covid 19 research paper outline

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

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

PRISMA flow diagram

Characteristics of included reviews

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

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

Population and study designs

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

Systematic review findings

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

A meta-analysis of the prevalence of mortality

Clinical symptoms

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

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgments

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

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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

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

Thilo Caspar von Groote

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Livia Puljak

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

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

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

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

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

Additional file 5: Appendix 5.

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

Additional file 6: Appendix 6.

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

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

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

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Virology, transmission, and pathogenesis of SARS-CoV-2

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What you need to know

SARS-CoV-2 is genetically similar to SARS-CoV-1, but characteristics of SARS-CoV-2—eg, structural differences in its surface proteins and viral load kinetics—may help explain its enhanced rate of transmission

In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, indicating the highest infectiousness potential just before or within the first five days of symptom onset

Reverse transcription polymerase chain reaction (RT-PCR) tests can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days; however, detection of viral RNA does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness

Symptomatic and pre-symptomatic transmission (1-2 days before symptom onset), is likely to play a greater role in the spread of SARS-CoV-2 than asymptomatic transmission

A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity of illness but wane over time

Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterise the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail). 1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the mechanisms and assumptions discussed in the article and in our understanding of covid-19 may be revised as further evidence emerges.

What we know about the virus

SARS-CoV-2 is an enveloped β-coronavirus, with a genetic sequence very similar to SARS-CoV-1 (80%) and bat coronavirus RaTG13 (96.2%). 2 The viral envelope is coated by spike (S) glycoprotein, envelope (E), and membrane (M) proteins ( fig 1 ). Host cell binding and entry are mediated by the S protein. The first step in infection is virus binding to a host cell through its target receptor. The S1 sub-unit of the S protein contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE 2). In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target. The virus structure and replication cycle are described in figure 1 .

(1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host’s transmembrane serine protease 2 (cell surface protein), which is principally expressed in the airway epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages (3-7) show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release

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Coronaviruses have the capacity for proofreading during replication, and therefore mutation rates are lower than in other RNA viruses. As SARS-CoV-2 has spread globally it has, like other viruses, accumulated some mutations in the viral genome, which contains geographic signatures. Researchers have examined these mutations to study virus characterisation and understand epidemiology and transmission patterns. In general, the mutations have not been attributed to phenotypic changes affecting viral transmissibility or pathogenicity. The G614 variant in the S protein has been postulated to increase infectivity and transmissibility of the virus. 3 Higher viral loads were reported in clinical samples with virus containing G614 than previously circulating variant D614, although no association was made with severity of illness as measured by hospitalisation outcomes. 3 These findings have yet to be confirmed with regards to natural infection.

Why is SARS-CoV-2 more infectious than SARS-CoV-1?

SARS-CoV-2 has a higher reproductive number (R 0 ) than SARS-CoV-1, indicating much more efficient spread. 1 Several characteristics of SARS-CoV-2 may help explain this enhanced transmission. While both SARS-CoV-1 and SARS-CoV-2 preferentially interact with the angiotensin-converting enzyme 2 (ACE 2) receptor, SARS-CoV-2 has structural differences in its surface proteins that enable stronger binding to the ACE 2 receptor 4 and greater efficiency at invading host cells. 1 SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and conjunctiva, 5 thus can infect the upper respiratory tract and can conduct airways more easily. 6

Viral load dynamics and duration of infectiousness

Viral load kinetics could also explain some of the differences between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness, with subsequent decline thereafter, which indicates the highest infectiousness potential just before or within the first five days of symptom onset ( fig 2 ). 7 In contrast, in SARS-CoV-1 the highest viral loads were detected in the upper respiratory tract in the second week of illness, which explains its minimal contagiousness in the first week after symptom onset, enabling early case detection in the community. 7

After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations, ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from https://www.sciencedirect.com/science/article/pii/S009286742030475X ; https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30230-7/fulltext )

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) technology can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days (maximum 83 days) after symptom onset. 7 However, detection of viral RNA by qRT-PCR does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness. 5 This corresponds to what is known about transmission based on contact tracing studies, which is that transmission capacity is maximal in the first week of illness, and that transmission after this period has not been documented. 8 Severely ill or immune-compromised patients may have relatively prolonged virus shedding, and some patients may have intermittent RNA shedding; however, low level results close to the detection limit may not constitute infectious viral particles. While asymptomatic individuals (those with no symptoms throughout the infection) can transmit the infection, their relative degree of infectiousness seems to be limited. 9 10 11 People with mild symptoms (paucisymptomatic) and those whose symptom have not yet appeared still carry large amounts of virus in the upper respiratory tract, which might contribute to the easy and rapid spread of SARS-CoV-2. 7 Symptomatic and pre-symptomatic transmission (one to two days before symptom onset) is likely to play a greater role in the spread of SARS-CoV-2. 10 12 A combination of preventive measures, such as physical distancing and testing, tracing, and self-isolation, continue to be needed.

Route of transmission and transmission dynamics

Like other coronaviruses, the primary mechanism of transmission of SARS-CoV-2 is via infected respiratory droplets, with viral infection occurring by direct or indirect contact with nasal, conjunctival, or oral mucosa, when respiratory particles are inhaled or deposited on these mucous membranes. 6 Target host receptors are found mainly in the human respiratory tract epithelium, including the oropharynx and upper airway. The conjunctiva and gastrointestinal tracts are also susceptible to infection and may serve as transmission portals. 6

Transmission risk depends on factors such as contact pattern, environment, infectiousness of the host, and socioeconomic factors, as described elsewhere. 12 Most transmission occurs through close range contact (such as 15 minutes face to face and within 2 m), 13 and spread is especially efficient within households and through gatherings of family and friends. 12 Household secondary attack rates (the proportion of susceptible individuals who become infected within a group of susceptible contacts with a primary case) ranges from 4% to 35%. 12 Sleeping in the same room as, or being a spouse of an infected individual increases the risk of infection, but isolation of the infected person away from the family is related to lower risk of infection. 12 Other activities identified as high risk include dining in close proximity with the infected person, sharing food, and taking part in group activities 12 The risk of infection substantially increases in enclosed environments compared with outdoor settings. 12 For example, a systematic review of transmission clusters found that most superspreading events occurred indoors. 11 Aerosol transmission can still factor during prolonged stay in crowded, poorly ventilated indoor settings (meaning transmission could occur at a distance >2 m). 12 14 15 16 17

The role of faecal shedding in SARS-CoV-2 transmission and the extent of fomite (through inanimate surfaces) transmission also remain to be fully understood. Both SARS-CoV-2 and SARS-CoV-1 remain viable for many days on smooth surfaces (stainless steel, plastic, glass) and at lower temperature and humidity (eg, air conditioned environments). 18 19 Thus, transferring infection from contaminated surfaces to the mucosa of eyes, nose, and mouth via unwashed hands is a possible route of transmission. This route of transmission may contribute especially in facilities with communal areas, with increased likelihood of environmental contamination. However, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated by commonly used disinfectants, emphasising the potential value of surface cleaning and handwashing. SARS-CoV-2 RNA has been found in stool samples and RNA shedding often persists for longer than in respiratory samples 7 ; however, virus isolation has rarely been successful from the stool. 5 7 No published reports describe faecal-oral transmission. In SARS-CoV-1, faecal-oral transmission was not considered to occur in most circumstances; but, one explosive outbreak was attributed to aerosolisation and spread of the virus across an apartment block via a faulty sewage system. 20 It remains to be seen if similar transmission may occur with SARS-CoV-2.

Pathogenesis

Viral entry and interaction with target cells.

SARS-CoV-2 binds to ACE 2, the host target cell receptor. 1 Active replication and release of the virus in the lung cells lead to non-specific symptoms such as fever, myalgia, headache, and respiratory symptoms. 1 In an experimental hamster model, the virus causes transient damage to the cells in the olfactory epithelium, leading to olfactory dysfunction, which may explain temporary loss of taste and smell commonly seen in covid-19. 21 The distribution of ACE 2 receptors in different tissues may explain the sites of infection and patient symptoms. For example, the ACE 2 receptor is found on the epithelium of other organs such as the intestine and endothelial cells in the kidney and blood vessels, which may explain gastrointestinal symptoms and cardiovascular complications. 22 Lymphocytic endotheliitis has been observed in postmortem pathology examination of the lung, heart, kidney, and liver as well as liver cell necrosis and myocardial infarction in patients who died of covid-19. 1 23 These findings indicate that the virus directly affects many organs, as was seen in SARS-CoV-1 and influenzae.

Much remains unknown. Are the pathological changes in the respiratory tract or endothelial dysfunction the result of direct viral infection, cytokine dysregulation, coagulopathy, or are they multifactorial? And does direct viral invasion or coagulopathy directly contribute to some of the ischaemic complications such as ischaemic infarcts? These and more, will require further work to elucidate.

Immune response and disease spectrum ( figure 2 )

After viral entry, the initial inflammatory response attracts virus-specific T cells to the site of infection, where the infected cells are eliminated before the virus spreads, leading to recovery in most people. 24 In patients who develop severe disease, SARS-CoV-2 elicits an aberrant host immune response. 24 25 For example, postmortem histology of lung tissues of patients who died of covid-19 have confirmed the inflammatory nature of the injury, with features of bilateral diffuse alveolar damage, hyaline-membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation consistent with acute respiratory distress syndrome (ARDS), and is similar to the lung pathology seen in severe Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). 26 27 A distinctive feature of covid-19 is the presence of mucus plugs with fibrinous exudate in the respiratory tract, which may explain the severity of covid-19 even in young adults. 28 This is potentially caused by the overproduction of pro-inflammatory cytokines that accumulate in the lungs, eventually damaging the lung parenchyma. 24

Some patients also experience septic shock and multi-organ dysfunction. 24 For example, the cardiovascular system is often involved early in covid-19 disease and is reflected in the release of highly sensitive troponin and natriuretic peptides. 29 Consistent with the clinical context of coagulopathy, focal intra-alveolar haemorrhage and presence of platelet-fibrin thrombi in small arterial vessels is also seen. 27 Cytokines normally mediate and regulate immunity, inflammation, and haematopoiesis; however, further exacerbation of immune reaction and accumulation of cytokines in other organs in some patients may cause extensive tissue damage, or a cytokine release syndrome (cytokine storm), resulting in capillary leak, thrombus formation, and organ dysfunction. 24 30

Mechanisms underlying the diverse clinical outcomes

Clinical outcomes are influenced by host factors such as older age, male sex, and underlying medical conditions, 1 as well as factors related to the virus (such as viral load kinetics), host-immune response, and potential cross-reactive immune memory from previous exposure to seasonal coronaviruses ( box 1 ).

Risk factors associated with the development of severe disease, admission to intensive care unit, and mortality

Underlying condition.

Hypertension

Cardiovascular disease

Chronic obstructive pulmonary disease

Presentation

Higher fever (≥39°C on admission)

Dyspnoea on admission

Higher qSOFA score

Laboratory markers

Neutrophilia/lymphopenia

Raised lactate and lactate dehydrogenase

Raised C reactive protein

Raised ferritin

Raised IL-6

Raised ACE2

D-dimer >1 μg/mL

Sex-related differences in immune response have been reported, revealing that men had higher plasma innate immune cytokines and chemokines at baseline than women. 31 In contrast, women had notably more robust T cell activation than men, and among male participants T cell activation declined with age, which was sustained among female patients. These findings suggest that adaptive immune response may be important in defining the clinical outcome as older age and male sex is associated with increased risk of severe disease and mortality.

Increased levels of pro-inflammatory cytokines correlate with severe pneumonia and increased ground glass opacities within the lungs. 30 32 In people with severe illness, increased plasma concentrations of inflammatory cytokines and biomarkers were observed compared with people with non-severe illness. 30 33 34

Emerging evidence suggests a correlation between viral dynamics, the severity of illness, and disease outcome. 7 Longitudinal characteristics of immune response show a correlation between the severity of illness, viral load, and IFN- α, IFN-γ, and TNF-α response. 34 In the same study many interferons, cytokines, and chemokines were elevated early in disease for patients who had severe disease and higher viral loads. This emphasises that viral load may drive these cytokines and the possible pathological roles associated with the host defence factors. This is in keeping with the pathogenesis of influenza, SARS, and MERS whereby prolonged viral shedding was also associated with severity of illness. 7 35

Given the substantial role of the immune response in determining clinical outcomes, several immunosuppressive therapies aimed at limiting immune-mediated damage are currently in various phases of development ( table 1 ).

Therapeutics currently under investigation

• View inline

Immune response to the virus and its role in protection

Covid-19 leads to an antibody response to a range of viral proteins, but the spike (S) protein and nucleocapsid are those most often used in serological diagnosis. Few antibodies are detectable in the first four days of illness, but patients progressively develop them, with most achieving a detectable response after four weeks. 36 A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity but wane over time. 37 The duration and protectivity of antibody and T cell responses remain to be defined through studies with longer follow-up. CD-4 T cell responses to endemic human coronaviruses appear to manifest cross-reactivity with SARS-CoV-2, but their role in protection remains unclear. 38

Unanswered questions

Further understanding of the pathogenesis for SARS-CoV-2 will be vital in developing therapeutics, vaccines, and supportive care modalities in the treatment of covid-19. More data are needed to understand the determinants of healthy versus dysfunctional response and immune markers for protection and the severity of disease. Neutralising antibodies are potential correlates of protection, but other protective antibody mechanisms may exist. Similarly, the protective role of T cell immunity and duration of both antibody and T cell responses and the correlates of protection need to be defined. In addition, we need optimal testing systems and technologies to support and inform early detection and clinical management of infection. Greater understanding is needed regarding the long term consequences following acute illness and multisystem inflammatory disease, especially in children.

Education into practice

How would you describe SARS-CoV-2 transmission routes and ways to prevent infection?

How would you describe to a patient why cough, anosmia, and fever occur in covid-19?

Questions for future research

What is the role of the cytokine storm and how could it inform the development of therapeutics, vaccines, and supportive care modalities?

What is the window period when patients are most infectious?

Why do some patients develop severe disease while others, especially children, remain mildly symptomatic or do not develop symptoms?

What are the determinants of healthy versus dysfunctional response, and the biomarkers to define immune correlates of protection and disease severity for the effective triage of patients?

What is the protective role of T cell immunity and duration of both antibody and T cell responses, and how would you define the correlates of protection?

How patients were involved in the creation of this article

No patients were directly involved in the creation of this article.

How this article was created

We searched PubMed from 2000 to 18 September 2020, limited to publications in English. Our search strategy used a combination of key words including “COVID-19,” “SARS-CoV-2,” “SARS”, “MERS,” “Coronavirus,” “Novel Coronavirus,” “Pathogenesis,” “Transmission,” “Cytokine Release,” “immune response,” “antibody response.” These sources were supplemented with systematic reviews. We also reviewed technical documents produced by the Centers for Disease Control and Prevention and World Health Organization technical documents.

Author contributions: MC, KK, JK, MP drafted the first and subsequent versions of the manuscript and all authors provided critical feedback and contributed to the manuscript.

Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Provenance and peer review: commissioned; externally peer reviewed.

This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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REVIEW article

Coronavirus disease (covid-19): comprehensive review of clinical presentation.

• 1 Department of Medicine, King Edward Medical University/ Mayo Hospital, Lahore, Pakistan
• 2 Department of Anesthesia and Intensive Care, Post-Graduate Medical Institute/LGH, Lahore, Pakistan
• 3 Rajarshee Chhatrapati Shahu Maharaj Government Medical College, Kolhapur, India
• 4 Department of Medicine, Faculty of Medicine, University of Tlemcen, Tlemcen, Algeria
• 5 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
• 6 Institute of Research and Development, Duy Tan University, Da Nang, Vietnam

COVID-19 is a rapidly growing pandemic with its first case identified during December 2019 in Wuhan, Hubei Province, China. Due to the rampant rise in the number of cases in China and globally, WHO declared COVID-19 as a pandemic on 11th March 2020. The disease is transmitted via respiratory droplets of infected patients during coughing or sneezing and affects primarily the lung parenchyma. The spectrum of clinical manifestations can be seen in COVID-19 patients ranging from asymptomatic infections to severe disease resulting in mortality. Although respiratory involvement is most common in COVID-19 patients, the virus can affect other organ systems as well. The systemic inflammation induced by the disease along with multisystem expression of Angiotensin Converting Enzyme 2 (ACE2), a receptor which allows viral entry into cells, explains the manifestation of extra-pulmonary symptoms affecting the gastrointestinal, cardiovascular, hematological, renal, musculoskeletal, and endocrine system. Here, we have reviewed the extensive literature available on COVID-19 about various clinical presentations based on the organ system involved as well as clinical presentation in specific population including children, pregnant women, and immunocompromised patients. We have also briefly discussed about the Multisystemic Inflammatory Syndrome occurring in children and adults with COVID-19. Understanding the various clinical presentations can help clinicians diagnose COVID-19 in an early stage and ensure appropriate measures to be undertaken in order to prevent further spread of the disease.

Introduction

COVID-19 is a growing pandemic with initial cases identified in Wuhan, Hubei province, China toward the end of December 2019. Labeled as Novel Coronavirus 2019 (2019-nCoV) initially by the Chinese Center for Disease Control and Prevention (CDC) which was subsequently renamed as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) due to its homology with SARS-CoV by the International Committee on Taxonomy of Viruses (ICTV) ( 1 , 2 ). The World Health Organization (WHO) later renamed the disease caused by SARS-CoV-2 as Coronavirus Disease-2019 (COVID-19) ( 3 ). COVID-19 is primarily a disease of the respiratory system affecting lung parenchyma with fever, cough, and shortness of breath as the predominant symptoms. Recent studies have shown that it can affect multiple organ systems and cause development of extra-pulmonary symptoms. Presence of extra-pulmonary symptoms can often lead to late diagnosis and sometimes even mis-diagnosis of COVID-19 which can be detrimental to patients. As researchers globally continue to understand COVID-19 and its implications on the human body, knowledge about the various clinical presentations of COVID-19 is paramount in early diagnosing and treatment in order to decrease the morbidity and mortality caused by the disease.

Epidemiology and Pathophysiology

While studying the early transmission dynamics of COVID-19 outbreak in Wuhan, many cases were found to be linked to the Huanan wholesale seafood market. Further investigation revealed <10% of the total cases could be linked to the market which led to the conclusion of human-to-human transmission of the virus occurring through respiratory droplets and contact transmission contributing to the rise in the number of affected individuals ( 4 ). The exponential rise in the number of cases in China and reporting of cases outside China in multiple countries led WHO to declare COVID-19 as a pandemic on 11th March 2020 ( 5 ).

SARS-CoV-2 tends to infect all age groups and is transmitted via direct contact or respiratory droplets generated during coughing or sneezing by the infected patient during both symptomatic or pre-symptomatic phase of infection. Other routes of transmission include fecal-oral route and fomites along with small risk of vertical transmission from mother to child if infection occurs during third trimester of pregnancy ( 6 , 7 ). There has also been evidence of asymptomatic transmission of COVID-19 ( 8 ). The concept of super spreaders in relation to COVID-19 is emerging where a single individual either symptomatic or asymptomatic can infect a disproportionately large number of individuals in an appropriate super spreading conditions such as mass gathering due to production of large number of infectious agent for prolonged duration of time ( 9 ). As per the literature, the incubation period of COVID-19 ranges from 2 to 14 days with a mean incubation period of 3 days ( 10 ). The basic Reproduction number (Ro) of SARS-CoV-2 is 2–2.5. Each individual infected with COVID-19 can infect 2–2.5 other individuals in a naïve population which also explains the exponential growth in the number of cases ( 10 ). The disease tends to be of mild to moderate severity in roughly 80% of patients, and severe disease is associated with infants, elderly patients above 65 years, and patients with other comorbidities such as diabetes mellitus, hypertension, coronary artery disease, and other chronic conditions ( 1 , 2 ). COVID-19 has also been found to be more severe in males than in females with a case fatality rate of 2.8% in males and 1.7% in females ( 11 ). The major organ system affected by the virus is the respiratory system, but it can affect other organ systems either directly or by the effect of host immune response. SARS-CoV-2, the causative agent of COVID-19, after entering the human host initially replicates in the epithelial mucosa of the upper respiratory tract (nose and pharynx) followed by migration to the lungs where further replication of virus occurs causing transient viraemia. The virus uses Angiotensin Converting Enzyme 2 (ACE2) receptor as a primary entry to cells. ACE2 is found abundantly in the mucosal lining of the respiratory tract, vascular endothelial cells, heart, intestine, and kidney. Thus, the virus has potential for replication in all these organs. After entry into cells, the virus undergoes further rapid replication within the target cells and induces extensive epithelial and endothelial dysfunction leading to exponential inflammatory response with the production of a large amount of proinflammatory cytokines and chemokines. Activation of proinflammatory cytokines and chemokines leads to neutrophil activation and migrations and results in the characteristic cytokine storm. The immunological downregulation of ACE2 by the virus contributes to acute lung injury in COVID-19. ACE2 also regulates the renin angiotensin system (RAS); thus, downregulation of ACE2 also causes dysfunction of RAS which contributes to enhanced inflammation ( 2 , 11 – 15 ). These entire factors contribute to symptoms of COVID-19 with sepsis, multi-organ dysfunction, acute respiratory distress syndrome (ARDS), and prothrombotic state leading to an exacerbation of organ dysfunction.

Clinical Manifestation

We review here the system based clinical features of COVID-19.

Respiratory

According to report from WHO-China-Joint Mission on COVID-19, 55,924 laboratories confirmed cases of COVID-19 had fever (87.9%), dry cough (67.7%), fatigue (38.1%), sputum production (33.4%), difficulty breathing (18.6%), sore throat (13.9%), chills (11.4%), nasal congestion (4.8%), and hemoptysis (0.9%) ( 1 ).

Some patients may rapidly progress to acute lung injury and ARDS with septic shock. The median interval between the onset of initial symptoms to development of dyspnea, hospital admission, and ARDS was 5, 7, and 8 days respectively ( 10 ). Some patients with COVID-19 may have reduced oxygen saturation in blood (≤ 93%) with oxygen saturation down to 50 or 60% but remained stable without significant distress, and as such, were termed as salient hypoxia or happy hypoxia ( 16 , 17 ). Trial of oxygen therapy, prone positioning, high flow continuous positive airway pressure, non-re-breathable mask alongside trial of anticoagulation are often used to manage these patients ( 16 , 17 ). However, further study is required to define the role of these strategies in management.

The most frequent radiological abnormality among 975 patients with COVID-19 in computed tomography (CT) scan of chest was ground glass opacity (56.4%) and bilateral patchy shadowing (51.8%) ( 18 ). A scientific review of 2,814 patients have shown that the most common chest CT finding in COVID-19 patients was ground glass opacity followed by consolidation. However, the findings can vary in different patients and at various stages of diseases. Other CT findings include interlobular septal thickening, reticular pattern, crazy paving, etc. Atypical findings like air bronchogram, bronchial wall thickening, nodule, pleural effusion, and lymphadenopathy have also been noted in some studies ( 19 ). A study showed that among 877 patients with non-severe diseases and 173 patients with severe diseases, 17.9 and 2.9% of the patients did not have any detectable radiological abnormalities, respectively ( 18 ).

ENT (Ear, Nose, and Throat)

ENT manifestations are one of the most frequent symptoms encountered by physicians in COVID-19. A peculiar clinical presentation in some COVID-19 patients includes the deterioration of sense, taste (dysgeusia), and loss of smell (anosmia). A systematic review and meta-analysis of 10 studies with 1,627 participants surveyed for olfactory deterioration and 9 studies with 1,390 participants examined for gustatory symptoms demonstrated prevalence of 52.73 and 43.93% of these symptoms among COVID-19 patients, respectively. These clinical features may often present at earlier stages of the disease ( 20 ). Additionally, sore throat, rhinorrhea, nasal congestion, tonsil edema, and enlarged cervical lymph nodes are commonly seen among otolaryngological dysfunctions in patients ( 21 ). A large observational study of 1,099 COVID-19 patients reported tonsils swelling in 23 patients (2.1%), throat congestion in 19 patients (1.7%) and enlarged lymph nodes in 2 patients (0.2%) ( 18 ). This can be explained by the fact that there is a high expression of ACE2 receptors on the epithelial cells of the oral and nasal mucosa including the tongue. It has been known that the novel coronavirus has a strong binding affinity to ACE2 receptors through which it invades host cells ( 22 ). This theory may explain the exhibition of extra-respiratory symptoms including ENT manifestations as part of COVID-19 symptoms.

Cardiovascular

Cardiac manifestation in patient with COVID-19 can occur due to cardiac strain secondary to hypoxia and respiratory failure, direct effect of SARS-CoV-2 on heart or secondary to inflammation and cytokine storm, metabolic derangements, rupture of plaque and coronary occlusion by thrombus, and consequences of drugs used for treatment ( 23 – 25 ). The need for intensive care admission, non-invasive ventilation (46.3 vs. 3.9%), and invasive mechanical ventilation (22 vs. 4.2%) were higher among patients with cardiac ailments as compared to those without cardiac involvement as well as higher hospital mortality than those without myocardial involvement (51.2 vs. 4.5%) ( 26 ). These patients tend to have electrocardiographic (ECG) changes as well as elevations in high sensitivity cardiac troponin (hsCTn) and N- terminal pro-B-type natriuretic peptide (NT proBNP) which corresponded to raised inflammatory markers. Hypertension, acute and fulminant myocarditis, ventricular arrhythmias, atrial fibrillation, stress cardiomyopathy, hypotension and heart failure, acute coronary syndrome (ACS) with ST elevation or depression MI with normal coronaries have been reported ( 23 , 27 ). In a Chinese cohort of 138 patients, 16.7% had arrhythmias with risk higher among those needing ICU care with no mention of the type of arrhythmia that was present ( 28 ). Less frequently, cardiac symptoms like chest pain or tightness and palpitation can be the initial presenting features without fever producing a diagnostic dilemma. Some of these patients eventually go on to develop respiratory symptoms as diseases progress ( 29 ). Patients who have recovered from acute illness may develop arrhythmias as a result of myocardial scar and need future monitoring ( 27 ). One important point to note is use of Renin Angiotensin Aldosterone System (RAAS) modulators in patients with COVID-19. Guidelines from ACC/AHA/HFSA recommends continuing them in high risk patient based on goal directed therapy approach supported by a recent systematic review and meta-analysis conducted by Hasan et. Al. which demonstrated use of ACEI/ARB in COVID-19 patients is associated with lower odds/ hazards of mortality and development of severe/critical diseases as compared to no use of ACEI/ARB ( 30 , 31 ).

Gastrointestinal

In the initial cohort of patients from China, nausea or vomiting and diarrhea were present in 5 and 3.7% of patients ( 1 ). Review of data from 2,023 patients showed anorexia to be the most frequently occurring gastrointestinal symptom in adults. Diarrhea was the most common presenting gastrointestinal symptom in both adults and children while vomiting was found to be more common in children ( 32 ). Other rare symptoms included nausea, abdominal pain, and gastrointestinal bleeding. There have been few instances where COVID-19 patients presented with only gastrointestinal symptoms without the development of fever or respiratory symptoms at the onset and during disease progression ( 33 ). In a smaller cohort of 204 patients, 50.5% had some form of intestinal symptoms and of those, 5.8% had only intestinal symptoms while the remaining patients developed respiratory symptoms subsequently. The most common symptoms reported among them was anorexia (78.64%), non-dehydrating diarrhea (34%), vomiting (3.9%), and abdominal pain (1.94%) ( 34 ). In addition, those with GI symptoms tend to have a longer interval between symptom onset and hospital admission (9 vs. 7.3 days) possibly due to lack of clinical suspicion and delay in diagnosis. Patients with gastrointestinal symptoms tend to have higher elevation in AST and ALT indicating coexistent liver injury ( 34 ). The mechanism behind GI illness is not clearly known but could be due to direct invasion of virus via ACE2 receptor in the intestinal mucosa. This can be supported by the fact that viral RNA can be detected in stool samples of COVID-19 patients which may also hint toward possible fecal-oral transmission ( 35 ). Liver dysfunction is likely secondary to the use of hepatotoxic drugs, hypoxia induced liver injury, systemic inflammation, and multi organ failure ( 36 ).

Renal manifestation in patients with COVID-19 can occur due to direct invasion of podocytes and proximal tubular cells by SARS-CoV-2 virus, secondary endothelial dysfunction causing effacement of foot process with vacuolation and detachment of podocytes, and acute proximal tubular dysfunction ( 37 ). Furthermore, hypoxia, cytokine storm, rhabdomyolysis, nephrotoxic drugs, and overlying infections can all exacerbate renal injury ( 38 ). Based on initial reports, prevalence of Acute Kidney Injury (AKI) among COVID-19 hospitalized patients range from 0.5 to 29%. In a cohort of 701 patients, proteinuria (43.9%), hematuria (26.7%), elevated creatinine (14.4%), elevated blood urea nitrogen (13.1%), and low glomerular filtration rate (≤ 60 ml/min/1.73 m 2 ) (13.1%) were present at the time of hospital admission with 5.1% developing AKI during the illness. AKI was more prevalent among those with baseline renal impairment ( 39 ). In another large cohort of 5,449 patients, 36.6% had AKI with prevalence higher among mechanically ventilated patients compared to non-ventilated patients (89.7 vs. 21.7%) ( 40 ). Patients developing renal impairment are prone to have higher mortality within the hospital. Another point to highlight is the presentation of COVID-19 in renal transplant recipients. Due to immunosuppression, these patients are likely to have low fever at presentation with swift clinical decline and requirement for mechanical ventilation with high mortality as compared to the general population ( 41 ).

Neurological

Most patients with COVID-19 develop neurological symptoms along with respiratory symptoms during the course of illness; however, several case reports in review of literature document patient presentation of neurological dysfunction without typical symptoms of fever, cough, and difficulty breathing ( 42 ). There is a 2.5-fold enhanced risk of severe illness and increased death in patients with a history of previous stroke with similar findings among those with Parkinson's diseases. The prevalence of neurological features ranges from 6 to 36% along with hypoxic ischemic encephalopathy up to 20% in some series of patients ( 43 ). Neurological symptoms tend to occur early in the course of illness (median 1–2 days) with most common neurological features being headache, confusion, delirium, anosmia or hyposmia, dysgeusia or ageusia, altered mental status, ataxia, and seizures ( 44 ). Among patients admitted with COVID-19, the prevalence of ischemic stroke ranges from 2.5 to 5% despite receiving prophylaxis for venous thromboembolism. Patients prone to have established cardiovascular risk factors are likely to have a more severe diseases ( 43 ). Other presentations include viral encephalitis, acute necrotizing encephalopathy (ANE), infectious toxic encephalopathy, meningitis, Guillain Barre Syndrome (GBS), Miller Fisher syndrome, and polyneuritis cranialis with GBS being the first feature of COVID-19 in few cases ( 42 , 43 , 45 ). In COVID-19 patients, CNS features are possibly due to direct invasion of neurons and glial cells by SARS-CoV-2 as well as by endothelial dysfunction of blood brain barrier (BBB). Virus can gain access to CNS via hematogenous spread or retrograde movement across the olfactory bulb. The virus can be detected in CSF by RT-PCR and on brain parenchyma during autopsy. The fact that most patients develop anosmia or hyposmia during illness support this theory ( 45 ). After entry, the virus can cause reactive gliosis with activation of the inflammatory cascade. The combination of systemic inflammation, cytokine storm, and coagulation dysfunction can impair BBB function and alter brain equilibrium causing neuronal death ( 42 ).

Ocular manifestations can vary from conjunctival injection to frank conjunctivitis. In a Chinese cohort of 38 patients, 31.6% had ocular symptoms consisting primarily of conjunctivitis while conjunctival hyperemia, foreign body sensation in eye, chemosis, tearing or epiphora were more common among severe COVID-19 patients. Among them SARS-CoV-2 can be demonstrated in conjunctival as well as nasopharyngeal swab in 5.2% of patients, indicating a potential route for viral transmission ( 46 ). Conjunctivitis or tearing can be the initial presenting symptoms of COVID-19. Despite this fact, there is no documented case of severe ocular features relating to COVID-19.

Similar to other viral infections, SARS-CoV-2 can also produce varied dermatological features. A study of 88 patients from Italy showed that about 20.4% had some form of skin manifestations with 44.4% developing features at onset and duration of the disease progression ( 47 ). Maculopapular exanthem (36.1%) was identified as most common dermatological features followed by papulovesicular rash (34.7%), painful acral red purple papules (15.3%), urticaria (9.7%), livedo reticularis (2.8%), and petechiae (1.4%) ( 48 ). A study of 375 COVID-19 cases in Spain identified five different patterns of cutaneous manifestations in patients: acral areas of erythema with vesicles or pustules (pseudo-chilblain) (19%), other vesicular eruptions (9%), urticarial lesions (19%), maculopapular eruptions (47%), and livedo or necrosis (6%) ( 49 ). Majority of patients had lesions on the trunk with some experiencing lesions on hands and feet. There are case reports of COVID-19 associated with erythema multiforme and Kawasaki Disease in children ( 50 , 51 ). Pathogenesis behind skin involvement remains unclear with some features explained by small vessel vasculitis, thrombotic events like DIC, hyaline thrombus formation, acral ischemia, or the direct effect of the virus like other viral illnesses ( 52 ).

Musculoskeletal

The initial report from China revealed 14.8% of patients had myalgia or arthralgia among 55,924 COVID-19 patients. A review article reports that of 12,046 patients, fatigue was identified in 25.6% and myalgia and/or arthralgia in 15.5% with most patients reporting symptoms from the start of illness ( 53 ). There are reports suggesting myositis and rhabdomyolysis with markedly elevated creatinine kinase can occur during COVID-19 illness especially in patients with severe diseases and multi organ failure. Additionally, in some patients, rhabdomyolysis has been documented as the initial presentation of COVID-19 illness without typical respiratory symptoms ( 54 , 55 ). A case series of four patients developing acute arthritis during hospital admission for COVID-19 has been reported with exacerbation of crystal arthropathy (gout and calcium pyrophosphate diseases) but negative for SARS-CoV-2 RT-PCR in synovial fluid ( 56 ). Treatment with steroids and colchicine was used in all four cases. An important consideration to note was that all four patients developed arthritis despite previous treatment with immunomodulatory therapy (hydroxychloroquine, tocilizumab, and pulse methylprednisolone).

Hematological

As stated, COVID-19 is a systemic disease inducing systemic inflammation and occasionally cytokine storm. This can significantly impact the process of hematopoiesis and hemostasis. During early disease, normal or decreased leukocyte and lymphocyte counts were documented with marked lymphopenia as the diseases progressed, especially in those with cytokine storms and severe disease. In a study of 1,099 patients, lymphopenia, thrombocytopenia, and leukopenia were present in 83.2, 36.2, and 33.7%, respectively, with findings more marked in those with severe diseases ( 18 ). Leukocytosis in COVID-19 patients might suggest a bacterial infection or a superinfection with leukocytosis found more commonly in severe cases (11.4%) as compared to mild and moderate cases (4.8%) ( 18 ). Similarly, thrombocytopenia has been found to be more common (57.7%) in severe cases in contrast to mild and moderate cases (31.6%) ( 18 ). Lymphopenia was also linked with an increased necessity for ICU admission and the risk of ARDS. Thrombocytosis with elevated platelet to lymphocyte ratio may indicate a more marked cytokine storm ( 57 ).

Also, coagulation abnormality can manifest in the form of thrombocytopenia, prolonged prothrombin time (PT), low serum fibrinogen level, and raised D-dimer suggesting Disseminated Intravascular Coagulation (DIC) with these changes more marked in those with severe diseases ( 58 ). Raised lactate dehydrogenase (LDH) and serum ferritin were also present and correlated with the degree of systemic inflammation. In a study of 426 COVID-19 patients, C-Reactive Protein (CRP) was noted to be increased in 75–93% of patients, more commonly in patients with severe disease. Serum procalcitonin levels might not be altered at admission, but progressive increase in its value can suggest a worsening prognosis. Severe disease is linked to increased ALT, bilirubin, serum urea, creatinine, and lowered serum albumin ( 59 ). A study of 1,426 patients showed that Interleukin-6 (IL-6) were raised more in patients with severe COVID-19 than non-severe COVID-19 with progressive rise indicating an increased risk of mortality. Thus, its levels could be regarded as an important prognostic indicator for the extensive inflammation and cytokine storm in COVID-19 patients ( 60 ). Other plasma cytokines and chemokines like IL1B, IFNγ, IP10, MCP, etc. have also been found to be elevated in patients with COVID-19 both in severe and non-severe diseases. Additionally, GCSF, IP10, IL2, IL7, IL10, MCP1, MIP1A, and TNFα were increased in patients who require ICU admission which indicates that cytokine storm is associated with a severe disease ( 61 ).

Endocrine and Reproductive

From the available literature there is no doubt that diabetes mellitus is an important risk factor for COVID-19 illness and is associated with increased risk of development of severe disease. Additionally, there are case reports of subacute thyroiditis linked to SARS-CoV-2 infection ( 62 , 63 ). Based on the statement released from European Society of Endocrinology, patients with primary adrenal failure and congenital adrenal hyperplasia may have theoretically increased susceptibility to infection with higher risk of complications and ultimately mortality but there is no current evidence to support this ( 64 ). The dose of steroids may need to be doubled if there is a clinical suspicion of infection in these patients.

Several claims have been made regarding the impact of COVID-19 on male reproductive function, hypothesizing that COVID-19 can cause potential testicular damage either by binding directly to testicular ACE2 receptors, which are highly expressed in the testicles or by damaging the testis indirectly by exciting local immune system ( 65 ). A study comparing 81 male COVID-19 patients with 100 age matched healthy adults highlighted the presence of low testosterone levels, high levels of luteinizing hormone (LH), low testosterone/LH ratios, low Follicle stimulating hormone (FSH) to LH ratio, and raised serum prolactin. This may suggest a potential COVID-19 testicular damage affecting the Leydig cells in the testis ( 66 ). COVID-19 infected male patients may have reduced sperm count and decreased motility leading to diminished male fertility for 3 months post-infection ( 67 ).

Clinical Presentation in Specific Population

In children.

A case series of 72,314 cases published by the Chinese Center for Disease Control and Prevention reported that 0.9% of the total patients were between 0 and 9 years of age, and 1.2% of the total patients were between 10 and 19 years of age ( 68 ). The most common symptoms found in children are fever, (59%), cough (46%), few cases (12%) of gastrointestinal symptoms, and some cases (26%) showed no specific symptoms initially with patchy consolidation and ground glass opacities in CT chest findings ( 69 ). Chilblain-like acral eruptions, purpuric, and erythema multiforme-like lesions have been found to be more common in children and young adult patients mainly with asymptomatic or mild disease ( 70 ). Lymphopenia in children is relatively less common which is in direct contrast in cases of SARS in children where lymphopenia was more commonly noted ( 69 ).

Multisystem inflammatory syndrome (MIS) is another feared complication of Covid-19 seen in children. Abrams et al. systematically summarized the clinical evidence of 8 studies reporting MIS in 440 children. The median age of patients ranged from 7.3 to 10 years with 59% of all patients being male. The greatest proportion of patients had gastrointestinal symptoms (87%) followed by mucocutaneous symptoms (73%) and cardiovascular symptoms (71%) while fewer patients reported respiratory (47%), neurologic (22%), and musculoskeletal (21%) symptoms. Ferritin and d-dimer were elevated in 50% of patients, and C-reactive protein, interleukin-6, and fibrinogen were elevated in at least 75% of patients. Additionally, 100% of children with cardiovascular involvement reported elevated cardiac-damage markers such as Troponin. Although respiratory manifestation is most frequently expressed in adults, children with MIS exhibited less pulmonary symptoms and more of the other manifestations ( 71 ).

In Pregnant Women

The most common symptoms reported in pregnant women are fever (61.96%), cough (38.04%), malaise (30.49%), myalgia (21.43%), sore throat (12%), and dyspnea (12.05%). Other symptoms found in pregnant women are diarrhea and nasal congestion ( 72 ). In a systematic review including 92 patients, 67.4% manifested diseases at presentation with 31.7% having negative RT-PCR though they had features of viral pneumonia. Only one patient required admission to intensive care and 0% mortality. Fetal outcomes were reported as: 63.8% preterm delivery, 61.1% fetal distress, 80% Cesarean section delivery, 76.92% neonatal intensive care admission, 42.8% low birth weight, and 66.67% had lymphopenia ( 72 ). There was no evidence of vertical transmission. A study of 41 pregnant women with COVID-19 showed that consolidation was more commonly found in CT of pregnant women in contrast to ground-glass opacities in CT of non-pregnant adults ( 73 ). WHO also recommends encouraging lactating mothers with confirmed or suspected COVID-19 to begin or continue breastfeeding including 24-h rooming in, skin to skin contact, and kangaroo mother care especially in immediate postnatal period ( 74 ). On July 14th, 2020, Vivanti et al. published the first case of transplacental transmission of COVID-19 from a 23-years-old pregnant woman to her baby ( 75 ). Thereafter, more studies reported the possibility of the vertical transmission of COVID-19. In this context, Kotlayer et al. published a systematic review of 38 studies. Out of 936 neonates from COVID-19 mothers, 27 tested positive for the virus indicating a pooled proportion of 3.2% (2.2–4.3) for vertical transmission ( 7 ).

In Immuno-Compromised Population

Due to their impaired immune response, it is not surprising that immunocompromised patients with COVID-19 infection might be at greater risk of developing severe forms of the disease and co-infections in comparison to normal populations. Nevertheless, recent studies showed the association between cytokine storm syndrome and the overreaction of the immune system with COVID-19 raising the possibility that immunodeficient states might alleviate the overexpression of the host immune system and thereby prevent deadly forms of the disease ( 76 ). After the RECOVERY trial ( 77 ) that showed the efficacy of dexamethasone in lowering the mortality in severe forms of the disease, many questions were raised regarding whether immunocompromised patients have a greater or lower risk of developing severe forms of the disease. In order to address these questions, Minotti et al. recently published a systematic review that included 16 studies with 110 patients presenting mostly with cancer along with transplantation and immunodeficiency. Out of the 110 patients, 72 (65.5%) recovered without being admitted to the intensive care unit while 23 (20.9%) died ( 76 ). The authors concluded that immunosuppression in both children and adults seem to have a better disease course in comparison to normal population. One of the limitations of this study is that the conclusion was made only based on qualitative synthesis and no meta-analysis was performed. On the other hand, Gao et al. performed a meta-analysis on 8 relevant studies with 4,007 patients. The study showed that immunosuppression and immunodeficiency were associated with non-statistically significant increased risk of severe COVID-19 disease ( 78 ). Additionally, Mirzaei et al. summarized the clinical evidence of 252 HIV positive patients co-infected with COVID-19. The clinical manifestation did not differ from that of the general population. However, out of the 252 patients, 204 (80.9%) were male. Low CD4 count (<200 cells/mm 3 ) were reported for 23 of 176 patients (13.1%). COVID-19 symptoms were present in 223 patients with the most common symptoms of fever in 165 (74.0%) patients, cough in 130 (58.3%), headache in 44 (19.7%), arthralgia and myalgia in 33 (14.8%), gastrointestinal symptoms in 29 (13.0%) followed by sore throat in 18 (8.1%) patients ( 79 ). The number of deaths accounted for 36 (14.3%). Similar to the general population, immunocompromised, and HIV patients were no different in terms of clinical manifestation or severity. However, the results from these studies should be interpreted with caution and more studies are recommended to establish the link between this particular group of patients with severity of the disease.

Multisystem Involvement in COVID-19

As evident from the discussion above, SARS-CoV-2 can affect multiple organ systems and produce a wide array of clinical presentation of COVID-19. Certain studies conducted in Europe and United States have shown that COVID-19 can also have a multi-systemic presentation in individuals in form of a multi-system inflammatory syndrome (MIS) which has been found in both children and adults and is known as MIS-C and MIS-A, respectively ( 80 – 83 ).

According to a recent CDC report about MIS-A, it was found that only half of the patients with MIS-A had preceding respiratory symptoms of COVID-19 ~2–5 weeks before ( 80 ). The most common clinical signs and symptoms included fever, chest pain, palpitations, diarrhea, abdominal pain, vomiting, skin rash, etc. Nearly all patients had electro-cardiological abnormalities like arrythmias, elevated troponin levels, and electrocardiography evidence of left or right ventricular dysfunction. Even though most patients had minimal respiratory symptoms, chest imaging had features of ground glass opacity and pleural effusion. All patients had signs of elevated laboratory markers of inflammation, coagulation markers, and lymphopenia ( 80 ).

MIS-C can clinically mimic Kawasaki Disease ( 81 ). By the end of July, about 570 cases of MIS-C with COVID-19 were found in the United States ( 81 ). In MIS-C, there is involvement of at least four organ systems, most commonly the gastrointestinal system followed by cardiovascular and dermatological systems ( 81 ). Prominent signs and symptoms found in children with MIS-C were abdominal pain, vomiting, skin rash, diarrhea, hypotension, and conjunctival injection. The majority of the children needed ICU admission due to the development of severe complications including cardiac dysfunction, shock, myocarditis, coronary artery aneurysm, and acute kidney injury ( 81 ).

Association Between Clinical Presentations, COVID-19 Severity and Prognosis

Evaluation of 55,924 laboratory confirmed COVID-19 cases in China, the presence of dyspnea, respiratory rate ≥ 30/min, blood saturation levels ≤ 93%, PaO2/FiO2 ratio ≤ 300, lung infiltrates ≥ 50% of the lung fields between 12 and 48 h were associated with severe COVID-19 infection ( 1 ). Clinical signs suggestive of respiratory failure, septic shock, or multiple organ dysfunction/failure were associated with critical disease and poor prognosis ( 1 ). Individuals at highest risk of severe disease and deaths were patients with age > 80 years and associated co-morbidities such as underlying cardiovascular disease, diabetes, hypertension, chronic respiratory disease, and cancer ( 1 ). Another study done with 418 patients in Catalonia (Spain) showed that dyspnea was an important predictor of severe disease while confusion was an important predictor of death, and the presence of cough was strongly associated with good prognosis ( 84 ). Advanced age, male sex, and obesity were independent markers of poor prognosis while eosinophilia was a marker of less severe disease ( 84 ). The mortality was lower in patients with symptoms of diarrhea, arthromyalgia, headache, and loss of smell and taste sensations while low oxygen saturation, high CRP levels, and higher number of lung quadrants affected on Xray were found to be associated with severe disease and death ( 84 ).

COVID-19 is a viral illness which can cause multi-systemic manifestations. Review of existing literature concludes that SARS-CoV-2 can affect any organ system either directly or indirectly leading to a myriad of clinical presentation. The most commonly affected system is the respiratory system with presenting symptoms of fever, cough, and shortness of breath, etc. Other systems which can be affected in COVID-19 include ENT (sore throat, loss of taste, smell, and sensations, and rhinorrhea), cardiovascular system (chest pain, chest tightness, palpitations, and arrhythmias), gastrointestinal system (anorexia, diarrhea, vomiting, nausea, and abdominal pain), renal (proteinuria, hematuria, and acute kidney injury), neurological (headache, confusion, delirium, and altered mental status), ocular (conjunctival hyperemia, foreign body sensation in the eye, chemosis, and tearing), cutaneous (rash, papules, and urticaria), musculoskeletal system (myalgia and arthralgia), hematological (lymphopenia, thrombocytopenia, leukopenia, elevated inflammatory markers, and elevated coagulation markers), endocrine (low testosterone, low FSH, and high LH) and reproductive system (decreased sperm count and decreased sperm motility). Clinical presentation in specific populations like children, pregnant women, and immunocompromised people may vary which emphasizes the importance of further investigation in order to avoid late diagnosis of COVID-19. Severe multi-systemic involvement in COVID-19 in the form of MIS-C and MIS-A can cause significant morbidity and mortality if undiagnosed. The clinical presentations of respiratory failure, acute kidney injury, septic shock, cardiovascular arrest is associated with severe COVID-19 disease and can result in poor prognosis. In the light of exponentially growing pandemic, every patient presenting to hospital must be tested for SARS-CoV-2 by RT-PCR if resources are available to detect early presentations of diseases even if the features are atypical. Understanding of the various clinical presentations of COVID-19 will help the clinicians in early detection, treatment, and isolation of patients in order to contain the virus and slow down the pandemic.

Author Contributions

All authors have contributed equally to the work, and all agreed to be accountable for the content of the work.

Conflict of Interest

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

Acknowledgments

We would like to thank Ms. Sairah Zia (American University of Caribbean, School of Medicine, Sint Maarten), a native speaker of English, for proofreading the manuscript.

Abbreviations

ACC/AHA/HFSA, American College of Cardiology/American Heart Association/Heart Failure Society of America; IL1B, Interleukin 1B; IFNγ, Interferon Gamma; IP10, Interferon-inducible Protein 10; MCP1, Monocyte Chemoattractant Protein 1; GCSF, Granulocyte Colony Stimulating Factor; IL2, Interleukin 2; IL7, Interleukin 7; IL10, Interleukin 10; MIP1A, Macrophage Inflammatory Protein-1 alpha; TNFα, Tumor Necrosis Factor alpha.

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76. Minotti C, Tirelli F, Barbieri E, Giaquinto C, Donà D. How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? a systematic review. J Infect. (2020) 81:e61–6. doi: 10.1016/j.jinf.2020.04.026

77. Europe PMC . (2020). Available online at: https://europepmc.org/articles/pmc7383595/bin/nejmoa2021436_appendix.pdf (accessed November 20, 2020).

78. Gao Y, Chen Y, Liu M, Shi S, Tian J. Impacts of immunosuppression and immunodeficiency on COVID-19: a systematic review and meta-analysis. J Infect. (2020) 81:e93–5. doi: 10.1016/j.jinf.2020.05.017

79. Mirzaei H, McFarland W, Karamouzian M, Sharifi H. COVID-19 among people living with HIV: a systematic review. AIDS Behav. (2020) 1–8. doi: 10.1007/s10461-020-02983-2. [Epub ahead of print].

80. Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan S, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection — United Kingdom and United States, March–August 2020. Morb Mortal Wkly Rep. (2020) 69:1450–6. doi: 10.15585/mmwr.mm6940e1

81. Godfred-Cato S, Bryant B, Leung J, Oster ME, Conklin L, Abrams J, et al. COVID-19–Associated Multisystem Inflammatory Syndrome in Children — United States, March–July 2020. Morb Mortal Wkly Rep. (2020) 69:1074–80. doi: 10.15585/mmwr.mm6932e2

82. Belot A, Antona D, Renolleau S, Javouhey E, Hentgen V, Angoulvant F, et al. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May (2020. Eurosurveillance. (2020) 25:2001010. doi: 10.2807/1560-7917.ES.2020.25.22.2001010

83. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. (2020) 324:259. doi: 10.1001/jama.2020.10369

84. Rodríguez-Molinero A, Gálvez-Barrón C, Miñarro A, Macho O, López GF, Robles MT, et al. Association between COVID-19 prognosis and disease presentation, comorbidities and chronic treatment of hospitalized patients. PLoS ONE. (2020) 15:e0239571. doi: 10.1371/journal.pone.0239571

Keywords: SARS-CoV-2, Covid-19, symptomatology, clinical presentation, signs and symptoms, clinical features, coronavirus

Citation: Mehta OP, Bhandari P, Raut A, Kacimi SEO and Huy NT (2021) Coronavirus Disease (COVID-19): Comprehensive Review of Clinical Presentation. Front. Public Health 8:582932. doi: 10.3389/fpubh.2020.582932

Received: 13 July 2020; Accepted: 15 December 2020; Published: 15 January 2021.

Reviewed by:

Copyright © 2021 Mehta, Bhandari, Raut, Kacimi and Huy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Nguyen Tien Huy, tienhuy@nagasaki-u.ac.jp

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

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• NATURE PODCAST
• 17 December 2020

Coronapod: The big COVID research papers of 2020

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• Noah Baker &
• Traci Watson

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

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

Papers discussed

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Important announcement:  

The CDC Database of COVID-19 Research Articles became a collaboration with the WHO to create the  WHO COVID-19 database  during the pandemic to make it easier for results to be searched, downloaded, and used by researchers worldwide.

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Materials listed in these guides are selected to provide awareness of quality public health literature and resources. A material’s inclusion does not necessarily represent the views of the U.S. Department of Health and Human Services (HHS), the Public Health Service (PHS), or the Centers for Disease Control and Prevention (CDC), nor does it imply endorsement of the material’s methods or findings.

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• To help inform CDC’s COVID-19 Response, as well as to help CDC staff stay up to date on the latest COVID-19 research, the Response’s Office of the Chief Medical Officer has collaborated with the CDC Office of Library Science to create a series called COVID-19 Science Update . This series, the first of its kind for a CDC emergency response, provides brief summaries of new COVID-19-related studies on many topics, including epidemiology, clinical treatment and management, laboratory science, and modeling. As of December 18, 2021, CDC has stopped production of the weekly COVID-19 Science Update.

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• The CDC Database of COVID-19 Research Articles is now a part of the WHO COVID-19 database .  Our new search results are now being sent to the WHO COVID-19 Database to make it easier for them to be searched, downloaded, and used by researchers worldwide.
• October 8 in Excel [XLS – 1 MB]
• October 7 in Excel [XLS – 1 MB]
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The following databases were searched from Dec. 2019-Oct. 9 2020 for articles related to COVID-19: Medline (Ovid and PubMed), PubMed Central, Embase, CAB Abstracts, Global Health, PsycInfo, Cochrane Library, Scopus, Academic Search Complete, Africa Wide Information, CINAHL, ProQuest Central, SciFinder, the Virtual Health Library, and LitCovid.  Selected grey literature sources were searched as well, including the WHO COVID-19 website, CDC COVID-19 website, Eurosurveillance, China CDC Weekly, Homeland Security Digital Library, ClinicalTrials.gov, bioRxiv (preprints), medRxiv (preprints), chemRxiv (preprints), and SSRN (preprints).

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Detailed search strategy for gathering COVID-19 articles, updated October 9, 2020 [PDF – 135 KB]

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• Open access
• Published: 26 June 2024

A health technology assessment of COVID-19 vaccination for Nigerian decision-makers: Identifying stakeholders and pathways to support evidence uptake

• Benjamin S. C. Uzochukwu 1 , 2 ,
• Chinyere Okeke   ORCID: orcid.org/0000-0002-2599-537X 1 , 2 ,
• Faisal Shuaib 3 ,
• Sergio Torres-Rueda 4 ,
• Anna Vassall 4 ,
• Mark Jit 5 , 6 ,
• Justice Nonvignon 7 ,
• Adaora C. Uzochukwu 8 &
• Francis Ruiz 4  

Health Research Policy and Systems volume  22 , Article number:  73 ( 2024 ) Cite this article

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Nigeria commenced rollout of vaccination for coronavirus disease 2019 (COVID-19) in March 2021 as part of the national public health response to the pandemic. Findings from appropriately contextualized cost–effectiveness analyses (CEA) as part of a wider process involving health technology assessment (HTA) approaches have been important in informing decision-making in this area. In this paper we outline the processes that were followed to identify COVID-19 vaccine stakeholders involved in the selection, approval, funding, procurement and rollout of vaccines in Nigeria, and describe the process routes we identified to support uptake of HTA-related information for evidence-informed policy in Nigeria.

Our approach to engaging with policy-makers and other stakeholders as part of an HTA of COVID vaccination in Nigeria consisted of three steps, namely: (i) informal discussions with key stakeholders; (ii) stakeholder mapping, analysis and engagement; and (iii) communication and dissemination strategies for the HTA-relevant evidence produced. The analysis of the stakeholder mapping uses the power/interest grid framework.

The informal discussion with key stakeholders generated six initial policy questions. Further discussions with policy-makers yielded three suitable policy questions for analysis: which COVID-19 vaccines should be bought; what is the optimal mode of delivery of these vaccines; and what are the cost and cost–effectiveness of vaccinating people highlighted in Nigeria’s phase 2 vaccine rollout prioritized by the government, especially the inclusion of those aged between 18 and 49 years. The stakeholder mapping exercise highlighted the range of organizations and groups within Nigeria that could use the information from this HTA to guide decision-making. These stakeholders included both public/government, private and international organizations The dissemination plan developed included disseminating the full HTA results to key stakeholders; production of policy briefs; and presentation at different national and international conferences and peer-reviewed publications.

Conclusions

HTA processes that involve stakeholder engagement will help ensure important policy questions are taken into account when designing any HTA including any underpinning evidence generation. Further guidance about stakeholder engagement throughout HTA is required, especially for those with low interest in vaccine procurement and use.

Peer Review reports

The first confirmed case of coronavirus disease 2019 (COVID-19) in Nigeria was recorded on 27 February 2020 [ 1 ]. During the first wave of COVID-19, the epicentres of infection were in Lagos, Kano and Abuja [ 2 ]. A sero-surveillance study conducted in October 2020 in three Nigerian states with 8000 individuals found the prevalence of severe acute respiratory syndrome (SARS-CoV-2) antibodies was 23% in Lagos and Enugu States, 19% in Nasarawa State and 9% in Gombe State [ 3 ]. The diversity of SARS-CoV-2 strains indicates multiple introductions of the virus into Nigeria from different parts of the world and adds to evidence of community transmission in different states of Nigeria [ 4 ]. As of 7 June 2023, 266,675 confirmed COVID-19 cases and 3155 related deaths have been reported to WHO [ 5 ].

Nigeria commenced rollout of vaccination for COVID-19 in March 2021 as part of the national public health response to fight the pandemic [ 6 ]. It was expected that mass vaccination would reduce the risk of infection and transmission. At the commencement of the vaccination programme, Nigeria set the ambitious target of vaccinating 40% of the population by December 2021 and 70% by December 2022. This was to be achieved through a four-phase rollout schedule starting with health/frontline workers and strategic leaders (Table  1 ).

Financing the cost of COVID-19 vaccination has proven difficult in low- and lower-middle-income countries, including Nigeria. In addition, a sudden increase in government spending coupled with a steep decline in fiscal revenue has caused an economic downturn and financing imbalances in Nigeria [ 7 , 8 ]. For the first 18 months of the pandemic, there was no significant discussion about the national purchase of COVID-19 vaccines; vaccines used in Nigeria were donated, with national authorities bearing the cost of logistics, training and distribution. However, the Johnson & Johnson COVID vaccine was purchased by the Government of Nigeria on the 11 August 2021 at $7.50 per dose, which is lower than its price of $10 per dose, through African Union’s African Vaccine Acquisition Trust (AVAT) [ 9 ]. Plans are in place to continue vaccinating Nigerian citizens and approval has been obtained from The World Bank Board of Directors for a $400 million credit to provide upfront financing for safe and effective COVID-19 vaccine acquisition and deployment within the country [ 7 ]; further discussions on vaccine purchases (and associated prices) will be necessary. Findings from evidence-informed health technology assessment (HTA)-type approaches will be important to inform decision-making in this area.

HTA is a framework for collating evidence on healthcare interventions as well as a decision-making framework to inform resource allocation decisions and increase the value of discretionary healthcare expenditures [ 10 , 11 ]. Cost–effectiveness evidence is key in HTA. Obtaining good value for money for COVID-19 vaccine procurement matters in Nigeria; in a highly resource-constrained setting, opportunity costs are high.

To ensure that evidence generated by the HTA process is taken up into policy, there is a need to involve key stakeholders in the conceptualization of the research (including model development) and the development of recommendations, as well as in communication and policy translation. Without stakeholder engagement, lack of awareness, understanding or confidence about economic models will hinder their use and impact [ 12 ]. Studies have also shown that adequate engagement of key stakeholders in evidence generation can lead to increased research uptake [ 13 , 14 , 15 , 16 ]. Stakeholder involvement can build political and social legitimacy for the evidence-to-policy process, which is particularly important in Nigeria, where the use of research findings by policy-makers and communities has traditionally been limited and challenging [ 17 ]. Inadequate communication between researchers and policy-makers, and a lack of involvement of policy-makers and the wider community in shaping research activities, has been observed [ 18 ].

In this paper we outline the processes followed to identify COVID-19 vaccine stakeholders involved in the selection, approval, funding, procurement and rollout of vaccines in Nigeria, and describe the process routes identified to support uptake of HTA-related information for evidence-informed policy in Nigeria. This work was part of a larger study that sought to explore the cost–effectiveness of COVID-19 vaccination in Nigeria, taking into account context-relevant policy questions [ 19 ]. The Nigerian government had already begun its phase 1 rollout of the COVID-19 vaccine when this work began (phase 1 focused on front-line health workers, etc.); our focus was on phase 2. The economic evaluation analysis we conducted broadly confirmed the “age group prioritization strategy of the Nigerian government (which focused on a 50+ cohort during phase 2 of the rollout) and different types of delivery made little difference to the results” [ 19 ].

The work was informed by relevant policy questions from Nigerian decision-makers. Indeed the Nigerian team assembled for this HTA included the involvement of relevant policy-makers in the project from its inception. For instance, represented in this project are members of the Ministerial Expert Advisory Committee on COVID-19 Health Sector Response and the Nigerian Academy of Science, as well as a health economist who serves as the personal assistant to the minister for health, and a member of the Nigerian Immunisation Technical Advisory Group (NGI-TAG). In addition, input into this work was also sought from the African Centre for Disease Control (CDC), and research outputs informed the research underpinning continental-level analyses and guidance. We aim to report on our experience of engaging with COVID-19 vaccine stakeholders in Nigeria. The work is expected to contribute to literature on linkages between policy-makers and research (especially HTA evidence), with COVID-19 specifically in mind, but more generally applicable to other disease areas. This work also provides insights that may be useful in other countries seeking to maximize stakeholder engagement and support evidence-informed policy.

Methodology

Our approach to engaging with policy-makers and other stakeholders as part of a cost–effectiveness analysis within the HTA process of COVID-19 vaccination in Nigeria was informed by experiences documented previously in Nigeria [ 16 ] and consisted of three steps: (i) informal discussions with key stakeholders; (ii) stakeholder mapping, analysis and engagement; and (iii) communication and dissemination strategies for the HTA-relevant evidence produced. We define a stakeholder as individuals, groups or organizations which have a direct interest in the topic under scrutiny and can potentially affect the goals or the performance of a sector, plan or policy [ 20 ].

Informal discussions with key stakeholders

The Federal Ministry of Health approached a team of researchers from the Health Policy Research Group of the College of Medicine, University of Nigeria Nsukka (and co-authors on this study), in December 2020, at the peak of the second wave of the COVID-19 pandemic, about the need to produce evidence on the relative cost–effectiveness of different vaccines for the control of COVID-19 in Nigeria. Several informal discussions were held with the Minister of Health’s office, the Nigerian Center for Disease Control (NCDC) and the National Primary Health Care Development Agency (NPHCDA) on the need for such evidence. These stakeholders stressed that such information could support them on investment decisions with respect to COVID-19 vaccines and the wider healthcare system as part of the ongoing response to the pandemic. This method to support engagement with stakeholders in Nigeria on evidence-informed policy-making was based on strategies (1 and 2) described and summarized in Fig.  1 [ 16 ].

Four evidence-informed policy-making strategies [ 21 ]. GRIPP, getting research into policy and practice

An informal consultative mechanism was used to reach policy developers and decision-makers (including policy-makers from the Minister of Health’s office, NCDC and NPHCDA), and key stakeholders related to COVID-19 vaccine selection, approval, funding, procurement and rollout in Nigeria. A decision problem formulation process was started, and the opinion of these stakeholders was sought as to what policy questions would guide their vaccine decision-making in the country. This took place over a 3-week period, with key policy questions fine-tuned by the research team to ensure they could be addressed with the available analytical tools and within the timeframe of this study. Further input was then sought from policy-makers and also from stakeholders within the Africa Centre for Disease Control and Prevention (Africa CDC), leading to further adjustments to the selected questions.

Stakeholder mapping, analysis and engagement

Stakeholder mapping.

The researchers identified an initial set of influential stakeholders on the basis of their in-depth knowledge of COVID-19 vaccine selection, approval, funding, procurement and rollout in Nigeria, including those who have formal bureaucratic and political authority to make relevant decisions on COVID-19 vaccination and those who have interest in the outcome of the decision. These stakeholders ( n  = 12 individuals) were comprised of a representative member from each of the following groups: the Presidential Steering Committee (PSC), Federal Ministry of Health (FMoH), NPHCDA, State Primary Health Care Agency/Board, NCDC, Nigeria Immunization Technical Advisory Group (NGI-TAG), legislators, Nigeria Medical Association (NMA), Development Partners, National Agency for Food and Drug Administration and Control (NAFDAC), Ministerial Expert Advisory Committee on COVID-19 Health Sector Response (MEACoC-HSR) and National COVID-19 Vaccine Introduction Technical Working Group.

The identification of a broad variety of pertinent stakeholders was made possible using a snowballing strategy. Initial informants were asked to name people and organizations that had a say in the COVID-19 vaccine selection, approval, funding, procurement and distribution. This technique made it possible to identify both the individuals frequently seen as significant, and those who may have been less well-known or influential but who may nevertheless have an impact on the development and use of vaccines. The strategy used was adapted from elsewhere [ 21 ].

The study team then narrowed down the stakeholders on the basis of relevance and role. This took place over 2 weeks. To support further identification of priority stakeholders to help maximize research impact, a categorization scheme was applied on the basis of a qualitative assessment of relative power and interest in the policy area [ 22 ]. Here, power is defined as the potential capacity to influence policy decisions, and the power judgment is based on an assessment of stakeholders’ resources [ 23 ]. Interest is defined as the degree to which stakeholders are likely to be affected by policy change. The degree of interest or concern stakeholders have about a policy will influence how the stakeholder’s resources, and how much of those resources, will be used in the policy debate [ 23 ]. The stakeholders were grouped into four categories depending on their interest and power in COVID-19 vaccine selection, approval, funding, procurement and rollout in Nigeria: (i) high power and high interest; (ii) high power and low interest; (iii) low power and high interest, and (iv) low power and low interest. This provided information on their relative influence and likely interest in the findings of the COVID vaccination cost–effectiveness analysis (CEA), allowing the authors to prioritize stakeholders who would need to be kept informed. In addition, the roles of the stakeholders were identified. The mapping was supported with document reviews.

Stakeholder analysis

Stakeholder analysis is the systematic identification, evaluation and prioritization of individuals or organizations who can influence or have an interest in a project or program. [ 24 ]. The approach can assist with the development of an effective stakeholder communication and engagement strategy and is a fundamental element of an organization’s stakeholder management plan. We used three key steps as set out elsewhere [ 23 ] to conduct the stakeholder analysis, namely:

Identifying the groups and individuals (the stakeholders) relevant to the policy issue of focus (in this case cost–effectiveness of COVID-19 vaccines);

Determining the current position (in terms of support or opposition) of each stakeholder on the issue;

Determining the relative power of each stakeholder over the issue.

To define the power/influence, in the stakeholder analysis, we relied on researchers’ knowledge of the stakeholder’s organizations and through informal discussions with other stakeholders.

Stakeholder engagement: crafting the policy questions

Input from Nigerian policy-makers (some of whom are listed in Table  2 ) was sought through informal emails and discussions, on the key policy questions that need to be addressed to support decision-making in Nigeria and in the Africa CDC at large, with regards to COVID-19 vaccine selection, approval, funding, procurement and rollout activities. These questions were shared with colleagues from the Health Economics Programme at the Africa CDC and the economics and modelling team from the London School of Hygiene & Tropical Medicine (LSHTM). This input was important in helping determine whether the policy questions could be addressed with the modelling tools available.

Communication and dissemination to support uptake of the HTA evidence

A team of Nigerian experts was established to collect evidence on relevant economic evaluations and HTA studies on vaccines and assess their actual use in decision-making processes. There was involvement of relevant policy-makers in the project from its inception. For instance, members of the MEACoC-HSR, the Nigerian Academy of Science, a health economist from the office of the Minister of Health and a member of the Nigerian, NGI-TAG, were key members of the project. This team continued discussions with the Minister of Health’s office, NCDC and NPHCDA on the study progress. As research partners in this study, a research link was established between the LSHTM-Nigeria research team and the Africa CDC; the latter also provided input into the policy and research questions identified for this study.

Stakeholders mapping, analysis and engagement

The stakeholder mapping exercise highlighted the range of organizations and groups within Nigeria that could use the information from the HTA to guide decision-making. It was anticipated that these organizations would benefit from the findings of the study, either in costing their programs or in the use of the evidence for policy and decision-making and as a tool for advocacy. The results may also offer useful data and opportunities for resource allocation, strengthening of the health system and knowledge translation, resulting in improved health outcomes and better-informed decision-making. The names, roles and responsibilities of the various stakeholders that were mapped are shown in Table  2 .

Figure  2 illustrates key stakeholders involved with the decision-making of COVID-19 vaccine procurement and their interaction with one another. They either make the decisions or are impacted by the decisions made. For example, the Presidential Steering Committee (PSC) reports directly to the President of Nigeria. The PSC interacts with the FMoH, which is responsible for developing vaccine policy for the country and ensuring implementation. The FMoH interacts with all the other agencies, as shown in Fig.  2 . The NPHCDA receives and coordinates the distribution of the vaccines until it gets to the end users and, with the FMoH, jointly decides on the types of vaccine to be procured and the quantity needed, as well as on issues linked to storage capacity. The NAFDAC regulates and licences potential vaccines prior to use. Figure  2 also shows other important actors, including the various technical working groups, development partners (DPs) and regional bodies.

Interaction of actors involved in decision-making on vaccine procurement

It is important to highlight that the NGI-TAG provides evidence-based recommendations to the NAFDAC, NCDC and NPHCDA. The Federal Ministry of Finance (FMoF) provides funds for the procurement, and the regional bodies and DPs liaise with the manufacturers for bulk purchase at reduced prices. The National Council on Health (NCH), professional health groups and healthcare providers provide feedback via various organizations to the FMoH. This feedback helps determine the type of vaccines to procure. Finally, stakeholders, such as academia, research forums and the media, support the production and dissemination of evidence for use by policy-makers, including adverse events from vaccines. The general population represent the end users, that is, the groups that will receive the procured vaccines.

The stakeholders in Fig.  2 were categorized using a power/interest grid framework [ 23 ], as shown in Fig.  3 .

Power/interest grid of COVID-19 vaccine selection, approval, funding, procurement and rollout in Nigeria

The resulting matrix (Fig.  3 ) identified key stakeholders who could assist with the prioritization of resources within the context of COVID-19 vaccination and as such provided a foundation for a communication and engagement plan. Thus, the stakeholders were categorized into four groups:

High power and high interest (upper right quadrant): These are the most important stakeholders and are mainly the decision-makers, having the biggest impact on the project’s success. They were considered a high priority for obtaining feedback on the HTA results as well as the conduct of the HTA.

High power and low interest (upper left quadrant): Because of their influence in Nigeria, we also prioritized these stakeholders given the power that they could wield, and we aimed to keep them abreast with the evidence despite their relatively low interest.

Low power and high interest (lower right quadrant): We aimed to keep these stakeholders informed of the evidence to maintain their high interest in the HTA.

Low power and low interest (lower left quadrant): This group was considered a low priority for communication and dissemination activities.

Development of research questions

Initially, a list of policy-relevant questions that could be considered in a CEA/HTA were drafted:

Which COVID-19 vaccines should be bought?

How much of each vaccine should be bought?

What is the maximum price to pay for each specific vaccine?

What is the best way to deliver vaccines (for example, fixed posts at health facilities, campaigns or targeted campaigns)?

Which enabling interventions can best support vaccination?

How much funding can and should be allocated to support uptake and address vaccine hesitancy, and to which groups (for example, young people, ethnic minorities, women, certain religions and those from socially deprived backgrounds)?

Taking into account the broad policy questions described above, the researchers and key stakeholders agreed that the focus for the de novo CEA within the HTA should be framed around three analytically feasible questions:

Which COVID-19 vaccines should be bought, and what is the maximum price to pay?

What is the best way to deliver the vaccines?

What are the cost and cost–effectiveness of vaccinating people aged 18–49 years?

These three policy-relevant questions were further expanded by the researchers through an interactive and consultative process into the context-specific decision problem, as set out in Table  3 . This was used as the basis for modelling the cost–effectiveness of the selected vaccines.

Table 3 shows the summary of the decision problems modelled in the study. The epidemiological model of virus transmission parametrized with Nigeria-specific data shown in Table  3 was combined with a costing model that incorporated local resource use assumptions and prices, both for vaccine delivery as well as costs associated with care and treatment of COVID-19. Scenarios of vaccination were compared with no vaccination [ 19 ].

Communication and dissemination to support the uptake of the HTA evidence

For the purpose of this HTA, the following outline dissemination plan was developed and used to support dissemination in an ongoing process (Table  4 ):

1. Final results (full HTA report) presented to the Minister of Health and PSC on COVID-19.

2. Production and distribution of policy briefs and blogs for stakeholders, particularly decision-makers to enable decisions to be taken on the basis of scientific evidence, and appropriate sustainable actions to be undertaken. We used this type of evidence format because some of the policy-makers might be non-specialized audiences but still need to make decisions about vaccine procurement.

3. Presentation at the National Council on Health meetings (the highest decision-making body on health).

4. Organizing policy dialogues with decision-makers in the FMoH, FMoF, NCDC, NPHCDA, NHIS, NGI-TAG and PSC. Policy dialogues will raise the profile of vaccine procurement and promote relationships between these stakeholders.

5. Co-production: preparation of peer-reviewed articles and blogs (as necessary) in collaboration with members of the team and policy-makers.

6. Presentation at the conference of the Association of Public Health Physicians of Nigeria at the annual scientific meeting of the West African College of Physicians, and other local conferences that will come up in the country.

Table 4 shows the dissemination of the results with the different messages that were shared with different stakeholders on the basis of the stakeholder analysis done. The stakeholders included academia, policy-makers from both the national and sub-national levels, and the Africa CDC. The results were well received by these stakeholders, and it is still ongoing.

In this study, we report on our experience of engaging with COVID-19 vaccine stakeholders in Nigeria involved in the selection, approval, funding, procurement and rollout of vaccines and describe the process routes to support policy uptake of HTA-related findings. Our study contributes to the literature linking policy-makers to research (especially cost–effectiveness evidence) with COVID-19 specifically in mind but is also applicable to other disease areas. This work could help inform the development of an HTA mechanism in Nigeria, which is currently absent. In addition, it also provides learning for other countries on how to maximize stakeholder engagement and garner support for evidence-informed policy.

The importance of decision-makers comprehending HTA requirements, uses and scope as well as the optimal approaches to incorporating HTA components into the design of decision-making mechanisms has been emphasized by a number of authors. [ 25 ]. HTA is not a narrow technocratic exercise, and as such it is important to also identify or develop methods of wider citizen and stakeholder involvement that could be considered best practice internationally. For example, the evidence-informed deliberative processes (EDPs) framework [ 26 ]), though not used in our research due to limited resources and time, can support the decision-making process in HTA bodies and, thus, contribute to the legitimacy of recommendations and decisions. How any EDP process is implemented as part of HTA institutionalization in a particular setting would likely be shaped by local conditions and preferences.

Although stakeholder involvement is key to improving the HTA process, the form and timing of such improvements must be adapted to local contexts and data. In Nigeria, the perceived availability and accessibility of suitable local data to support HTA varies widely but is mostly considered inadequate and limited [ 27 ]. In our study, it was necessary to ensure that the cost–effectiveness analyses were consistent with the epidemiological context and that stakeholders were involved in (at least) initial discussions around study design to enhance credibility and engagement [ 28 ]. Inadequate understanding of the links between HTA-related outputs and decision-making can lead to key stakeholder exclusion and loss of policy relevance [ 29 ]. To maximize the relevance and timeliness of COVID-19 vaccine HTAs (or indeed HTAs for any topic), it is important to first identify the stakeholders and processes for decision-making on technology procurement [ 30 ].

Given the large number of stakeholders in COVID-19 vaccine procurement and use, it was necessary to identify priority actors to guide the dissemination of research findings. As noted by some authors, this process should not be considered as a one-off activity, but rather an ongoing pattern of engagement, to allow for changes in the stakeholders’ positioning [ 24 ]. Overall, the power/interest matrix is a useful tool for stakeholder analysis since it offers a structured method for comprehending stakeholder dynamics, setting priorities for engagement initiatives, and successfully managing relationships. However, other criteria could also be considered when grouping stakeholders, such as influence, legitimacy, expertise, attitude and resources, which could provide a more nuanced understanding of stakeholders and help to inform engagement strategies that are tailored to their needs and concerns [ 31 ].

The experience set out in the present study demonstrates the importance of identifying key stakeholders early on as part of any evidence-driven activity and ensuring an ongoing degree of engagement to enhance the value of the research findings. Despite the depth of the stakeholder mapping, issues with power dynamics and representation of stakeholder interests are regularly encountered when trying to acquire a true reflection of the balance of all stakeholders. [ 32 , 33 ]. Ensuring representation of stakeholder interests, power balance and transparency of decision-making are critical in COVID-19 vaccine procurement and use in Nigeria. However, it is difficult to say how this played out in our study, as there are multiple stakeholders involved, and the situation is constantly evolving. We found it easier to engage some stakeholder groups such as government workers and academia, than those in the private sector such as the CACOVID in this study. Even though efforts have been made to involve stakeholders and ensure transparency, there is always room for improvement, such as inclusive stakeholder representation, early and ongoing engagement, establishing mechanisms for two-way communication, allowing stakeholders to provide feedback and making decisions that are informed by the input of all stakeholders. Ongoing communication and engagement with stakeholders are crucial to addressing their concerns and ensuring accountability. Researchers need concrete information on potential stakeholder groups affected by COVID-19 immunization to be more inclusive. Nevertheless, structured guidance on how to maximize stakeholder involvement in HTA is needed.

Manufacturers of vaccines were not included as a stakeholder group in this work for two reasons. First, we focused on an independent assessment of the cost–effectiveness of COVID-19 vaccination that could be used by the FMoH and others in a wider procurement process that could involve discussions with the industry. Secondly, we deliberately did not model specific products, describing our interventions instead as viral vectors or mRNA vaccines. Modelling of specific products would have certainly lengthened the assessment of vaccine effectiveness and introduced industry consultation steps that would have required active approval and leadership from relevant Nigerian authorities.

Identifying a long list of policy-relevant questions informed by discussion with Nigerian decision-makers was seen as necessary to enhance uptake and support meeting expectations set out in early discussions. In addition, our findings are also anticipated to assist Africa CDC in their planning around the role of cost–effectiveness evidence in vaccine rollouts generally, and the development of HTA-informed decision-making processes to inform resource allocation decisions.

Policy-makers in this study highlighted the importance of supply chain consequences, especially with cold chain, and storage when decisions are made on vaccine selection. It is well known that investing in vaccinations to prevent COVID-19 infections might have a significant return on investment. [ 34 ]. However, there could be very significant budgetary or resource consequences for the government and other payers from very rapid vaccine rollouts, especially where there are important cold chain requirements. Formal cost–effectiveness analysis combined with an assessment of budget impact features typical of the HTA process are clearly needed to support appropriate vaccine selection in a given context. Information regarding the highest price charged for each COVID vaccine choice was also requested by policy-makers.

Policy-makers were interested in knowing what vaccines, and critically at what price, should be purchased. However, in addition, policy-makers were concerned about the costs of delivery to inform the best way to deliver each of the vaccines. The aim here was to support policy-makers in deciding which method provides more cost–effective coverage, considering the high level of hesitancy observed in the uptake of the COVID vaccine [ 35 , 36 , 37 ].

The policy question regarding the cost and cost–effectiveness of immunizing those aged 18 to 49 years with or without underlying diseases was significant in guiding government decisions on whether to implement this prioritization approach. It is especially important to be clear about the decision problem and the evidence-to-policy process from the outset in urgent or high-stakes situations such as pandemics to ensure that a range of information is taken into account and avoid misunderstandings or delays.

It is pertinent to note that, prior to the delivery of the cost–effectiveness study carried out in response to policy-maker requests, the primary choices about vaccine deployment had been made in Nigeria. However, the results were crucial in reaffirming the key choices made regarding age prioritization and delivery strategies and in giving a framework for how comparable issues can be dealt with in the future.

As shown in our study, a strategy for communication and dissemination should be informed by a stakeholder mapping exercise. Arguably the more important a stakeholder is (in terms of power and interest for example), the more important it is to establish an effective means of communication with that stakeholder. Timeliness is also an important consideration, and it is a challenge for HTA systems everywhere. Findings need to be delivered quickly (especially in pandemic contexts) and in a style that is clear and useful to the target group. Consequently, policy and decision-makers must be included in the study process. Additionally, it is important to share plain-language research summaries through a variety of platforms, such as social media and in-person meetings between researchers and end users [ 38 , 39 ].

Aside from the production of a detailed full HTA report on COVID-19 vaccination in Nigeria, other dissemination materials were produced and disseminated by the study team, including a policy brief [ 40 ], blogs [ 41 , 42 ], conference presentations and a peer-reviewed publication [ 19 ]. These products were tailored to the needs of the various stakeholders and delivered at different time points in the study.

We found that modelling results can only be effective in shaping policy when they are pertinent to the most important policy-based decision problems and are effectively communicated. However, to prepare the results for dissemination to policy-makers, some authors have suggested essential items that modellers should disclose before making any policy suggestions such as models’ objectives, methods, assumptions, data sources and fitness-for-purpose in context, and whether they actively involved decision-makers and policy-makers to determine their needs.

The results of this study could have significant implications for the development of policies and the improvement of public health in Nigeria, especially in the context of managing future pandemics. The study’s primary objective of determining the optimal COVID-19 vaccines for procurement holds significant importance for the Nigerian government. To optimize resource allocation and ensure the population receives the most effective protection against the virus, it is important to understand the most relevant vaccinations based on variables such as efficacy, safety and cost–effectiveness, given the wide range of alternatives available. This has been noted by Santoli et al., who noted that economic evaluation data for mass vaccination is crucial for decision-makers to make evidence-based, value-based decisions to ensure equitable access and reduce the global COVID-19 burden [ 43 ].

The stakeholder mapping exercise done during the study emphasizes the significance of engaging a diverse array of organizations and people in decision-making processes. Incorporating the participation of public/government, private and international organizations guarantees the inclusion of a wide range of viewpoints, hence enhancing the probability of formulating policies and plans that are pertinent, agreeable and efficient across different sectors of society. This has been echoed in a study that addresses the under-researched issue of stakeholder identification and engagement in problem-structuring interventions [ 44 ].

The devised dissemination plan for the study, encompassing the disclosure of comprehensive HTA outcomes, the creation of concise policy briefs and the delivery of presentations at both national and international conferences, is crucial for effectively converting research findings into implementable policies and practices. The study’s wide dissemination of findings can have a significant impact on decision-making processes at several levels and facilitate evidence-based policy formulation not only in Nigeria but also in other regions. The study highlights the significance of involving stakeholders in HTA procedures to guarantee the examination of pertinent policy inquiries and the production of supporting evidence. Offering advice on how to engage stakeholders effectively, especially those who are not very interested in vaccine procurement and usage, will improve the inclusivity and efficacy of future HTA programmes. This, in turn, will strengthen health systems and lead to better public health outcomes. Uzochukwu et al. (2020) noted that stakeholder participation in identifying HTA topics and conducting relevant research will enhance the use of HTA evidence produced for decision-making [ 27 ].

In summary, the study’s results can be used to shape policy-making and public health practices in Nigeria. This includes making informed decisions about COVID-19 vaccine procurement, delivery and cost–effectiveness. Additionally, the study encourages stakeholder involvement and evidence-based decision-making in future health technology assessments. The importance of the research, especially in managing future pandemics in the country cannot be over-stressed.

As this paper set out to to identify COVID-19 vaccine stakeholders involved in the selection, approval, funding, procurement and rollout of vaccines in Nigeria, and describe the process routes to support uptake of HTA-related information for evidence-informed policy in Nigeria, and given the study’s findings and the policy problems that have been identified, we provide some practical recommendations and consequences for policy and practice:

Utilize health technology assessments (HTAs) and cost–effectiveness studies in collaboration with key stakeholders to inform decisions regarding vaccination acquisition and prioritization in the country.

Policy-makers should evaluate the economic and social ramifications of vaccination techniques, guaranteeing that policies promote both public health and economic revitalization.

Facilitate coordination among public/government, commercial and international organizations to guarantee a synchronized approach to vaccine procurement, delivery and monitoring. It is therefore essential to involve stakeholders throughout the decision-making process to improve openness, establish agreement and resolve issues around vaccine acquisition and utilization and secure their buy-in and enhance getting research into policy practice.

Develop and execute a comprehensive strategy to effectively communicate the HTA findings to important stakeholders in a prompt and easily understandable way. This entails generating policy briefings that succinctly outline significant discoveries, delivering presentations of findings at both domestic and global conferences and publishing articles that have undergone peer review to promote the dissemination of knowledge and enable well-informed decision-making.

Deliver training and guidance on efficient methods of engaging stakeholders, specifically targeting individuals with limited interest in vaccine procurement and utilization. Empower stakeholders with the necessary expertise and resources to actively engage in HTA processes, promoting a cooperative and all-encompassing approach to making decisions on the basis of evidence.

Finally, to enhance the efficacy of COVID-19 vaccination endeavours in Nigeria, officials might apply these suggestions to optimize resource allocation and fortify the country’s entire response to the pandemic. Additionally, fostering stakeholder engagement and knowledge sharing can build trust, promote accountability and facilitate sustainable health system improvements beyond the current crisis.

Limitations of the study

The sampling of stakeholders was not a nationally representative sample. The analysis might not have a complete picture of the many perspectives and interests across various backgrounds and sectors in Nigeria. As a result, there may be an incomplete picture of the stakeholders involved in COVID-19 vaccine selection, approval, funding, procurement and rollout in Nigeria and their possible impact on the process, which could lead to resistance or mistrust from stakeholders who believe their opinions are not adequately represented. However, our sample of policy-makers and stakeholders was not intended to be representative of the whole country, but rather based on those with in-depth knowledge of COVID-19 vaccine selection, approval, funding, procurement and rollout in Nigeria. Also, to mitigate this limitation, the study provided a clear rationale for the selection criteria of policy-makers and stakeholders, that is, those who were involved in vaccine selection, etc. Also, the qualitative insights gained from the interviewed stakeholders supported our approach.

The roles of the media and community members in the HTA process were not assessed. It is possible that important information about public opinion and expectations was overlooked by not consulting the media. Without involving the community, important clues about their issues can go unnoticed. Engaging the community and the media encourages cooperation and stakeholder buy-in. In general, the absence of the media and the community from the stakeholder analysis may restrict the scope and depth of the stakeholder understanding, and may hinder the decision-making process and buy-in from important stakeholders. This will form a basis for a further study.

There was no mention and analysis specifically done for those living in difficult terrains, security-compromised areas of Nigeria and those living with physical, intellectual and developmental disabilities. These are important groups that we were unable to explore in the present work because of time and data constraints. Extensive additional analytic work would be needed (including primary data collection) to gather the evidence necessary to parametrize a model to consider the cost–effectiveness of vaccination for these different groups and any support programmes that may be needed (that is, to improve access). This was not considered feasible within the time frame of the HTA. However, authors can take this gap and explore filling it in future studies.

HTA provides an evidence-informed framework for guiding decisions on the adoption and rollout of health interventions. An important aspect of HTA is ensuring key stakeholder engagement in the selection of policy choices subject to any analysis. Based on the authors’ experience with evaluating COVID-19 vaccination in Nigeria, including the conduct of a locally relevant cost–effectiveness analysis, stakeholders’ experience and knowledge can be used to pinpoint important policy issues, which in turn helps determine the emphasis of any HTA and ensures its usefulness for policy. Engaging stakeholders throughout the process from formulating policy questions and helping shape the study design, to the final dissemination of results, is a necessary part of an evidence to policy framework such as HTA.

HTA serves as a link between those responsible for developing policy and those who can provide the evidence needed to inform those policy choices. It is not a purely technical exercise limited to the delivery of cost–effectiveness analyses. Stakeholder engagement in HTA approaches will guarantee that significant policy concerns are taken into account when identifying and generating the required evidence. To inform decision-making processes and support any future pandemic response, in Nigeria and sub-Saharan Africa, researchers in Nigeria and Africa and policy-makers may need more direction on stakeholder participation approaches when utilizing HTA-based approaches.

Availability of data and materials

Not applicable.

Abbreviations

Africa Centre for Disease Control and Prevention

Coalition against COVID-19

Cost–effectiveness analysis

Federal Ministry of Health

• Health technology assessment

Ministerial Expert Advisory Committee on COVID-19 Health Sector Response

National Agency for Food and Drug Administration and Control

Nigerian Centre for Disease Control

Nigerian Immunisation Technical Advisory Group

National Primary Health Care Development Agency

National Vaccine Deployment Plan

Technical Working Group

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Acknowledgements

The authors acknowledge the Nigerian Federal Ministry of Health and the National Primary Health Care Development Agency for their input and support of this work and Africa CDC for their input into this project. The authors wish to also acknowledge the support of the management of the University of Nigeria Nsukka, Enugu campus for providing the enabling environment to undertake this research.

This work received funding support from the Bill and Melinda Gates Foundation (OPP1202541) through the International Decision Support Initiative (iDSI).

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Benjamin S. C. Uzochukwu & Chinyere Okeke

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National Primary Health Care Development Agency Abuja, Abuja, Nigeria

Faisal Shuaib

Department of Global Health & Development, Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK

Sergio Torres-Rueda, Anna Vassall & Francis Ruiz

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom

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Health Economics Programme, Africa Center for Disease Control and Prevention, Addis Ababa, Ethiopia

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F.R., B.U., C.P., M.J. and A.V. conceptualized the study, B.U., C.O., F.R., S.T., A.U., A.V. and M.J. carried out the study and the analysis. B.U. wrote the first draft of the manuscript. All authors revised and agreed on the final draft. All authors read and approved the final manuscript.

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Correspondence to Chinyere Okeke .

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Uzochukwu, B.S.C., Okeke, C., Shuaib, F. et al. A health technology assessment of COVID-19 vaccination for Nigerian decision-makers: Identifying stakeholders and pathways to support evidence uptake. Health Res Policy Sys 22 , 73 (2024). https://doi.org/10.1186/s12961-024-01158-y

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An Introduction to COVID-19

Simon james fong.

4 Department of Computer and Information Science, University of Macau, Taipa, Macau, China

Nilanjan Dey

5 Department of Information Technology, Techno International New Town, Kolkata, West Bengal India

Jyotismita Chaki

6 School of Information Technology and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu India

A novel coronavirus (CoV) named ‘2019-nCoV’ or ‘2019 novel coronavirus’ or ‘COVID-19’ by the World Health Organization (WHO) is in charge of the current outbreak of pneumonia that began at the beginning of December 2019 near in Wuhan City, Hubei Province, China [1–4]. COVID-19 is a pathogenic virus. From the phylogenetic analysis carried out with obtainable full genome sequences, bats occur to be the COVID-19 virus reservoir, but the intermediate host(s) has not been detected till now.

A Brief History of the Coronavirus Outbreak

A novel coronavirus (CoV) named ‘2019-nCoV’ or ‘2019 novel coronavirus’ or ‘COVID-19’ by the World Health Organization (WHO) is in charge of the current outbreak of pneumonia that began at the beginning of December 2019 near in Wuhan City, Hubei Province, China [ 1 – 4 ]. COVID-19 is a pathogenic virus. From the phylogenetic analysis carried out with obtainable full genome sequences, bats occur to be the COVID-19 virus reservoir, but the intermediate host(s) has not been detected till now. Though three major areas of work already are ongoing in China to advise our awareness of the pathogenic origin of the outbreak. These include early inquiries of cases with symptoms occurring near in Wuhan during December 2019, ecological sampling from the Huanan Wholesale Seafood Market as well as other area markets, and the collection of detailed reports of the point of origin and type of wildlife species marketed on the Huanan market and the destination of those animals after the market has been closed [ 5 – 8 ].

Coronaviruses mostly cause gastrointestinal and respiratory tract infections and are inherently categorized into four major types: Gammacoronavirus, Deltacoronavirus, Betacoronavirus and Alphacoronavirus [ 9 – 11 ]. The first two types mainly infect birds, while the last two mostly infect mammals. Six types of human CoVs have been formally recognized. These comprise HCoVHKU1, HCoV-OC43, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) which is the type of the Betacoronavirus, HCoV229E and HCoV-NL63, which are the member of the Alphacoronavirus. Coronaviruses did not draw global concern until the 2003 SARS pandemic [ 12 – 14 ], preceded by the 2012 MERS [ 15 – 17 ] and most recently by the COVID-19 outbreaks. SARS-CoV and MERS-CoV are known to be extremely pathogenic and spread from bats to palm civets or dromedary camels and eventually to humans.

COVID-19 is spread by dust particles and fomites while close unsafe touch between the infector and the infected individual. Airborne distribution has not been recorded for COVID-19 and is not known to be a significant transmission engine based on empirical evidence; although it can be imagined if such aerosol-generating practices are carried out in medical facilities. Faecal spreading has been seen in certain patients, and the active virus has been reported in a small number of clinical studies [ 18 – 20 ]. Furthermore, the faecal-oral route does not seem to be a COVID-19 transmission engine; its function and relevance for COVID-19 need to be identified.

For about 18,738,58 laboratory-confirmed cases recorded as of 2nd week of April 2020, the maximum number of cases (77.8%) was between 30 and 69 years of age. Among the recorded cases, 21.6% are farmers or employees by profession, 51.1% are male and 77.0% are Hubei.

However, there are already many concerns regarding the latest coronavirus. Although it seems to be transferred to humans by animals, it is important to recognize individual animals and other sources, the path of transmission, the incubation cycle, and the features of the susceptible community and the survival rate. Nonetheless, very little clinical knowledge on COVID-19 disease is currently accessible and details on age span, the animal origin of the virus, incubation time, outbreak curve, viral spectroscopy, dissemination pathogenesis, autopsy observations, and any clinical responses to antivirals are lacking among the serious cases.

How Different and Deadly COVID-19 is Compared to Plagues in History

COVID-19 has reached to more than 150 nations, including China, and has caused WHO to call the disease a worldwide pandemic. By the time of 2nd week of April 2020, this COVID-19 cases exceeded 18,738,58, although more than 1,160,45 deaths were recorded worldwide and United States of America became the global epicentre of coronavirus. More than one-third of the COVID-19 instances are outside of China. Past pandemics that have existed in the past decade or so, like bird flu, swine flu, and SARS, it is hard to find out the comparison between those pandemics and this coronavirus. Following is a guide to compare coronavirus with such diseases and recent pandemics that have reformed the world community.

Coronavirus Versus Seasonal Influenza

Influenza, or seasonal flu, occurs globally every year–usually between December and February. It is impossible to determine the number of reports per year because it is not a reportable infection (so no need to be recorded to municipality), so often patients with minor symptoms do not go to a physician. Recent figures placed the Rate of Case Fatality at 0.1% [ 21 – 23 ].

There are approximately 3–5 million reports of serious influenza a year, and about 250,000–500,000 deaths globally. In most developed nations, the majority of deaths arise in persons over 65 years of age. Moreover, it is unsafe for pregnant mothers, children under 59 months of age and individuals with serious illnesses.

The annual vaccination eliminates infection and severe risks in most developing countries but is nevertheless a recognized yet uncomfortable aspect of the season.

In contrast to the seasonal influenza, coronavirus is not so common, has led to fewer cases till now, has a higher rate of case fatality and has no antidote.

Coronavirus Versus Bird Flu (H5N1 and H7N9)

Several cases of bird flu have existed over the years, with the most severe in 2013 and 2016. This is usually from two separate strains—H5N1 and H7N9 [ 24 – 26 ].

The H7N9 outbreak in 2016 accounted for one-third of all confirmed human cases but remained confined relative to both coronavirus and other pandemics/outbreak cases. After the first outbreak, about 1,233 laboratory-confirmed reports of bird flu have occurred. The disease has a Rate of Case Fatality of 20–40%.

Although the percentage is very high, the blowout from individual to individual is restricted, which, in effect, has minimized the number of related deaths. It is also impossible to monitor as birds do not necessarily expire from sickness.

In contrast to the bird flu, coronavirus becomes more common, travels more quickly through human to human interaction, has an inferior cardiothoracic ratio, resulting in further total fatalities and spread from the initial source.

Coronavirus Versus Ebola Epidemic

The Ebola epidemic of 2013 was primarily centred in 10 nations, including Sierra Leone, Guinea and Liberia have the greatest effects, but the extremely high Case Fatality Rate of 40% has created this as a significant problem for health professionals nationwide [ 27 – 29 ].

Around 2013 and 2016, there were about 28,646 suspicious incidents and about 11,323 fatalities, although these are expected to be overlooked. Those who survived from the original epidemic may still become sick months or even years later, because the infection may stay inactive for prolonged periods. Thankfully, a vaccination was launched in December 2016 and is perceived to be effective.

In contrast to the Ebola, coronavirus is more common globally, has caused in fewer fatalities, has a lesser case fatality rate, has no reported problems during treatment and after recovery, does not have an appropriate vaccination.

Coronavirus Versus Camel Flu (MERS)

Camel flu is a misnomer–though camels have MERS antibodies and may have been included in the transmission of the disease; it was originally transmitted to humans through bats [ 30 – 32 ]. Like Ebola, it infected only a limited number of nations, i.e. about 27, but about 858 fatalities from about 2,494 laboratory-confirmed reports suggested that it was a significant threat if no steps were taken in place to control it.

In contrast to the camel flu, coronavirus is more common globally, has occurred more fatalities, has a lesser case fatality rate, and spreads more easily among humans.

Coronavirus Versus Swine Flu (H1N1)

Swine flu is the same form of influenza that wiped 1.7% of the world population in 1918. This was deemed a pandemic again in June 2009 an approximately-21% of the global population infected by this [ 33 – 35 ].

Thankfully, the case fatality rate is substantially lower than in the last pandemic, with 0.1%–0.5% of events ending in death. About 18,500 of these fatalities have been laboratory-confirmed, but statistics range as high as 151,700–575,400 worldwide. 50–80% of severe occurrences have been reported in individuals with chronic illnesses like asthma, obesity, cardiovascular diseases and diabetes.

In contrast to the swine flu, coronavirus is not so common, has caused fewer fatalities, has more case fatality rate, has a longer growth time and less impact on young people.

Coronavirus Versus Severe Acute Respiratory Syndrome (SARS)

SARS was discovered in 2003 as it spread from bats to humans resulted in about 774 fatalities. By May there were eventually about 8,100 reports across 17 countries, with a 15% case fatality rate. The number is estimated to be closer to 9.6% as confirmed cases are counted, with 0.9% cardiothoracic ratio for people aged 20–29, rising to 28% for people aged 70–79. Similar to coronavirus, SARS had bad results for males than females in all age categories [ 36 – 38 ].

Coronavirus is more common relative to SARS, which ended in more overall fatalities, lower case fatality rate, the even higher case fatality rate in older ages, and poorer results for males.

Coronavirus Versus Hong Kong Flu (H3N2)

The Hong Kong flu pandemic erupted on 13 July 1968, with 1–4 million deaths globally by 1969. It was one of the greatest flu pandemics of the twentieth century, but thankfully the case fatality rate was smaller than the epidemic of 1918, resulting in fewer fatalities overall. That may have been attributed to the fact that citizens had generated immunity owing to a previous epidemic in 1957 and to better medical treatment [ 39 ].

In contrast to the Hong Kong flu, coronavirus is not so common, has caused in fewer fatalities and has a higher case fatality rate.

Coronavirus Versus Spanish Flu (H1N1)

The 1918 Spanish flu pandemic was one of the greatest occurrences of recorded history. During the first year of the pandemic, lifespan in the US dropped by 12 years, with more civilians killed than HIV/AIDS in 24 h [ 40 – 42 ].

Regardless of the name, the epidemic did not necessarily arise in Spain; wartime censors in Germany, the United States, the United Kingdom and France blocked news of the disease, but Spain did not, creating the misleading perception that more cases and fatalities had occurred relative to its neighbours

This strain of H1N1 eventually affected more than 500 million men, or 27% of the world’s population at the moment, and had deaths of between 40 and 50 million. At the end of 1920, 1.7% of the world’s people had expired of this illness, including an exceptionally high death rate for young adults aged between 20 and 40 years.

In contrast to the Spanish flu, coronavirus is not so common, has caused in fewer fatalities, has a higher case fatality rate, is more harmful to older ages and is less risky for individuals aged 20–40 years.

Coronavirus Versus Common Cold (Typically Rhinovirus)

Common cold is the most common illness impacting people—Typically, a person suffers from 2–3 colds each year and the average kid will catch 6–8 during the similar time span. Although there are more than 200 cold-associated virus types, infections are uncommon and fatalities are very rare and typically arise mainly in extremely old, extremely young or immunosuppressed cases [ 43 , 44 ].

In contrast to the common cold, coronavirus is not so prevalent, causes more fatalities, has more case fatality rate, is less infectious and is less likely to impact small children.

Reviews of Online Portals and Social Media for Epidemic Information Dissemination

As COVID-19 started to propagate across the globe, the outbreak contributed to a significant change in the broad technology platforms. Where they once declined to engage in the affairs of their systems, except though the possible danger to public safety became obvious, the advent of a novel coronavirus placed them in a different interventionist way of thought. Big tech firms and social media are taking concrete steps to guide users to relevant, credible details on the virus [ 45 – 48 ]. And some of the measures they’re doing proactively. Below are a few of them.

Facebook started adding a box in the news feed that led users to the Centers for Disease Control website regarding COVID-19. It reflects a significant departure from the company’s normal strategy of placing items in the News Feed. The purpose of the update, after all, is personalization—Facebook tries to give the posts you’re going to care about, whether it is because you’re connected with a person or like a post. In the virus package, Facebook has placed a remarkable algorithmic thumb on the scale, potentially pushing millions of people to accurate, authenticated knowledge from a reputable source.

Similar initiatives have been adopted by Twitter. Searching for COVID-19 will carry you to a page highlighting the latest reports from public health groups and credible national news outlets. The search also allows for common misspellings. Twitter has stated that although Russian-style initiatives to cause discontent by large-scale intelligence operations have not yet been observed, a zero-tolerance approach to network exploitation and all other attempts to exploit their service at this crucial juncture will be expected. The problem has the attention of the organization. It also offers promotional support to public service agencies and other non-profit groups.

Google has made a step in making it better for those who choose to operate or research from home, offering specialized streaming services to all paying G Suite customers. Google also confirmed that free access to ‘advanced’ Hangouts Meet apps will be rolled out to both G Suite and G Suite for Education clients worldwide through 1st July. It ensures that companies can hold meetings of up to 250 people, broadcast live to up to about 100,000 users within a single network, and archive and export meetings to Google Drive. Usually, Google pays an additional $13 per person per month for these services in comparison to G Suite’s ‘enterprise’ membership, which adds up to a total of about $25 per client each month.

Microsoft took a similar move, introducing the software ‘Chat Device’ to help public health and protection in the coronavirus epidemic, which enables collaborative collaboration via video and text messaging. There’s an aspect of self-interest in this. Tech firms are offering out their goods free of charge during periods of emergency for the same purpose as newspapers are reducing their paywalls: it’s nice to draw more paying consumers.

Pinterest, which has introduced much of the anti-misinformation strategies that Facebook and Twitter are already embracing, is now restricting the search results for ‘coronavirus’, ‘COVID-19’ and similar words for ‘internationally recognized health organizations’.

Google-owned YouTube, traditionally the most conspiratorial website, has recently introduced a connection to the World Health Organization virus epidemic page to the top of the search results. In the early days of the epidemic, BuzzFeed found famous coronavirus conspiratorial videos on YouTube—especially in India, where one ‘explain’ with a false interpretation of the sources of the disease racketeered 13 million views before YouTube deleted it. Yet in the United States, conspiratorial posts regarding the illness have failed to gain only 1 million views.

That’s not to suggest that misinformation doesn’t propagate on digital platforms—just as it travels through the broader Internet, even though interaction with friends and relatives. When there’s a site that appears to be under-performing in the global epidemic, it’s Facebook-owned WhatsApp, where the Washington Post reported ‘a torrent of disinformation’ in places like Nigeria, Indonesia, Peru, Pakistan and Ireland. Given the encrypted existence of the app, it is difficult to measure the severity of the problem. Misinformation is also spread in WhatsApp communities, where participation is restricted to about 250 individuals. Knowledge of one category may be readily exchanged with another; however, there is a considerable amount of complexity of rotating several groups to peddle affected healing remedies or propagate false rumours.

Preventative Measures and Policies Enforced by the World Health Organization (WHO) and Different Countries

Coronavirus is already an ongoing epidemic, so it is necessary to take precautions to minimize both the risk of being sick and the transmission of the disease.

WHO Advice [ 49 ]

• Wash hands regularly with alcohol-based hand wash or soap and water.
• Preserve contact space (at least 1 m/3 feet between you and someone who sneezes or coughs).
• Don’t touch your nose, head and ears.
• Cover your nose and mouth as you sneeze or cough, preferably with your bent elbow or tissue.
• Try to find early medical attention if you have fatigue, cough and trouble breathing.
• Take preventive precautions if you are in or have recently go to places where coronavirus spreads.

The first person believed to have become sick because of the latest virus was near in Wuhan on 1 December 2019. A formal warning of the epidemic was released on 31 December. The World Health Organization was informed of the epidemic on the same day. Through 7 January, the Chinese Government addressed the avoidance and regulation of COVID-19. A curfew was declared on 23 January to prohibit flying in and out of Wuhan. Private usage of cars has been banned in the region. Chinese New Year (25 January) festivities have been cancelled in many locations [ 50 ].

On 26 January, the Communist Party and the Government adopted more steps to contain the COVID-19 epidemic, including safety warnings for travellers and improvements to national holidays. The leading party has agreed to prolong the Spring Festival holiday to control the outbreak. Universities and schools across the world have already been locked down. Many steps have been taken by the Hong Kong and Macau governments, in particular concerning schools and colleges. Remote job initiatives have been placed in effect in many regions of China. Several immigration limits have been enforced.

Certain counties and cities outside Hubei also implemented travel limits. Public transit has been changed and museums in China have been partially removed. Some experts challenged the quality of the number of cases announced by the Chinese Government, which constantly modified the way coronavirus cases were recorded.

Italy, a member state of the European Union and a popular tourist attraction, entered the list of coronavirus-affected nations on 30 January, when two positive cases in COVID-19 were identified among Chinese tourists. Italy has the largest number of coronavirus infections both in Europe and outside of China [ 51 ].

Infections, originally limited to northern Italy, gradually spread to all other areas. Many other nations in Asia, Europe and the Americas have tracked their local cases to Italy. Several Italian travellers were even infected with coronavirus-positive in foreign nations.

Late in Italy, the most impacted coronavirus cities and counties are Lombardia, accompanied by Veneto, Emilia-Romagna, Marche and Piedmonte. Milan, the second most populated city in Italy, is situated in Lombardy. Other regions in Italy with coronavirus comprised Campania, Toscana, Liguria, Lazio, Sicilia, Friuli Venezia Giulia, Umbria, Puglia, Trento, Abruzzo, Calabria, Molise, Valle d’Aosta, Sardegna, Bolzano and Basilicata.

Italy ranks 19th of the top 30 nations getting high-risk coronavirus airline passengers in China, as per WorldPop’s provisional study of the spread of COVID-19.

The Italian State has taken steps like the inspection and termination of large cultural activities during the early days of the coronavirus epidemic and has gradually declared the closing of educational establishments and airport hygiene/disinfection initiatives.

The Italian National Institute of Health suggested social distancing and agreed that the broader community of the country’s elderly is a problem. In the meantime, several other nations, including the US, have recommended that travel to Italy should be avoided temporarily, unless necessary.

The Italian government has declared the closing (quarantine) of the impacted areas in the northern region of the nation so as not to spread to the rest of the world. Italy has declared the immediate suspension of all to-and-fro air travel with China following coronavirus discovery by a Chinese tourist to Italy. Italian airlines, like Ryan Air, have begun introducing protective steps and have begun calling for the declaration forms to be submitted by passengers flying to Poland, Slovakia and Lithuania.

The Italian government first declined to permit fans to compete in sporting activities until early April to prevent the potential transmission of coronavirus. The step ensured players of health and stopped event cancellations because of coronavirus fears. Two days of the declaration, the government cancelled all athletic activities owing to the emergence of the outbreak asking for an emergency. Sports activities in Veneto, Lombardy and Emilia-Romagna, which recorded coronavirus-positive infections, were confirmed to be temporarily suspended. Schools and colleges in Italy have also been forced to shut down.

Iran announced the first recorded cases of SARS-CoV-2 infection on 19 February when, as per the Medical Education and Ministry of Health, two persons died later that day. The Ministry of Islamic Culture and Guidance has declared the cancellation of all concerts and other cultural activities for one week. The Medical Education and Ministry of Health has also declared the closing of universities, higher education colleges and schools in many cities and regions. The Department of Sports and Culture has taken action to suspend athletic activities, including football matches [ 52 ].

On 2 March 2020, the government revealed plans to train about 300,000 troops and volunteers to fight the outbreak of the epidemic, and also send robots and water cannons to clean the cities. The State also developed an initiative and a webpage to counter the epidemic. On 9 March 2020, nearly 70,000 inmates were immediately released from jail owing to the epidemic, presumably to prevent the further dissemination of the disease inside jails. The Revolutionary Guards declared a campaign on 13 March 2020 to clear highways, stores and public areas in Iran. President Hassan Rouhani stated on 26 February 2020 that there were no arrangements to quarantine areas impacted by the epidemic and only persons should be quarantined. The temples of Shia in Qom stayed open to pilgrims.

South Korea

On 20 January, South Korea announced its first occurrence. There was a large rise in cases on 20 February, possibly due to the meeting in Daegu of a progressive faith community recognized as the Shincheonji Church of Christ. Any citizens believed that the hospital was propagating the disease. As of 22 February, 1,261 of the 9,336 members of the church registered symptoms. A petition was distributed calling for the abolition of the church. More than 2,000 verified cases were registered on 28 February, increasing to 3,150 on 29 February [ 53 ].

Several educational establishments have been partially closing down, including hundreds of kindergartens in Daegu and many primary schools in Seoul. As of 18 February, several South Korean colleges had confirmed intentions to delay the launch of the spring semester. That included 155 institutions deciding to postpone the start of the semester by two weeks until 16 March, and 22 institutions deciding to delay the start of the semester by one week until 9 March. Also, on 23 February 2020, all primary schools, kindergartens, middle schools and secondary schools were declared to postpone the start of the semester from 2 March to 9 March.

South Korea’s economy is expected to expand by 1.9%, down from 2.1%. The State has given 136.7 billion won funding to local councils. The State has also coordinated the purchase of masks and other sanitary supplies. Entertainment Company SM Entertainment is confirmed to have contributed five hundred million won in attempts to fight the disease.

In the kpop industry, the widespread dissemination of coronavirus within South Korea has contributed to the cancellation or postponement of concerts and other programmes for kpop activities inside and outside South Korea. For instance, circumstances such as the cancellation of the remaining Asian dates and the European leg for the Seventeen’s Ode To You Tour on 9 February 2020 and the cancellation of all Seoul dates for the BTS Soul Tour Map. As of 15 March, a maximum of 136 countries and regions provided entry restrictions and/or expired visas for passengers from South Korea.

The overall reported cases of coronavirus rose significantly in France on 12 March. The areas with reported cases include Paris, Amiens, Bordeaux and Eastern Haute-Savoie. The first coronaviral death happened in France on 15 February, marking it the first death in Europe. The second death of a 60-year-old French national in Paris was announced on 26 February [ 54 ].

On February 28, fashion designer Agnès B. (not to be mistaken with Agnès Buzyn) cancelled fashion shows at the Paris Fashion Week, expected to continue until 3 March. On a subsequent day, the Paris half-marathon, planned for Sunday 1 March with 44,000 entrants, was postponed as one of a series of steps declared by Health Minister Olivier Véran.

On 13 March, the Ligue de Football Professional disbanded Ligue 1 and Ligue 2 (France’s tier two professional divisions) permanently due to safety threats.

Germany has a popular Regional Pandemic Strategy detailing the roles and activities of the health care system participants in the case of a significant outbreak. Epidemic surveillance is carried out by the federal government, like the Robert Koch Center, and by the German governments. The German States have their preparations for an outbreak. The regional strategy for the treatment of the current coronavirus epidemic was expanded by March 2020. Four primary goals are contained in this plan: (1) to minimize mortality and morbidity; (2) to guarantee the safety of sick persons; (3) to protect vital health services and (4) to offer concise and reliable reports to decision-makers, the media and the public [ 55 ].

The programme has three phases that may potentially overlap: (1) isolation (situation of individual cases and clusters), (2) safety (situation of further dissemination of pathogens and suspected causes of infection), (3) prevention (situation of widespread infection). So far, Germany has not set up border controls or common health condition tests at airports. Instead, while at the isolation stage-health officials are concentrating on recognizing contact individuals that are subject to specific quarantine and are tracked and checked. Specific quarantine is regulated by municipal health authorities. By doing so, the officials are seeking to hold the chains of infection small, contributing to decreased clusters. At the safety stage, the policy should shift to prevent susceptible individuals from being harmed by direct action. By the end of the day, the prevention process should aim to prevent cycles of acute treatment to retain emergency facilities.

United States

The very first case of coronavirus in the United States was identified in Washington on 21 January 2020 by an individual who flew to Wuhan and returned to the United States. The second case was recorded in Illinois by another individual who had travelled to Wuhan. Some of the regions with reported novel coronavirus infections in the US are California, Arizona, Connecticut, Illinois, Texas, Wisconsin and Washington [ 56 ].

As the epidemic increased, requests for domestic air travel decreased dramatically. By 4 March, U.S. carriers, like United Airlines and JetBlue Airways, started growing their domestic flight schedules, providing generous unpaid leave to workers and suspending recruits.

A significant number of universities and colleges cancelled classes and reopened dormitories in response to the epidemic, like Cornell University, Harvard University and the University of South Carolina.

On 3 March 2020, the Federal Reserve reduced its goal interest rate from 1.75% to 1.25%, the biggest emergency rate cut following the 2008 global financial crash, in combat the effect of the recession on the American economy. In February 2020, US businesses, including Apple Inc. and Microsoft, started to reduce sales projections due to supply chain delays in China caused by the COVID-19.

The pandemic, together with the subsequent financial market collapse, also contributed to greater criticism of the crisis in the United States. Researchers disagree about when a recession is likely to take effect, with others suggesting that it is not unavoidable, while some claim that the world might already be in recession. On 3 March, Federal Reserve Chairman Jerome Powell reported a 0.5% (50 basis point) interest rate cut from the coronavirus in the context of the evolving threats to economic growth.

When ‘social distance’ penetrated the national lexicon, disaster response officials promoted the cancellation of broad events to slow down the risk of infection. Technical conferences like E3 2020, Apple Inc.’s Worldwide Developers Conference (WWDC), Google I/O, Facebook F8, and Cloud Next and Microsoft’s MVP Conference have been either having replaced or cancelled in-person events with internet streaming events.

On February 29, the American Physical Society postponed its annual March gathering, planned for March 2–6 in Denver, Colorado, even though most of the more than 11,000 physicist attendees already had arrived and engaged in the pre-conference day activities. On March 6, the annual South to Southwest (SXSW) seminar and festival planned to take place from March 13–22 in Austin, Texas, was postponed after the city council announced a local disaster and forced conferences to be shut down for the first time in 34 years.

Four of North America’s major professional sports leagues—the National Hockey League (NHL), National Basketball Association (NBA), Major League Soccer (MLS) and Major League Baseball (MLB) —jointly declared on March 9 that they would all limit the media access to player accommodations (such as locker rooms) to control probable exposure.

Emergency Funding to Fight the COVID-19

COVID-19 pandemic has become a common international concern. Different countries are donating funds to fight against it [ 57 – 60 ]. Some of them are mentioned here.

China has allocated about 110.48 billion yuan ($15.93 billion) in coronavirus-related funding.

Foreign Minister Mohammad Javad Zarif said that Iran has requested the International Monetary Fund (IMF) of about $5 billion in emergency funding to help to tackle the coronavirus epidemic that has struck the Islamic Republic hard.

President Donald Trump approved the Emergency Supplementary Budget Bill to support the US response to a novel coronavirus epidemic. The budget plan would include about $8.3 billion in discretionary funding to local health authorities to promote vaccine research for production. Trump originally requested just about $2 billion to combat the epidemic, but Congress quadrupled the number in its version of the bill. Mr. Trump formally announced a national emergency that he claimed it will give states and territories access to up to about $50 billion in federal funding to tackle the spread of the coronavirus outbreak.

California politicians approved a plan to donate about $1 billion on the state’s emergency medical responses as it readies hospitals to fight an expected attack of patients because of the COVID-19 pandemic. The plans, drawn up rapidly in reaction to the dramatic rise in reported cases of the virus, would include the requisite funds to establish two new hospitals in California, with the assumption that the state may not have the resources to take care of the rise in patients. The bill calls for an immediate response of about $500 million from the State General Fund, with an additional about $500 million possible if requested.

India committed about $10 million to the COVID-19 Emergency Fund and said it was setting up a rapid response team of physicians for the South Asian Association for Regional Cooperation (Saarc) countries.

South Korea unveiled an economic stimulus package of about 11.7 trillion won ($9.8 billion) to soften the effects of the biggest coronavirus epidemic outside China as attempts to curb the disease exacerbate supply shortages and drain demand. Of the 11,7 trillion won expected, about 3.2 trillion won would cover up the budget shortfall, while an additional fiscal infusion of about 8.5 trillion won. An estimated 10.3 trillion won in government bonds will be sold this year to fund the extra expenditure. About 2.3 trillion won will be distributed to medical establishments and would support quarantine operations, with another 3.0 trillion won heading to small and medium-sized companies unable to pay salaries to their employees and child care supports.

The Swedish Parliament announced a set of initiatives costing more than 300 billion Swedish crowns ($30.94 billion) to help the economy in the view of the coronavirus pandemic. The plan contained steps like the central government paying the entire expense of the company’s sick leave during April and May, and also the high cost of compulsory redundancies owing to the crisis.

In consideration of the developing scenario, an updating of this strategy is planned to take place before the end of March and will recognize considerably greater funding demands for the country response, R&D and WHO itself.

Artificial Intelligence, Data Science and Technological Solutions Against COVID-19

These days, Artificial Intelligence (AI) takes a major role in health care. Throughout a worldwide pandemic such as the COVID-19, technology, artificial intelligence and data analytics have been crucial in helping communities cope successfully with the epidemic [ 61 – 65 ]. Through the aid of data mining and analytical modelling, medical practitioners are willing to learn more about several diseases.

Public Health Surveillance

The biggest risk of coronavirus is the level of spreading. That’s why policymakers are introducing steps like quarantines around the world because they can’t adequately monitor local outbreaks. One of the simplest measures to identify ill patients through the study of CCTV images that are still around us and to locate and separate individuals that have serious signs of the disease and who have touched and disinfected the related surfaces. Smartphone applications are often used to keep a watch on people’s activities and to assess whether or not they have come in touch with an infected human.

Remote Biosignal Measurement

Many of the signs such as temperature or heartbeat are very essential to overlook and rely entirely on the visual image that may be misleading. However, of course, we can’t prevent someone from checking their blood pressure, heart or temperature. Also, several advances in computer vision can predict pulse and blood pressure based on facial skin examination. Besides, there are several advances in computer vision that can predict pulse and blood pressure based on facial skin examination.

Access to public records has contributed to the development of dashboards that constantly track the virus. Several companies are designing large data dashboards. Face recognition and infrared temperature monitoring technologies have been mounted in all major cities. Chinese AI companies including Hanwang Technology and SenseTime have reported having established a special facial recognition system that can correctly identify people even though they are covered.

IoT and Wearables

Measurements like pulse are much more natural and easier to obtain from tracking gadgets like activity trackers and smartwatches that nearly everybody has already. Some work suggests that the study of cardiac activity and its variations from the standard will reveal early signs of influenza and, in this case, coronavirus.

Chatbots and Communication

Apart from public screening, people’s knowledge and self-assessment may also be used to track their health. If you can check your temperature and pulse every day and monitor your coughs time-to-time, you can even submit that to your record. If the symptoms are too serious, either an algorithm or a doctor remotely may prescribe a person to stay home, take several other preventive measures, or recommend a visit from the doctor.

Al Jazeera announced that China Mobile had sent text messages to state media departments, telling them about the citizens who had been affected. The communications contained all the specifics of the person’s travel history.

Tencent runs WeChat, and via it, citizens can use free online health consultation services. Chatbots have already become important connectivity platforms for transport and tourism service providers to keep passengers up-to-date with the current transport protocols and disturbances.

Social Media and Open Data

There are several people who post their health diary with total strangers via Facebook or Twitter. Such data becomes helpful for more general research about how far the epidemic has progressed. For consumer knowledge, we may even evaluate the social network group to attempt to predict what specific networks are at risk of being viral.

Canadian company BlueDot analyses far more than just social network data: for instance, global activities of more than four billion passengers on international flights per year; animal, human and insect population data; satellite environment data and relevant knowledge from health professionals and journalists, across 100,000 news posts per day covering 65 languages. This strategy was so successful that the corporation was able to alert clients about coronavirus until the World Health Organization and the Centers for Disease Control and Prevention notified the public.

Automated Diagnostics

COVID-19 has brought up another healthcare issue today: it will not scale when the number of patients increases exponentially (actually stressed doctors are always doing worse) and the rate of false-negative diagnosis remains very high. Machine learning therapies don’t get bored and scale simply by growing computing forces.

Baidu, the Chinese Internet company, has made the Lineatrfold algorithm accessible to the outbreak-fighting teams, according to the MIT Technology Review. Unlike HIV, Ebola and Influenza, COVID-19 has just one strand of RNA and it can mutate easily. The algorithm is also simpler than other algorithms that help to determine the nature of the virus. Baidu has also developed software to efficiently track large populations. It has also developed an Ai-powered infrared device that can detect a difference in the body temperature of a human. This is currently being used in Beijing’s Qinghe Railway Station to classify possibly contaminated travellers where up to 200 individuals may be checked in one minute without affecting traffic movement, reports the MIT Review.

Singapore-based Veredus Laboratories, a supplier of revolutionary molecular diagnostic tools, has currently announced the launch of the VereCoV detector package, a compact Lab-on-Chip device able to detect MERS-CoV, SARS-CoV and COVID-19, i.e. Wuhan Coronavirus, in a single study.

The VereCoV identification package is focused on VereChip technology, a Lab-on-Chip device that incorporates two important molecular biological systems, Polymerase Chain Reaction (PCR) and a microarray, which will be able to classify and distinguish within 2 h MERS-CoV, SARS-CoV and COVID-19 with high precision and responsiveness.

This is not just the medical activities of healthcare facilities that are being charged, but also the corporate and financial departments when they cope with the increase in patients. Ant Financials’ blockchain technology helps speed-up the collection of reports and decreases the number of face-to-face encounters with patients and medical personnel.

Companies like the Israeli company Sonovia are aiming to provide healthcare systems and others with face masks manufactured from their anti-pathogenic, anti-bacterial cloth that depends on metal-oxide nanoparticles.

Drug Development Research

Aside from identifying and stopping the transmission of pathogens, the need to develop vaccinations on a scale is also needed. One of the crucial things to make that possible is to consider the origin and essence of the virus. Google’s DeepMind, with their expertise in protein folding research, has rendered a jump in identifying the protein structure of the virus and making it open-source.

BenevolentAI uses AI technologies to develop medicines that will combat the most dangerous diseases in the world and is also working to promote attempts to cure coronavirus, the first time the organization has based its product on infectious diseases. Within weeks of the epidemic, it used its analytical capability to recommend new medicines that might be beneficial.

Robots are not vulnerable to the infection, and they are used to conduct other activities, like cooking meals in hospitals, doubling up as waiters in hotels, spraying disinfectants and washing, selling rice and hand sanitizers, robots are on the front lines all over to deter coronavirus spread. Robots also conduct diagnostics and thermal imaging in several hospitals. Shenzhen-based firm Multicopter uses robotics to move surgical samples. UVD robots from Blue Ocean Robotics use ultraviolet light to destroy viruses and bacteria separately. In China, Pudu Technology has introduced its robots, which are usually used in the cooking industry, to more than 40 hospitals throughout the region. According to the Reuters article, a tiny robot named Little Peanut is distributing food to passengers who have been on a flight from Singapore to Hangzhou, China, and are presently being quarantined in a hotel.

Colour Coding

Using its advanced and vast public service monitoring network, the Chinese government has collaborated with software companies Alibaba and Tencent to establish a colour-coded health ranking scheme that monitors millions of citizens every day. The mobile device was first introduced in Hangzhou with the cooperation of Alibaba. This applies three colours to people—red, green or yellow—based on their transportation and medical records. Tencent also developed related applications in the manufacturing centre of Shenzhen.

The decision of whether an individual will be quarantined or permitted in public spaces is dependent on the colour code. Citizens will sign into the system using pay wallet systems such as Alibaba’s Alipay and Ant’s wallet. Just those citizens who have been issued a green colour code will be permitted to use the QR code in public spaces at metro stations, workplaces, and other public areas. Checkpoints are in most public areas where the body temperature and the code of individual are tested. This programme is being used by more than 200 Chinese communities and will eventually be expanded nationwide.

In some of the seriously infected regions where people remain at risk of contracting the infection, drones are used to rescue. One of the easiest and quickest ways to bring emergency supplies where they need to go while on an epidemic of disease is by drone transportation. Drones carry all surgical instruments and patient samples. This saves time, improves the pace of distribution and reduces the chance of contamination of medical samples. Drones often operate QR code placards that can be checked to record health records. There are also agricultural drones distributing disinfectants in the farmland. Drones, operated by facial recognition, are often used to warn people not to leave their homes and to chide them for not using face masks. Terra Drone uses its unmanned drones to move patient samples and vaccination content at reduced risk between the Xinchang County Disease Control Center and the People’s Hospital. Drones are often used to monitor public areas, document non-compliance with quarantine laws and thermal imaging.

Autonomous Vehicles

At a period of considerable uncertainty to medical professionals and the danger to people-to-people communication, automated vehicles are proving to be of tremendous benefit in the transport of vital products, such as medications and foodstuffs. Apollo, the Baidu Autonomous Vehicle Project, has joined hands with the Neolix self-driving company to distribute food and supplies to a big hospital in Beijing. Baidu Apollo has also provided its micro-car packages and automated cloud driving systems accessible free of charge to virus-fighting organizations.

Idriverplus, a Chinese self-driving organization that runs electrical street cleaning vehicles, is also part of the project. The company’s signature trucks are used to clean hospitals.

This chapter provides an introduction to the coronavirus outbreak (COVID-19). A brief history of this virus along with the symptoms are reported in this chapter. Then the comparison between COVID-19 and other plagues like seasonal influenza, bird flu (H5N1 and H7N9), Ebola epidemic, camel flu (MERS), swine flu (H1N1), severe acute respiratory syndrome, Hong Kong flu (H3N2), Spanish flu and the common cold are included in this chapter. Reviews of online portal and social media like Facebook, Twitter, Google, Microsoft, Pinterest, YouTube and WhatsApp concerning COVID-19 are reported in this chapter. Also, the preventive measures and policies enforced by WHO and different countries such as China, Italy, Iran, South Korea, France, Germany and the United States for COVID-19 are included in this chapter. Emergency funding provided by different countries to fight the COVID-19 is mentioned in this chapter. Lastly, artificial intelligence, data science and technological solutions like public health surveillance, remote biosignal measurement, IoT and wearables, chatbots and communication, social media and open data, automated diagnostics, drug development research, robotics, colour coding, drones and autonomous vehicles are included in this chapter.