these findings have been observed in long COVID studies in both adults and children (Box  1 ). Long COVID research has found mitochondrial dysfunction including loss of mitochondrial membrane potential 105 and possible dysfunctional mitochondrial metabolism 106 , altered fatty acid metabolism and dysfunctional mitochondrion-dependent lipid catabolism consistent with mitochondrial dysfunction in exercise intolerance 107 , redox imbalance 108 , and exercise intolerance and impaired oxygen extraction 100 , 109 , 110 . Studies have also found endothelial dysfunction 29 , cerebral blood flow abnormalities and metabolic changes 81 , 111 , 112 , 113 (even in individuals with long COVID whose POTS symptoms abate 114 ), extensive neuroinflammation 42 , 80 , reactivated herpesviruses 18 , 21 , 27 , deformed red blood cells 64 and many findings discussed elsewhere. Microclots and hyperactivated platelets are found not only in individuals with long COVID but also in individuals with ME/CFS 115 .

Dysautonomia, particularly POTS, is commonly comorbid with ME/CFS 116 and also often has a viral onset 117 . POTS is associated with G protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies, platelet storage pool deficiency, small fibre neuropathy and other neuropathologies 118 . Both POTS and small fibre neuropathy are commonly found in long COVID 111 , 119 , with one study finding POTS in 67% of a cohort with long COVID 120 .

Mast cell activation syndrome is also commonly comorbid with ME/CFS. The number and severity of mast cell activation syndrome symptoms substantially increased in patients with long COVID compared with pre-COVID and control individuals 121 , with histamine receptor antagonists resulting in improvements in the majority of patients 19 .

Other conditions that are commonly comorbid with ME/CFS include connective tissue disorders including Ehlers–Danlos syndrome and hypermobility, neuro-orthopaedic spinal and skull conditions, and endometriosis 33 , 122 , 123 . Evidence is indicating these conditions may be comorbid with long COVID as well. The overlap of postviral conditions with these conditions should be explored further.

Reproductive system

Impacts on the reproductive system are often reported in long COVID, although little research has been done to document the extent of the impact and sex-specific pathophysiology. Menstrual alterations are more likely to occur in women and people who menstruate with long COVID than in women and people who menstruate with no history of COVID and those who had COVID-19 but not long COVID 124 . Menstruation and the week before menstruation have been identified by patients as triggers for relapses of long COVID symptoms 7 . Declined ovarian reserve and reproductive endocrine disorder have been observed in people with COVID-19 (ref. 125 ), and initial theories suggest that SARS-CoV-2 infection affects ovary hormone production and/or the endometrial response due to the abundance of ACE2 receptors on ovarian and endometrial tissue 126 . Individuals with both COVID-19 and menstrual changes were more likely to experience fatigue, headache, body ache and pain, and shortness of breath than those who did not have menstrual changes, and the most common menstrual changes were irregular menstruation, increased premenstrual symptoms and infrequent menstruation 127 .

Research on ME/CFS shows associations between ME/CFS and premenstrual dysphoric disorder, polycystic ovarian syndrome, menstrual cycle abnormalities, ovarian cysts, early menopause and endometriosis 128 , 129 , 130 . Pregnancy, postpartum changes, perimenopause and menstrual cycle fluctuations affect ME/CFS and influence metabolic and immune system changes 129 . Long COVID research should focus on these relationships to better understand the pathophysiology.

Viral persistence in the penile tissue has been documented, as has an increased risk of erectile dysfunction, likely resulting from endothelial dysfunction 131 . In one study, impairments to sperm count, semen volume, motility, sperm morphology and sperm concentration were reported in individuals with long COVID compared with control individuals, and were correlated with elevated levels of cytokines and the presence of caspase 8, caspase 9 and caspase 3 in seminal fluid 132 .

Respiratory system

Respiratory conditions are a common phenotype in long COVID, and in one study occurred twice as often in COVID-19 survivors as in the general population 2 . Shortness of breath and cough are the most common respiratory symptoms, and persisted for at least 7 months in 40% and 20% of patients with long COVID, respectively 7 . Several imaging studies that included non-hospitalized individuals with long COVID demonstrated pulmonary abnormalities including in air trapping and lung perfusion 133 , 134 . An immunological and proteomic study of patients 3–6 months after infection indicated apoptosis and epithelial damage in the airway but not in blood samples 135 . Further immunological characterization comparing individuals with long COVID with individuals who had recovered from COVID-19 noted a correlation between decreased lung function, systemic inflammation and SARS-CoV-2-specific T cells 136 .

Gastrointestinal system

Long COVID gastrointestinal symptoms include nausea, abdominal pain, loss of appetite, heartburn and constipation 137 . The gut microbiota composition is significantly altered in patients with COVID-19 (ref. 23 ), and gut microbiota dysbiosis is also a key component of ME/CFS 138 . Higher levels of Ruminococcus gnavus and Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii have been found in people with long COVID compared with non-COVID-19 controls (from before the pandemic), with gut dysbiosis lasting at least 14 months; low levels of butyrate-producing bacteria are strongly correlated with long COVID at 6 months 24 . Persisting respiratory and neurological symptoms are each associated with specific gut pathogens 24 . Additionally, SARS-CoV-2 RNA is present in stool samples of patients with COVID-19 (ref. 139 ), with one study indicating persistence in the faeces of 12.7% of participants 4 months after diagnosis of COVID-19 and in 3.8% of participants at 7 months after diagnosis 61 . Most patients with long COVID symptoms and inflammatory bowel disease 7 months after infection had antigen persistence in the gut mucosa 140 . Higher levels of fungal translocation, from the gut and/or lung epithelium, have been found in the plasma of patients with long COVID compared with those without long COVID or SARS-CoV-2-negative controls, possibly inducing cytokine production 141 . Transferring gut bacteria from patients with long COVID to healthy mice resulted in lost cognitive functioning and impaired lung defences in the mice, who were partially treated with the commensal probiotic bacterium Bifidobacterium longum 25 .

The onset and time course of symptoms differ across individuals and by symptom type. Neurological symptoms often have a delayed onset of weeks to months: among participants with cognitive symptoms, 43% reported a delayed onset of cognitive symptoms at least 1 month after COVID-19, with the delay associated with younger age 83 . Several neurocognitive symptoms worsen over time and tend to persist longer, whereas gastrointestinal and respiratory symptoms are more likely to resolve 7 , 74 , 142 . Additionally, pain in joints, bones, ears, neck and back are more common at 1 year than at 2 months, as is paresthesia, hair loss, blurry vision and swelling of the legs, hands and feet 143 . Parosmia has an average onset of 3 months after the initial infection 144 ; unlike other neurocognitive symptoms, it often decreases over time 143 .

Few people with long COVID demonstrate full recovery, with one study finding that 85% of patients who had symptoms 2 months after the initial infection reported symptoms 1 year after symptom onset 143 . Future prognosis is uncertain, although diagnoses of ME/CFS and dysautonomia are generally lifelong.

Diagnostic tools and treatments

Although diagnostic tools exist for some components of long COVID (for example, tilt table tests for POTS 145 and MRI scans to detect cardiovascular impairment 68 ), diagnostic tools for long COVID are mostly in development, including imaging to detect microclots 63 , corneal microscopy to identify small fibre neuropathy 87 , new fragmentation of QRS complex on electrocardiograms as indicative of cardiac injury 146 and use of hyperpolarized MRI to detect pulmonary gas exchange abnormalities 147 . On the basis of the tests that are offered as standard care, the results for patients with long COVID are often normal; many providers are unaware of the symptom-specific testing and diagnostic recommendations from the ME/CFS community 148 . Early research into biomarkers suggests that levels of extracellular vesicles 85 and/or immune markers indicating high cytotoxicity 149 could be indicative of long COVID. Intriguingly, dogs can identify individuals with long COVID on the basis of sweat samples 150 . Biomarker research in ME/CFS may also be applicable to long COVID, including electrical impedance blood tests, saliva tests, erythrocyte deformation, sex-specific plasma lipid profiles and variables related to isocapnic buffering 151 , 152 , 153 , 154 . The importance of developing and validating biomarkers that can be used for the diagnosis of long COVID cannot be adequately emphasized — they will not only be helpful in establishing the diagnosis but will also be helpful for objectively defining treatment responses.

Although there are currently no broadly effective treatments for long COVID, treatments for certain components have been effective for subsets of populations (Table  1 ). Many strategies for ME/CFS are effective for individuals with long COVID, including pacing 7 , 37 and symptom-specific pharmacological options (for example, β-blockers for POTS, low-dose naltrexone for neuroinflammation 155 and intravenous immunoglobulin for immune dysfunction) and non-pharmacological options (including increasing salt intake for POTS, cognitive pacing for cognitive dysfunction and elimination diets for gastrointestinal symptoms) 96 . Low-dose naltrexone has been used in many diseases, including ME/CFS 155 , and has also shown promise in treating long COVID 156 . H 1 and H 2 antihistamines, often following protocols for mast cell activation syndrome and particularly involving famotidine, are used to alleviate a wide range of symptoms 19 , 157 , although they are not a cure. Another drug, BC007, potentially addresses autoimmunity by neutralizing G protein-coupled receptor autoantibody levels 158 . Anticoagulant regimens are a promising way to address abnormal clotting 159 ; in one study, resolution of symptoms was seen in all 24 patients receiving triple anticoagulant therapy 31 . Apheresis has also shown promise to alleviate long COVID symptoms; it has been theorized to help remove microclots 160 and has been shown to reduce autoantibodies in ME/CFS 161 . However, it is quite expensive, and its benefits are uncertain. Some supplements have shown promise in treating both long COVID and ME/CFS, including coenzyme Q 10 and d -ribose 162 , and may deserve further study.

Of note, exercise is harmful for patients with long COVID who have ME/CFS or postexertional malaise 110 , 163 and should not be used as a treatment 164 , 165 , 166 ; one study of people with long COVID noted that physical activity worsened the condition of 75% of patients, and less than 1% saw improvement 109 .

Pilot studies and case reports have revealed additional treatment options worth exploring. A case report noted resolution of long COVID following treatment with the antiviral Paxlovid 167 , and a study investigating the treatment of acute COVID-19 with Paxlovid showed a 25% reduction in the incidence of long COVID 168 ; Paxlovid should be investigated further for prevention and treatment of long COVID. A small trial of sulodexide in individuals with endothelial dysfunction saw a reduction in symptom severity 169 . Pilot studies of probiotics indicated potential in alleviating gastrointestinal and non-gastrointestinal symptoms 170 , 171 . Two patients with long COVID experienced substantial alleviation of dysautonomia symptoms following stellate ganglion block 172 . An early study noted that Pycnogenol statistically significantly improved physiological measurements (for example, reduction in oxidative stress) and quality of life (indicated by higher Karnofsky Performance Scale Index scores) 173 , 174 , as hypothesized on the basis of success in other clinical studies.

Taken together, the current treatment options are based on small-scale pilot studies in long COVID or what has been effective in other diseases; several additional trials are in progress 175 . There is a wide range of possible treatment options from ME/CFS covering various mechanisms, including improving natural killer cell function, removing autoantibodies, immunosuppressants, antivirals for reactivated herpesviruses, antioxidants, mitochondrial support and mitochondrial energy generation 176 , 177 ; most need to be clinically trialled, which should happen urgently. Many newer treatment options remain underexplored, including anticoagulants and SARS-CoV-2-specific antivirals, and a lack of funding is a significant limitation to robust trials.

Impact of vaccines, variants and reinfections

The impact of vaccination on the incidence of long COVID differs across studies, in part because of differing study methods, time since vaccination and definitions of long COVID. One study indicated no significant difference in the development of long COVID between vaccinated individuals and unvaccinated individuals 178 ; other studies indicate that vaccines provide partial protection, with a reduced risk of long COVID between 15% and 41% 4 , 5 , with long COVID continuing to impact 9% of people with COVID-19.

The different SARS-CoV-2 variants and level of (and time since) vaccination may impact the development of long COVID. The UK’s Office for National Statistics found that long COVID was 50% less common in double-vaccinated participants with Omicron BA.1 than in double-vaccinated participants Delta, but that there was no significant difference between triple-vaccinated participants; it also found long COVID was more common after Omicron BA.2 infection than after BA.1 infection in triple-vaccinated participants, with 9.3% developing long COVID from infection with the BA.2 variant 179 .

The impact of vaccination on long COVID symptoms in people who had already developed long COVID differs among patients, with 16.7% of patients experiencing a relief of symptoms, 21.4% experiencing a worsening of symptoms and the remainder experiencing unchanged symptoms 180 .

Reinfections are increasingly common 181 . The impact of multiple instances of COVID-19, including the rate of long COVID in those who recovered from a first infection but developed long COVID following reinfection, and the impact of reinfection on those with pre-existing long COVID is crucial to understand to inform future policy decisions. Early research shows an increasing risk of long COVID sequelae after the second and third infection, even in double-vaccinated and triple-vaccinated people 182 . Existing literature suggests multiple infections may cause additional harm or susceptibility to the ME/CFS-type presentation 33 , 183 .

There is also early evidence that certain immune responses in people with long COVID, including low levels of protective antibodies and elevated levels of autoantibodies, may suggest an increased susceptibility to reinfection 27 .

Challenges and recommendations

Issues with PCR and antibody testing throughout the pandemic, inaccurate pandemic narratives and widespread lack of postviral knowledge have caused downstream issues and biases in long COVID research and care.

Testing issues

Most patients with COVID-19 from the first waves did not have laboratory-confirmed infection, with PCR tests being difficult to access unless individuals were hospitalized. Only 1–3% of cases to March 2020 were likely detected 184 , and the CDC estimates that only 25% of cases in the USA were reported from February 2020 to September 2021 (ref. 185 ); that percentage has likely decreased with the rise in use of at-home rapid tests.

Although PCR tests are our best tool for detecting SARS-CoV-2 infections, their false negative rates are still high 186 . Further bias is caused by false negative rates being higher in women and adults younger than 40 years 187 , those with a low viral load 188 and children (Box  1 ), with several studies showing 52–90% of cases in children missed by PCR tests 189 , 190 . The high false negative PCR rate results in symptomatic patients with COVID-19, who seek a COVID-19 test but receive a false negative result, being included as a control in many studies. Those who have a positive PCR test result (who are more likely to be included in research) are more likely to be male or have a higher viral load. Additionally, the lack of test accessibility as well as the false negative rates has created a significant barrier to care, as many long COVID clinics require PCR tests for admission.

Similarly, there is a broad misconception that everyone makes and retains SARS-CoV-2 antibodies, and many clinicians and researchers are unaware of the limited utility of antibody tests to determine prior infection. Between 22% and 36% of people infected with SARS-CoV-2 do not seroconvert, and many others lose their antibodies over the first few months, with both non-seroconversion and seroreversion being more likely in women, children and individuals with mild infections 52 , 53 , 191 , 192 , 193 . At 4 and 8 months after infection, 19% and 61% of patients, respectively, who had mild infections and developed antibodies were found to have seroreverted, compared with 2% and 29% of patients, respectively who had severe infections 191 . Still, many clinicians and researchers use antibody tests to include or exclude patients with COVID-19 from control groups.

Furthermore, during periods of test inaccessibility, tests were given on the basis of patients having COVID-19-specific symptoms such as loss of smell and taste, fever, and respiratory symptoms, resulting in a bias towards people with those symptoms.

Misinformation on PCR and antibody tests has resulted in the categorization of patients with long COVID into non-COVID-19 control groups, biasing the research output. Because low or no antibody levels and viral load may be related to long COVID pathophysiology, including a clinically diagnosed cohort will strengthen the research.

Important miscues

The narrative that COVID-19 had only respiratory sequelae led to a delayed realization of the neurological, cardiovascular and other multisystem impacts of COVID-19. Many long COVID clinics and providers still disproportionately focus on respiratory rehabilitation, which results in skewed electronic health record data. Electronic health record data are also more comprehensive for those who were hospitalized with COVID-19 than for those who were in community care, leading to a bias towards the more traditional severe respiratory presentation and less focus on non-hospitalized patients, who tend to have neurological and/or ME/CFS-type presentations.

The narrative that initially mild COVID-19 cases, generally defined as not requiring hospitalization in the acute phase, would not have long-term consequences has also had downstream effects on research. These so-called mild cases that result in long COVID often have an underlying biology different from acute severe cases, but the same types of tests are being used to evaluate patients. This is despite basic tests such as D-dimer, C-reactive protein (CRP) and antinuclear antibody tests and complete blood count being known to often return normal results in patients with long COVID. Tests that return abnormal results in patients with ME/CFS and dysautonomia, such as total immunoglobulin tests, natural killer cell function tests, the tilt table or NASA lean test, the four-point salivary cortisol test, reactivated herpesvirus panels, small fibre neuropathy biopsy, and tests looking for abnormal brain perfusion 96 , should instead be prioritized. Other recurring issues include studies failing to include the full range of symptoms, particularly neurological and reproductive system symptoms, and not asking patients about symptom frequency, severity and disability. Cardinal symptoms such as postexertional malaise are not widely known, and therefore are rarely included in study designs.

Widespread lack of postviral knowledge and misinformation

The widespread lack of knowledge of viral-onset illnesses, especially ME/CFS and dysautonomia, as well as often imperfect coding, prevents these conditions from being identified and documented by clinicians; this means that they are frequently absent from electronic health record data. Further, because ME/CFS and dysautonomia research is not widely known or comprehensively taught in medical schools 194 , long COVID research is often not built on past findings, and tends to repeat old hypotheses. Additionally, long COVID research studies and medical histories tend to document only the risk factors for severe acute COVID-19, which are different from the risk factors for conditions that overlap with long COVID such as ME/CFS and dysautonomia (for example, connective tissue disorders such as Ehlers–Danlos syndrome, prior illnesses such as infectious mononucleosis and mast cell involvement) 33 , 195 , 196 .

Clinicians who are not familiar with ME/CFS and dysautonomia often misdiagnose mental health disorders in patients; four in five patients with POTS receive a diagnosis with a psychiatric or psychological condition before receiving a POTS diagnosis, with only 37% continuing to have the psychiatric or psychological diagnosis once they have received their POTS diagnosis 117 . Researchers who are unfamiliar with ME/CFS and dysautonomia often do not know to use specific validated tools when conducting mental health testing, as anxiety scales often include autonomic symptoms such as tachycardia, and depression scales often include symptoms such as fatigue, both of which overestimate mental health disorder prevalence in these conditions 197 , 198 .

Recommendations

Although research into long COVID has been expansive and has accelerated, the existing research is not enough to improve outcomes for people with long COVID. To ensure an adequate response to the long COVID crisis, we need research that builds on existing knowledge and is inclusive of the patient experience, training and education for the health-care and research workforce, a public communication campaign, and robust policies and funding to support research and care in long COVID.

We need a comprehensive long COVID research agenda that builds on the existing knowledge from ME/CFS, dysautonomia and other viral-onset conditions, including but not limited to brain and brainstem inflammation, appropriate neuroimaging techniques, neuroimmunology, metabolic profiling, impaired endothelial function, mitochondrial fragmentation, antiviral and metabolic phenotypes, hypoperfusion/cerebral blood flow, nanoneedle diagnostic testing, overlaps with connective tissue disorders, autoimmunity and autoantibodies, viral/microbial persistence, intracranial hypertension, hypermobility, craniocervical obstructions, altered T and B cells, metabolomics and proteomics, elevated blood lactate level, herpesvirus reactivations, immune changes in the early versus late postviral years, and changes to the gut microbiota. The mechanisms of and overlaps between long COVID and connective tissue involvement, mast cells and inflammatory conditions such as endometriosis are particularly understudied and should be focused on. Because of the high prevalence of ME/CFS, POTS and other postinfectious illnesses in patients with long COVID, long COVID research should include people who developed ME/CFS and other postinfectious illnesses from a trigger other than SARS-CoV-2 in comparator groups to improve understanding of the onset and pathophysiology of these illnesses 113 . Additionally, there is a known immune exhaustion process that occurs between the second and third year of illness in ME/CFS, with test results for cytokines being different between patients who have been sick for shorter durations (less than 2 years) than for those who have been sick for longer durations 43 . Because of this, studies should implement subanalyses based on the length of time participants have been ill. Because ME/CFS and dysautonomia research is not widely known across the biomedical field, long COVID research should be led by experts from these areas to build on existing research and create new diagnostic and imaging tools.

Robust clinical trials must be a priority moving forward as patients currently have few treatment options. In the absence of validated treatment options, patients and physicians conduct individual experiments, which result in the duplication of efforts without generalizable knowledge and pose undue risks to patients. Robust study design and knowledge sharing must be prioritized by both funding institutions and clinician-researchers.

It is critical that research on long COVID be representative of (or oversample) the populations who had COVID-19 and are developing long COVID at high rates, which is disproportionately people of colour 35 . Medical research has historically under-represented these populations, and over-representation of white and socio-economically privileged patients has been common in long COVID research. Researchers must work within communities of colour, LGBTQ+ communities and low-income communities to build trust and conduct culturally competent studies that will provide insights and treatments for long COVID for marginalized populations.

As a subset of patients will improve over time, and others will have episodic symptoms, care should be taken to incorporate the possibility of alleviation of symptoms into the study design, and care should be taken not to ascribe improvement to a particular cause without proper modelling.

Finally, it is critical that communities of patients with long COVID and associated conditions are meaningfully engaged in long COVID research and clinical trials. The knowledge of those who experience an illness is crucial in identifying proper study design and key research questions and solutions, improving the speed and direction of research.

Training and education of the health-care and research workforce

To prepare the next generation of health-care providers and researchers, medical schools must improve their education on pandemics, viruses and infection-initiated illnesses such as long COVID and ME/CFS, and competency evaluations should include these illnesses. As of 2013, only 6% of medical schools fully cover ME/CFS across the domains of treatment, research and curricula, which has created obstacles to care, accurate diagnosis, research and treatment 194 . To ensure people with long COVID and associated conditions can receive adequate care now, professional societies and government agencies must educate the health-care and research workforce on these illnesses, including the history of and current best practices for ME/CFS to not repeat mistakes of the past, which have worsened patients’ prognoses. The research community has made a misstep in its efforts to treat ME/CFS 199 , and some physicians, poorly educated in the aetiology and pathophysiology of the disorder, still advise patients to pursue harmful interventions such as graded exercise therapy and cognitive behavioural therapy, despite the injury that these interventions cause 200 and the fact that they are explicitly not advised as treatments 163 , 164 , 166 .

Public communications campaign

In addition to providing education on long COVID to the biomedical community, we need a public communications campaign that informs the public about the risks and outcomes of long COVID.

Policies and funding

Finally, we need policies and funding that will sustain long COVID research and enable people with long COVID to receive adequate care and support. For instance, in the USA, the creation of a national institute for complex chronic conditions within the NIH would go a long way in providing a durable funding mechanism and a robust research agenda. Further, we need to create and fund centres of excellence, which would provide inclusive, historically informed and culturally competent care, as well as conduct research and provide medical education to primary care providers. Additionally, research and clinical care do not exist in silos. It is critical to push forward policies that address both the social determinants of health and the social support that is needed for disabled people.

Conclusions

Long COVID is a multisystemic illness encompassing ME/CFS, dysautonomia, impacts on multiple organ systems, and vascular and clotting abnormalities. It has already debilitated millions of individuals worldwide, and that number is continuing to grow. On the basis of more than 2 years of research on long COVID and decades of research on conditions such as ME/CFS, a significant proportion of individuals with long COVID may have lifelong disabilities if no action is taken. Diagnostic and treatment options are currently insufficient, and many clinical trials are urgently needed to rigorously test treatments that address hypothesized underlying biological mechanisms, including viral persistence, neuroinflammation, excessive blood clotting and autoimmunity.

Acknowledgements

We would like to thank the long COVID and associated conditions patient and research community and the entire team at Patient-Led Research Collaborative. E.J.T. was supported by National Center for Advancing Translational Sciences (NCATS) grant UL1TR002550.

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Julia Moore Vogel & Eric J. Topol

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Davis, H.E., McCorkell, L., Vogel, J.M. et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 21 , 133–146 (2023). https://doi.org/10.1038/s41579-022-00846-2

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Accepted : 05 December 2022

Published : 13 January 2023

Issue Date : March 2023

DOI : https://doi.org/10.1038/s41579-022-00846-2

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