covid 19 literature review

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

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

PRISMA flow diagram

Characteristics of included reviews

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

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

Population and study designs

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

Systematic review findings

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

A meta-analysis of the prevalence of mortality

Clinical symptoms

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

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgments

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

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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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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• Review Article
• Published: 17 July 2020

A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children

• Matteo Di Nardo 1 ,
• Grace van Leeuwen 2 ,
• Alessandra Loreti 3 ,
• Maria Antonietta Barbieri 4 ,
• Yit Guner 5 ,
• Franco Locatelli 6 &
• Vito Marco Ranieri 7  

Pediatric Research volume  89 ,  pages 1101–1108 ( 2021 ) Cite this article

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At the time of writing, there are already millions of documented infections worldwide by the novel coronavirus 2019 (2019-nCoV or severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)), with hundreds of thousands of deaths. The great majority of fatal events have been recorded in adults older than 70 years; of them, a large proportion had comorbidities. Since data regarding the epidemiologic and clinical characteristics in neonates and children developing coronavirus disease 2019 (COVID-19) are scarce and originate mainly from one country (China), we reviewed all the current literature from 1 December 2019 to 7 May 2020 to provide useful information about SARS-CoV2 viral biology, epidemiology, diagnosis, clinical features, treatment, prevention, and hospital organization for clinicians dealing with this selected population.

Children usually develop a mild form of COVID-19, rarely requiring high-intensity medical treatment in pediatric intensive care unit.

Vertical transmission is unlikely, but not completely excluded.

Children with confirmed or suspected COVID-19 must be isolated and healthcare workers should wear appropriate protective equipment.

Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects (more patchy shadow opacities on CT scan images than ground-glass opacities).

Supportive and symptomatic treatments (oxygen therapy and antibiotics for preventing/treating bacterial coinfections) are recommended in these patients.

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Introduction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. 1 Since its first outbreak in Wuhan, in the Hubei province of China in early December 2019, 2 SARS-CoV2 has spread all over the world infecting millions of people and causing hundreds of thousands o deaths [case fatality rate (CFR): 6.25%, John Hopkins Coronavirus Resource Center, accessed 7 May 2020]. 3

Respiratory viral infections, in general, are more frequent and severe in children than in adults. SARS-CoV2, instead, showed a different scenario. Infection rates appear to be similar between children and adults; however, children develop a milder illness with a low CFR (<0.1%). 3 , 4 , 5 , 6 , 7 The reasons for this milder severity in childhood are not yet understood, and the actual epidemiologic and clinical data of infected neonates and children are not sufficient to solve these gaps. Thus, due to the scarcity of data on SARS-CoV2 in children, we aimed at evaluating the current literature available to provide useful information for clinicians dealing with this particular population.

Search strategy

References for this review were identified through searches on PubMED, Ovid MEDLINE, and EMBASE from 1 December 2019 to 7 May 2020, by two highly experienced librarians at Children’s Hospital Bambino Gesù by using relevant terms related to 2019-nCoV, COVID-19, and SARS-CoV2 in neonates and children (Supplementary Material  1 ). Reference lists of the articles identified by this search strategy were also searched. Earlier reports were not excluded, especially if they were highly cited articles. Only articles published in English were included in this review. Three hundred and seventy-four papers were published in PubMed, 117 in Ovid MEDLINE, and 119 in EMBASE. Among them, 73 were deemed relevant to the purposes of this review (PRISMA flowchart Supplementary Material  2 ).

Biological mechanisms of viral infection and lung injury

Coronaviruses are single-strand, positive-sense RNA viruses with spike-like projections on their surface. 8 These viruses can infect both animals and humans. Among human-infecting coronaviruses, four types (HKU1, NL63, 229E, and OC43) are responsible for mild forms of respiratory disease. 9 , 10 SARS-CoV2, SARS-CoV, and the Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic viruses and can infect humans, causing severe respiratory infections, only crossing from animals (Fig.  1 ).

Summary of coronavirus diseases (adapted from Zimmermann and Curtis 8 ).

SARS-CoV2 infects the host cells through an envelope spike (S) protein that mediates the binding and membrane fusion through the angiotensin-converting enzyme 2 (ACE-2) receptor (Fig.  2a, b ). The spike protein is functionally divided into an S1 domain, responsible for receptor binding, and an S2 domain, responsible for cell membrane fusion. 11 SARS-CoV2 employs the transmembrane serine protease 2 of the host cell to prime the S protein and bind the ACE-2 receptor. Other transmembrane pore-forming viral proteins (viroporins) can trigger the NLRP3 (NOD-like receptor 3 inflammasome)-inducing pyroptosis in the host cell. 12

a Renin–angiotensin system (RAS): normal physiology. Renin converts angiotensinogen in angiotensin 1 (ANG 1). Angiotensin-converting enzyme (ACE) converts ANG1 in angiotensin 2 (ANG2). Angiotensin-converting enzyme 2 (ACE-2), a homolog of ACE, is a monocarboxypeptidase that converts ANG2 into angiotensin 1–7 (ANG1–7), which, by virtue of its actions on the MasR (mitocondrial assembly receptor), opposes the molecular and cellular effects of ANG2. ANG2 promotes vasoconstriction, inflammation, and oxidative stress via the activation of AT1R (angiotensin 2 receptor 1). b  SARS-CoV2 host cell entry mechanism: Spike protein (S1) binds the ACE-2 receptor once primed by the transmembrane protease serine 2 inhibitor (TMPRSS2). This binding leads to viral entry and replication and induces mechanisms of lung injury. c  Potential therapeutic strategies against SARS-COV2. Spike protein-based vaccine; TMPRSS2 inhibitors to block the priming of the spike protein; surface ACE-2 receptor blocker; soluble form of ACE-2 receptor compete with the binding of SARS-CoV2 to the surface ACE-2 receptor.

ACE-2 receptors are expressed in many tissues; however, the majority are present on the alveolar epithelial type II cells. 13 In addition, gene ontology enrichment analysis showed that the ACE-2-expressing epithelial cells have high levels of multiple viral process-related genes, including regulatory genes for viral processes, life cycle, assembly, and genome replication. 13 All these features strongly support the hypothesis that the ACE-2 receptor mediates SARS-CoV2 replication in the lung. SARS-CoV2, through the binding to the ACE-2 receptor, downregulates the ACE-2 intracellular signaling (mitochondrial assembly receptor), causing inflammation, vasoconstriction, and fibrosis in the lung. 13

Epidemiology and pathogenesis in neonates and children

Published data and anecdotal reports support the notion that the number of children found to be infected by SARS-CoV2 is small and their clinical manifestations of COVID-19 are milder compared to adults. 4 , 5 , 6 , 14 , 15 , 16 , 17 , 18

The incidence of SARS-CoV2 confirmed that pediatric cases are low and variable among countries (China: 2–12.3%, 4 , 5 Italy: 1.2%, 19 Korea: 4.8%, 20 USA: 5% 21 ). Several reasons justify this variable incidence: testing availability, testing policy 22 , 23 (at the beginning of pandemics some countries tested only children with established contact with a person with COVID-19, then only hospitalized children with symptoms), and the fact that the infection in children is mild or without symptoms. 24 , 25 Available data also suggest that all ages (0–18) can be infected, but infants seem to be most vulnerable. 5 , 26

Human-to-human transmission (mainly family clustered) is the major transmission mode. 4 , 5 , 27 Children can be infected by inhalation of large droplets generated during coughing or sneezing or by contact with contaminated surface (fomite). 9 , 10 , 28 , 29 , 30 As the virus can be also released in the stool, the fecal–oral transmission cannot be ruled out. 31 , 32 , 33 , 34 Similar to SARS-CoV and MERS-CoV, nosocomial transmission of SARS-CoV2 is high, 9 , 10 , 35 , 36 although no cases of nosocomial infections have been described in children during hospital recovery.

Despite the absence of clinical features of infection or positive microbiological findings in neonates born from SARS-CoV2-positive mothers, 14 , 18 , 37 , 38 , 39 , 40 , 41 , 42 vertical maternal–fetal transmission cannot be ruled out completely. 43 , 44 Conversely, SARS-CoV2 has not been isolated from cord blood, amniotic fluid, and breast milk to date. However, it is crucial to screen pregnant women, implement strict infection control measures on those who tested positive, and monitor the neonates at risk. 44 , 45

Since the incubation period (median 5–7 days) in children and young adolescent varies from 2 to 14 days, but is generally longer than in adults, 10 , 46 , 47 , 48 dynamic observation is mandatory for suspected children. 49 , 50 The median period from symptom onset to hospital admission for patients who were hospitalized is 2 days (1.00–3.50). Recovery generally happens in 1–2 weeks after onset. 40 , 48 Both symptomatic patients and asymptomatic carriers can transmit SARS-CoV2. 49 , 51 , 52

The basic case reproduction (R0) of SARS-CoV2 is variable (2–3.5 in the early stage of the disease); 9 however, the R0 of SARS-CoV2 is higher than SARS-CoV and H1N1. 10 The CFR is ~6.25% (data from 7 May, John Hopkins Coronavirus Resource Center) 3 and varies among countries, 53 patients’ age, and is influenced by testing availability. 54 CFR of patients below 18 years is below <0.1% (adapted from John Hopkins Coronavirus Resource center at 7 May 2020). 3 , 7

This age specificity is still not completely understood. 24 , 55 It is speculated that children, as compared with adults, may have a higher expression of ACE-2 receptors in the type II lung pneumocytes, protecting them from the severe clinical manifestation of COVID-19 (low cytokine release, low pulmonary vascular permeability, etc.). 55 Other immunologic mechanisms (trained immunity, an early and high polyclonal B cell response to SARS-CoV2 with the production of substantial numbers of plasmablasts, and an high level natural killer cells) could also contribute to explain this age-specific characteristic. 55 , 56 A less intense mechanism of antibody-dependent enhancement, instead, could explain why COVID-19 clinical features are milder in children than in adults. 12

Since the World Health Organization (WHO) recently declared COVID-19 a pandemic on 11 March 2020, every patient presenting with evidence of fever, respiratory symptoms, gastrointestinal symptoms, or fatigue should be considered potentially infected (suspected case) with SARS-CoV-2.

Diagnosis of COVID-19 is made by using real-time polymerase chain reaction (RT-PCR) on samples from nasopharyngeal, oropharyngeal swabs, and lower respiratory tract samples whenever possible. 4 , 5 Negative nasopharyngeal swab is generally re-tested after 24 h due to the low negative predictive value of this testing. 57 SARS-CoV2 can be also detected on stools. 33 , 58 , 59 A “positive” RT-PCR result reflects only the detection of viral RNA and does not necessarily indicate the presence of a viable virus. 52

Confirmed cases are defined by positive molecular tests, while asymptomatic cases are defined by positive molecular tests without symptoms.

In children, more than in adults, COVID-19 poses important diagnostic challenges due to the longer incubation period that includes a prolonged interval (~5–6 days) of viral shedding prior to the onset of symptoms. 51 , 60 Moreover, the duration of asymptomatic shedding is not only variable, but also differs according to the anatomic level (upper versus lower airways) of the infection. 49 , 50

At present, among adult patients in affected areas, the most common cause of viral pneumonia with unclear etiology is SARS-CoV2; 2 conversely, in children several other pathogens (influenza, para-influenza, adenovirus, respiratory syncytial virus, metapneumovirus, or other human coronaviruses) can produce very similar clinical and radiologic findings and should be considered in the differential diagnosis. 6 , 8 , 26 , 61 Atypical microorganisms, such as chlamydia pneumoniae and mycoplasma, must be also excluded. 10

No laboratory investigations and radiological findings are diagnostic of SARS-CoV2. 4 , 5 , 6 , 10 , 47 , 62

Clinical features

Clinical manifestations of COVID-19 in neonates and children reported are generally mild and similar among countries. 4 , 5 , 6 , 14 , 16 , 22 , 23 , 37 , 38 , 46 , 63 , 64 , 65 Most commonly, at hospital admission, children presented with fever and respiratory symptoms with cough, sore throat, pharyngeal erythema, nasal congestion, tachypnea/dyspnea, and tachycardia. 22 , 23 , 65 Often, gastrointestinal symptoms, including abdominal pain, nausea, vomiting, and diarrhea, were the first manifestations. 4 , 5 , 15 , 46 , 64 , 66 Neurological manifestations such as seizures, dystonia, and altered mental status were rare. 66 Neonates, instead, showed tachypnea, cough, grunting, nasal flaring, vomiting, poor feeding, diarrhea, and lethargy. 45 , 61 , 67 , 68 , 69 Hospital admission was higher in Italy and Spain than in China and USA; 4 , 21 , 22 , 65 however, this was mainly due to local policies (testing availability and policy, need of patient isolation) rather than clinical condition. 22 , 65

In the largest retrospective cohort of COVID-19 pediatric patients reported so far [2134 patients including 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases], Dong et al. 5 defined the severity of COVID-19 in asymptomatic infection, mild, moderate, severe, and critical cases, based on the clinical features, laboratory testing, and X-ray imaging (Table  1 ). In this cohort, 4.4% of infected children were asymptomatic, while the remaining children presented a mild (50.9%) or moderate disease (38.8%), respectively. Only 5.2% had severe disease, while 0.6% had critical disease. The proportion of severe and critical cases was 10.6%, 7.3%, 4.2%, 4.1%, and 3.0% for the age group of <1, 1–5, 6–10, 11–15, and >16 years, respectively.

Lu et al. 4 showed 15.8% of COVID-19 children included in their retrospective cohort (171 SARS-CoV2 confirmed cases) were completely asymptomatic and did not show any radiological findings of pneumonia.

Respiratory coinfections were present in almost half of the cases. 4 , 5 , 26 Comorbidities, as in adult patients, 70 may affect outcome 23 and the likelihood of Pediatric Intensive Care Unit (PICU) admission. 4 , 23

In adults, the incidence of ICU admission was high and variable among countries (5% in China and 9% in Italy); 70 , 71 in children, the incidence was lower (0.21–5.2% among Chinese PICUs, 4 , 5 , 15 0.04% in USA 23 ). Of note, several biases (retrospective nature of these studies, 5 , 61 the proportion of the detected cases, the use of different PICU admission criteria among centers, 5 the use of the same data source with overlapping data—Chinese Centers for Disease Control and Prevention database—and the high number of suspected cases 47 ) could have affected the interpretation of these results.

Most of the laboratory abnormalities in children with COVID-19 are nonspecific. Henry et al. 62 reviewed the data of 66 children from 12 different studies and found that 69.2% of children had normal leukocyte counts and that neutrophilia or neutropenia were rare (<5%). Platelet count was variable among studies (generally higher than the normal range), while C-reactive protein and procalcitonin were increased in 13.6% and 10.6% of the cases, respectively. 62

Children admitted to the PICU 15 showed normal or increased whole blood counts (7/8) and increased C-reactive protein, procalcitonin, and lactate dehydrogenase (6/8). High levels of pro-inflammatory and anti-inflammatory cytokines were also present similarly to the adult patients. 72 , 73

Although lymphocytopenia is very common in adults with severe COVID-19 and associated with worse outcomes, 47 it is less common in children (2–3.5%), likely due to the constitutional high percentage of lymphocytes typical of this age. 62 , 74 In adult patients, high ferritin, high d -dimers, and coagulopathy were associated with poor prognosis, 70 but these laboratory findings were rare in children; high d -dimers levels were found in one of the two patients who died from COVID-19. 4 , 15 However, during April 2020, a surge of anecdotal cases showing a hyper-inflammatory state (pediatric multisystem inflammatory syndrome temporally associated with COVID-19) and features similar to atypical Kawasaki disease or Kawasaki disease shock syndrome were reported in Europe (United Kingdom, Spain, Italy). 75 , 76 Many of these patients had positive SARS-CoV2 antibodies and presented an inflammatory state (elevated concentration of C-reactive protein, procalcitonin, ferritin triglycerides, and d -dimers) with cutaneous rash, peripheral edema, conjunctivitis, myocardial dysfunction (elevated cardiac enzymes), and coronary vessels inflammation.

Radiologic findings of SARS-CoV2 viral pneumonia were also variable among children (Fig.  3 ). 4 At hospital admission, many children presented a chest X-ray showing an interstitial pneumonia, 26 while chest computed tomography (CT) scan showed patchy shadows (unilateral and bilateral) with opacities of high density. The typical adult feature of ground-glass opacity was less frequent at hospital admission (32.7%); 4 instead, it was more common in patients admitted to the PICU for respiratory failure. 4 , 5 , 6 , 26 , 77 , 78 , 79 Bedside lung ultrasonography was also used as a diagnostic tool in the emergency departments in a minority of patients; 80 90% of these received a diagnosis of interstitial lung syndrome without further radiographic imaging. 65

a Chest X ray and b chest computed tomography. Vital signs: respiratory rate 22 breaths/min, SpO 2 : 97% in room air. The patient was supported with high-flow nasal cannula 25 L/min, FiO 2 : 30% in the pediatric ward.

Treatment of COVID-19 in neonates and children mainly relies on supportive care. 4 , 10

Home isolation is the first step to manage children with mild symptoms and no underlying chronic conditions. Hospitalization may be considered if rapid deterioration is anticipated or if the patient is not able to urgently return to hospital when signs and symptoms of complicated disease arise. Moderate cases should be managed in hospital, monitoring vital signs and oxygen saturation. Supportive care for these children includes temperature control with antipyretics, bed rest, hydration, and good nutrition. Routine antibiotics and antifungal drugs must be avoided and used only when coinfections are proven or strongly suspected. 10 , 15

In hypoxic patients, oxygen therapy should be immediately initiated. 81 Several devices [low flow nasal cannula, high-flow nasal cannula (HFNC), and noninvasive ventilation (NIV)] can be used according to the centers’ experience. Caution must be taken, since all noninvasive techniques bear the risk of aerosol contamination; strict personal protection equipment (PPE) must be used when caring for these patients.

Invasive mechanical ventilation is indicated if: SpO 2 /FiO 2  < 221 or if there is no improvement in oxygenation (target SpO 2 92–97% with FiO 2  < 0.4) within 30–60 min of HFNC or if there is no improvement in oxygenation (target SpO 2 92–97% and FiO 2  < 0.6) within 60–90 min of CPAP/NIV. 81 Escalating therapies are recommended in case of refractory hypoxia (surfactant therapy in neonates, inhaled nitric oxide, high frequency oscillatory ventilation, and extracorporeal membrane oxygenation). 81 , 82 , 83

A small portion of children with COVID-19 developed septic shock; 5 , 15 , 84 thus, this condition must be always suspected and managed according to the current pediatric guidelines since specific issues for COVID-19 have not been reported so far. 85 Corticosteroids should not be used in pediatric patients, 86 except when required for other indications, such as asthma exacerbations, refractory shock, or evidence of cytokine storm. 16

Several treatment options (intravenous immunoglobulin, interleukin-1 (IL-1) blockade, IL-6 receptor blockade, azythromycin-chloroquine, plasma exchange, infusion of plasma from convalescent subjects, cytokine adsorption filters) have been used in critically ill adult patients; however, data on their efficacy and safety have not been reported yet, thus caution should be used also in children. 87

Antiviral drugs should be used with caution after weighing advantages and disadvantages. For those with mild symptoms, low dosage of interferon-α nebulization has been used 16 in combination with oral ribavirin. Lopinavir/litonavir 15 and remdesivir 88 , 89 have been used in more severe cases; however, their efficacy and safety in children remain to be determined. 90 Remdesivir should be preferred in children because of its positive effects in a recent adult trial; 88 , 89 however, when not available, or when patients are not good candidate to remdesivir, hydroxychloroquine could be considered. 88 The combination of three or more antiviral drugs is generally not recommended. 90

Potential therapeutic strategies for SARS-COV2 are the spike protein-based vaccine, the inhibitors of transmembrane protease serine 2 activity, and the delivery of excessive soluble form of ACE-2 or antibody against the surface of ACE-2 receptors (Fig.  2c ). 13

Prevention and healthcare organization

COVID-19 has no approved treatment in neonates and children and a large-scale vaccine is still under development; thus, prevention is crucial. 10 , 91

SARS-CoV-2 has unique characteristics that makes its prevention complex. SARS-CoV-2 can cause an asymptomatic infection, can be transmitted during the incubation period and after clinical recovery, 13 has a very high affinity to ACE-2 receptors, which are expressed on many mucosal surfaces, resulting in high transmissibility, and can be spread also by fomite. 10

The high transmissibility and low CFR, combined with the discouraging projections of the spread of the virus among adults, 70 fostered many governments, at the beginning of March 2020, to adopt stringent containment and self-isolation measures to reduce the spread of the virus. An intense public health response was started by many countries after the pandemic declaration and involved many strategies: lockdown of the cities and mass quarantine, social distancing mandates, schools closure, cancellation of public gatherings, reduction of domestic and international flights, development of environmental measures and personal protection procedures, and strict contacts tracings by the medical and public health professionals. These measures aim to delay major surges of patients and to lower the demand for hospital extra beds, while protecting the most vulnerable subjects from infection, especially the elderly and those with comorbidities. 92

Data showed that pediatric cases requiring high-intensity medical assistance are uncommon; 5 , 15 however, isolation of all suspected and confirmed patients remains mandatory to avoid the spread of SARS-CoV2 among caregivers and healthcare workers. Therefore, many pediatric hospitals have developed local guidelines and logistic plans (simulations and training courses, reduction of elective surgeries and visits to outpatient clinics, etc.) to identify in advance potential surge capacity in the form of dedicated environment with extra beds for isolation, quarantine, and dedicated staff. As stocks of PPE might run low during a period of pandemic, strict hospital policies should also be adopted according to the WHO guidelines. 93 Furthermore, considering the high number of adult ICU admissions and the difficulties associated to create extra beds in a short period of time, 70 pediatric intensivists and nurses should be ready and prepared to offer help by managing adult patients in PICU 94 or to help in adult ICUs.

Differently from adults, home isolation is not easily performed in children, because they often require the presence of the parents, limiting the use of protective distances (>1.5 m). In those cases, all people sharing a common environment with a SARS-CoV2-positive child should consider the use of gloves and face masks, if available. Hand hygiene practices are extremely important to prevent the spread of the COVID-19 virus at home and in public environments. The WHO recommends washing hands, especially after coughing or sneezing (including sneeze/cough into elbow or tissue), before eating and after using the toilet or sharing common spaces. 95 Hand washing also interrupts transmission of other viruses and bacteria causing common colds, flu, and pneumonia, thus reducing the general burden of disease. Relatives at risk (e.g., people over the age of 65 years, pregnant women, people who are immunocompromised or who have chronic heart, lung, or kidney conditions) 96 should be isolated in protected environment, avoiding exposures to infected children. Because infants cannot wear masks, parents must wear masks, wash hands before close contacts, and sterilize the toys and tablet regularly. 97

All suspected children requiring hospital assistance must be isolated in single rooms (whenever possible, or in dedicated environments, maintaining adequate distances between beds) until the results of the test are available; confirmed patients must be placed in dedicated area for quarantine. A dedicated algorithm must be adopted for the use of the operating theaters in suspected or confirmed COVID-19 cases, according to the urgency of the operation, anticipated viral burden at the surgical site, and the risk that a procedure could spread the virus by aereosol. 98 , 99 Negative pressure rooms are of help, but not mandatory to manage these patients. 10 All rooms and transition environments must be decontaminated after the patient discharge (Fig.  3 ).

Since a high number of health care workers has been infected by SARS-CoV2, all suspected patients, until proven negative, must be assisted by health care providers using PPE 93 and all aerosol generating procedures (intubation, bronchoscopy, tube/tracheostomy suctioning, etc.) must be also performed using airborne transmission precautions. 93

Enhanced traffic control bundling strategies must be adopted by all emergency departments, 100 including a triage zone, transition zones conduction to a quarantine ward or to an isolation ward (Fig.  4 ). A dedicated pathway for children non-SARS-CoV2 suspected (e.g., trauma, poisoning, etc.) must also be created in parallel to avoid contact. Telemedicine should be implemented to help reduce hospital and clinic visits, 101 , 102 by triaging low-acuity patients while delivering high-quality care. 103

Enhanced traffic control system used in Children’s Hospital Bambino Gesù, Rome, Italy.

The scarcity of pediatric cases and the current literature on the topic, as well as the absence of high-quality evidence-based guidelines, has led pediatricians to share experiences and personal communication via online meetings and open access medical education channels. The use of webinars and communication about newly released papers on social media channels such as Twitter, Telegram and WhatsApp, greatly improved the dissemination of knowledge among health care providers.

At the time of this review (7 May 2020), SARS-CoV2 has infected millions of people in the world and caused hundreds of thousands confirmed deaths, but data regarding the epidemiologic and clinical characteristics in neonates and children are still scarce. The purpose of this review was to evaluate the current literature that includes neonates and children to date, providing useful information for clinicians dealing with this selected population. The earliest epidemiologic data show that SARS-CoV2 has a dominant family-cluster transmission and that children present a mild form of COVID-19 (CFR: <0.1%), rarely requiring high-intensity medical treatment in PICU. Vertical transmission is unlikely, but not completely excluded. Diagnosis is performed primarily via molecular nucleic acid amplification testing. Patients with confirmed or suspected COVID-19 should be isolated and healthcare workers should wear appropriate protective equipment. Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects, including the presence of patchy shadow opacities on CT scan images. Treatment options are extrapolated from adult data. Thus, supportive and symptomatic treatments (oxygen therapy and antibiotics for bacterial coinfections) are recommended in these patients. More studies on neonates and children are needed to address these gaps and to provide more robust recommendations to manage COVID-19.

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Matteo Di Nardo

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Alessandra Loreti

Emergency Department, Bambino Gesù Children Hospital, Palidoro, Rome, Italy

Maria Antonietta Barbieri

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Each author made a substantial contribution to this review and met the Pediatric Research authorship requirements. M.D.N., G.V.L., and A.L. contributed to the review design, data acquisition, and screening. M.D.N., M.A.B., and Y.G. contributed to the interpretation of the data and article drafting. M.D.N., F.L., and V.M.R. contributed to the article drafting and revisions. All authors have approved the final manuscript.

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Di Nardo, M., van Leeuwen, G., Loreti, A. et al. A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children. Pediatr Res 89 , 1101–1108 (2021). https://doi.org/10.1038/s41390-020-1065-5

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Coronavirus disease 2019 (COVID-19): A literature review

Affiliations.

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

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

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

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

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• COVID-19 pandemic and Internal Medicine Units in Italy: a precious effort on the front line. Montagnani A, Pieralli F, Gnerre P, Vertulli C, Manfellotto D; FADOI COVID-19 Observatory Group. Montagnani A, et al. Intern Emerg Med. 2020 Nov;15(8):1595-1597. doi: 10.1007/s11739-020-02454-5. Epub 2020 Jul 31. Intern Emerg Med. 2020. PMID: 32737837 Free PMC article. No abstract available.

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Coronavirus Disease 2019 (COVID-19): A Literature Review from a Nursing Perspective

Amir emami zeydi.

1 Department of Medical-Surgical Nursing, Nasibeh School of Nursing and Midwifery, Mazandaran University of Medical Sciences, Sari, Iran

Mohammad Javad Ghazanfari

2 Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Kashan University of Medical Sciences, Kashan, Iran

Farzam Shaikhi Sanandaj

3 Student Research Committee, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran

Reza Panahi

Hamed mortazavi.

4 Geriatric Care Research Center, Department of Geriatric Nursing, School of Nursing and Midwifery, North Khorasan University of Medical Sciences, Bojnurd, Iran

Keyvan Karimifar

5 Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Samad Karkhah

6 Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Guilan University of Medical Sciences, Rasht, Iran

Joseph Osuji

7 School of Nursing and Midwifery, Faculty of Health, Community, and Education, Mount Royal University, Calgary, Alberta, Canada

Introduction

As the COVID-19 pandemic ravages the world, nursing resources, and capacities play an essential role in disease management. This literature review focuses on the central issues related to the nursing care of patients affected by COVID-19.

Material and methods

This literature review was conducted with an extensive search of databases, including PubMed, Web of Science (WOS), and Scopus, using the keywords “COVID19”, “2019-nCoV disease”, “2019 novel coronavirus infection”, “Nurse”, “NursingCare”, and” Nursing management.” The span of the literature search was between December 01, 2020, and January 12, 2021. A total of 28 original and English-language articles were selected for inclusion in the review.

Nursing interventions such as monitoring, oxygen therapy, and the use of Extra Corporeal Membrane Oxygenation (ECMO) in the care of COVID-19 patients, caring for ICU patients with COVID-19, rehabilitation of COVID-19 patients, nurses’ experiences and barriers in the care of patients with COVID-19, and also the ethical challenges in the care of patients with COVID-19, were found to be valuable in managing COVID-19 patients.

Nurses have a pivotal role to play in the care of patients with COVID-19. Therefore, providing comprehensive and quality nursing care supported by experience and research is necessary to successfully reduce the length of hospital stay and decrease the morbidity and mortality rates of COVID-19.

1. Introduction

After identifying several cases of unknown pneumonia caused by a Coronavirus variant, on December 8, 2019, in Wuhan, Hubei Province, China, concerns were raised among public health professionals about the spread of a new disease in the world [ 1 ]. This particular version of the coronaviruses was not known to infect human beings in the past. However, it is now identified as the infecting organism in some patients for unknown reasons, leading to wide-spread autoimmune reactions in those affected. The virus was also implicated in human to human infections, ultimately leading to a global pandemic [ 2 ]. Epidemiological studies in COVID-19 patients have shown that the main route of transmission is from person to person through coughing or sneezing [ 3 ].

With more than 20 million nursing workforces worldwide, nurses constitute the largest proportion of health care workers (HCW) [ 4 , 5 ], playing a pivotal role in the COVID-19 prevention, treatment, and rehabilitation. Considering that nurses work in different health care settings within the community, their multiple roles and responsibilities are crucial during the COVID-19 pandemic. Therefore, nurses should be well prepared to provide high quality, evidence-based, and comprehensive care for COVID-19 patients [ 5 , 6 ].

Although the COVID-19 pandemic is still raging and lots of information regarding the trajectory, treatment, prevention, and control are still unfolding, it is necessary to collate some of the latest scientific information pertinent to nursing management. This literature review aims to comprehensively review the literature focusing on the central issues related to the nursing care of patients affected by COVID-19.

2. Material and methods

This literature review was conducted via online databases, such as PubMed, Web of Science (WOS), and Scopus from December 1, 2020, to January 12, 2021. Keywords used for the search were selected using medical subject headings (MESH) and combined with other target keywords included “COVID19”, “2019-nCoV disease”, “2019 novel coronavirus infection”, “Nurse,” “Nursing Care” and “Nursing management.” In the study, all types of English-language published articles that could potentially become useful for caring for COVID-19 patients were evaluated and included. The search was performed by two authors independently. Gray literature search was not included in the review due to the uncertainty surrounding such a novel disease condition and the exponential amount of speculation that characterized the pandemic’s early stages. To achieve maximum search comprehensiveness, lists of references from eligible studies were evaluated manually. In order to manage the data, search results were entered into the EndNote X8 software. After removing duplicate studies, the titles, abstracts, and full texts of the eligible articles were evaluated by two researchers independently. A total of 688 articles were obtained initially using database searches. Then article titles and abstracts were screened to eliminate duplicate studies, leading to the exclusion of s 656 articles. Finally, full texts of selected articles were reviewed, and 28 eligible journal articles were finally included in the review from which data were extracted for analysis ( Fig. 1 ).

Flow diagram of study selection.

3.1. Epidemiologic features of COVID-19

3.1.1. prevalence of covid-19.

According to the World Health Organization, a total of 88,387,352 confirmed cases of COVID-19 had been identified around the world by January 12, 2021, out of which 1,919,204 deaths have occurred. The United States with 21,761,186 infected patients (365,886 deaths), India with 10,450,284 cases (150,999 deaths), and Brazil with 8,013,708 cases (201,460 deaths), were among the countries reporting the highest numbers of cases and mortality [ 7 ].

3.1.2. Clinical and epidemiologic features

Although it has been reported that one-fifth of individuals with COVID-19 remain asymptomatic [ 8 ], patients with mild infections may have nonspecific manifestations, such as fever, fatigue, cough (with or without fever), anorexia, weakness, myalgia, sore throat, shortness of breath, nasal congestion, and headache. Other uncommon symptoms such as nausea, vomiting, anosmia, dysgeusia, and diarrhea [ 2 , 9 , 10 ] have also been reported. In a recent meta-analysis, fever (78.8%), cough (53.9%), malaise (37.9%), and fatigue (32.2%) were listed as the most common clinical manifestations in patients with SARS-Cov2. The mean incubation period of the disease is reported to be 5.3 days [ 9 ]. Awareness of the incubation period has a useful role to play in screening and effective epidemiological control policies [ 11 ] for Covid-19.

3.1.3. Modes of Disease transmission

The main route of transmission of the virus is respiratory droplets. The SARS-CoV-2 is released in the respiratory tract when an infected person coughs, sneezes, or talks. Typically, the droplets do not travel beyond 26 feet and do not remain in the air. The highest risk of transmission occurs when a patient is symptomatic, although asymptomatic transmission has been confirmed [ 12 ]. Epidemiological studies have shown that the virus is transmitted from person to person through personal contact or by touching an infected surface and then touching the nose, mouth, and eyes. Initially, the transmission of the disease through aerosols’ release was questionable [ 13 ], but currently, there is enough data to confirm the possibility of SARS_Cov2 being released by aerosol-producing procedures [ 14 ]. Although the oral-fecal method is not the primary method of transmission, it cannot be ignored because the presence of SARS-CoV-2 in the feces has been confirmed. Coronaviruses have better survivability at humidity above 30% and 25°C temperature. SARS-CoV-2 stays alive on surfaces such as metal, glass, or plastic [ 15 ] mobile phones and door handles [ 13 ] for up to 9 days. However, these surfaces can be disinfected for 1 minute using disinfection methods with 62–71% ethanol, 0.5% hydrogen peroxide, or 0.1% sodium hypochlorite. The use of hand sanitizers and the disinfection of the environment and patient care equipment are essential infection prevention and control strategies, both within the hospital and in community settings [ 2 ].

3.1.4. Age-dependent effects of COVID-19

The age distribution of affected hospitalized patients is mostly middle-aged people (people older than 30 years) and older adults. Morbidity and mortality rates are highest among older adult patients hospitalized in the intensive care unit (ICU). The clinical manifestations in these patients progress more rapidly and often lead to severe respiratory failure (9). Also, it has been reported that up to 50.9% of COVID-19 patients had underlying diseases [ 16 ]. Evidence suggests that infection is rare in children and is usually mild, and when children are infected, about 18% of cases remain asymptomatic. The most common symptoms of COVID-19 in children have been reported as fever (51.2%) and cough (37%) [ 17 ].

3.1.5. Risk Factors for COVID-19 induced ARDS and Progression to Death

As the prevalence and spread of COVID-19 increases worldwide, many more deaths are likely to be recorded. Older adults and people with underlying diseases, such as respiratory and cardiovascular diseases, are at higher risk. Smoking and obesity are associated with an increased risk of death [ 18 ]. In Italy, the risk of death and disease severity was higher in smokers and men than in women [ 19 ]. A Recently published meta-analysis reveals that chronic respiratory diseases, hypertension, cardiovascular disease, chronic kidney disease, cerebrovascular disease, malignancy, diabetes, and obesity are most typical risk factors COVID-19 severity [ 20 ]. [ 20 ]The most common complication in patients with COVID-19, which causes high mortality, is acute respiratory distress syndrome (ARDS) [ 21 ]. In one study, 45% of people who died from COVID-19 were as a result of ARDS development [ 22 ]. The most common symptom of COVID-19 patients with ARDS is shortness of breath. The risk factors associated with the development of ARDS and progression from ARDS to death include older age (>65 years), neutrophilia, organ and coagulation dysfunction, and higher lactate dehydrogenase and D-dimer [ 23 ]. Vitamin D deficiency has been proposed as a risk factor for ARDS development in CIVID-19 patients. Vitamin D deficiency causes more cellular inflammation and cytokine release within 48 hours of the development of ARDS. Also, a deficiency of thiamine and selenium increases the risk of developing ARDS [ 24 , 25 ]. Despite all the risks factors mentioned above, the Italian healthcare system’s experience revealed that the increase in the nurses’ workload and the shortage of beds during the COVID-19 pandemic increased the mortality rate of the disease dramatically, underscoring the need to train more HCW and provide adequate care infrastructure in order to reduce morbidity and mortality of COVID-19 [ 26 ].

3.1.6. Infection prevention measures in the hospital setting

Today, millions of HCW, especially nurses, are in the front-line of the global battle to treat COVID-19 patients and flatten the curve of transmission. Reports from China show that about 3,300 HCW were infected by February 2020, with at least 22 of them dying by the end of March [ 27 ]. The results of a recently published systematic review regarding the global prevalence of infection and mortality from COVID-19 among HCW showed that a total of 152 888 infections and 1413 deaths were reported among HCWs during the early phases of the pandemic [ 28 ]. The high number of cases and deaths among HCW resulted in a severe shortage of staff, and extreme fatigue and stress among nurses, with the likelihood of weakening the immune system and subsequent increase in infection rates [ 29 ]. With the increasing prevalence of this disease, the lack of personal protective equipment (PPE) had become a significant concern for health care providers, as it is the first step in protecting them [ 30 ]. The availability and use of appropriate personal protective equipment (PPE) such as face masks, eye protectors, protective clothing, and body coverings, including shoes and safety goggles [ 31 , 2 ], are effective strategies used to prevent the spread of infections among HCW. To wear protective cover, nurses need to tie their hair, hold it in place, and remove watches and jewellery during patient care to prevent contamination. To prevent dehydration, it is essential for nurses to drink water before wearing PPE and use the bathroom as necessary. In the event of any contamination, damage, or rupture of full-body clothing, the PPE must be replaced. Nurses should also replace gloves when they get wet [ 31 ].

It is best to use N95 masks or surgical masks during patient care procedures [ 32 ]. It has been previously shown that the incidence rate of respiratory infections in HCW who wore a surgical mask was twice as high as those who wore N95 masks [ 33 , 34 ]. Comparatively, medical masks and N95 masks did not differ in protecting HCW during non–aerosol care. However, N95 should be used during short-term aerosol-generating procedures and high-risk care [ 35 ].

Given that protection against aerosols’ larger than 0.3 microns entry into N95 masks is unknown, research data suggests that N95 masks are more effective than surgical masks in preventing the spread of infections, but this has not been definitively clarified [ 36 ]. Patients whose care increases aerosol generation’s possibility should be placed in isolation units, with all precautions taken to prevent infecting those who care for them, especially nurses [ 14 ]. Nurses should avoid being infected by contaminated secretions of patients during interventions such as assisting patients with a nebulizer, chest physiotherapy, bronchoscopy, tracheostomy, intubation, orotracheal suction, manual ventilation before intubation, non-invasive ventilation, cardiopulmonary resuscitation, gastroscopy, and collection of laboratory samples [ 14 , 37 ]. Nurses should use PPE when collecting samples from COVID-19 patients or suspected patients, and then the samples should be sent separately in non-perforated bags, along with the laboratory requisition forms [ 37 ]. Preferably, immediately after the end of each day, all equipment, floors, nursing stations, and other areas of hospital wards must be disinfected with 2 or 3% hydrogen peroxide [ 38 ].

3.2. Nursing Care of Patients with COVID-19

3.2.1. monitoring.

Precise and continuous monitoring of COVID-19 patients by nurses is crucial for recognizing patients’ deterioration and occurrence of any potential complications. The patient’s vital signs should be monitored continuously, with particular attention paid to respiration rate, oxygen saturation (SPO2), and changes in consciousness level. Clinically, common and significant symptoms of COVID-19 such as cough, shortness of breath, fever, sputum, and chest tightness, should be monitored. If needed, the patient’s arterial blood gas (ABG) results should be evaluated at frequent intervals [ 39 ]. Patients’ temperature should be checked, and any temperature greater than 37.3°C should be reported and followed up. Surgical masks should be offered immediately to patients with symptoms of cough and sneezing. Liquids or IV fluid therapy should be used to prevent dehydration and worsening respiratory status when appropriate. As a result of the anorexia experienced by these patients and the need to strengthen their immunity, their diet should contain a balanced ratio of protein, carbohydrates, vitamins, and minerals [ 40 ]. Although continuous monitoring of the ‘ patients respiratory system is vital, nurses should not neglect other organs’ or forget to assess other body systems.

3.2.2. Oxygen therapy and ECMO in care of COVID-19 patients

Acute hypoxemic respiratory failure or ARDS is the most common and severe complication of COVID-19, which requires oxygen and ventilation therapy. For patients with mild or moderate respiratory problems and hypoxemia, oxygen therapy using a nasal cannula, simple face mask, or reservoir mask may be enough. The appropriate flow rate of oxygen should be determined based on the patient’s condition. If oxygen therapy does not achieve the oxygen saturation target range, nurses should investigate the potential causes and use other oxygen delivery devices or methods [ 41 , 2 ]. Extracorporeal Membrane Oxygenation (ECMO) may be an effective modality for COVID-19-related acute hypoxemic respiratory failure [ 42 ]. Given the effectiveness of ECMO in Middle East Respiratory Syndrome Coronavirus (MERS-COV) patients with ARDS, this method appears to be effective in COVID-19, but the data are inconsistent. Contrary to the recommendations for using ECMO in COVID-19 patients with ARDS [ 43 ], this treatment was not effective in some cases [ 44 ]. Care of patients receiving oxygen therapy using different devices is briefly shown in Table 1 .

Oxygen therapy in the care of COVID-19 patients.

3.2.3. Caring for ICU patients with COVID-19

In the ICU, two nurses per patient must perform proper safe care and isolation of patients with COVID-19 [ 37 ]. In COVID-19 patients with ARDS, a high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) are useful in maintaining positive end-expiratory pressure (PEEP) and preventing alveolar collapse. Prone positioning combined with low tidal volume (6 ml/kg of ideal body weight) and neuromuscular blocking agents improves ARDS patients’ oxygen therapy [ 45 , 46 ]. A systematic review revealed prone positioning could significantly improve the oxygenation and perfusion in COVID-19 patients [ 47 ]. Besides, prone positioning is recommended for oxygen improvement in mechanically ventilated COVID-19 patients with severe ARDS [ 48 ]. Patients who are ventilated and placed in the prone position are at risk for complications such as endotracheal tube displacement, limited access to the venous route, bruising around the mouth, bedsores, possible kinking of catheters, periorbital and facial edema, increased oral secretions, and skin damage [ 46 ]. In patients predisposed to pressure injuries, nurses must perform continuous risk assessments and change patients’ positions at regular intervals. [ 49 ]. Simultaneously, the nurse should examine the patient for bed sores and prevent falls, tube slipping, and eye damage caused by pressure, skin and mouth damage, and other complications [ 2 ]. A major limitation in patients in the prone position is a potential difficulty encountered if the patient requires to be intubated and the requirement for 3 to 5 people to participate in the procedure [ 50 ]. Restriction of fluid intake is effective in relieving pulmonary edema [ 43 ]. If the patient has ARDS or has the necessary criteria, the patient may require invasive mechanical ventilation. [ 2 ] Although there is no single ‘Silver Bullet’ to cure COVID-19, a clinical expert panel called the frontline COVID-19 Critical Care Alliance proposed a promising management protocol (MATH+: a combination of intravenous methylprednisolone, high dose intravenous ascorbic acid, thiamine, full anticoagulation with heparin and other co-interventions) as a life-saving approach in critically ill or other COVID-19 patients [ 51 , 52 ]. However, this treatment protocol should be investigated and confirmed in future studies in critical care units.

The use of a closed airway suction device, convalescent plasma therapy for severe and critically ill patients, the use of lung-protective strategy in patients with ARDS, avoidance of excessive PEEP, fluid resuscitation with crystalloids, monitoring of signs of secondary infection in patients admitted to ICU> 48 h, and early nutrition therapy during 24–48 hours after admission are other recommended interventions in ICU COVID-19 patients [ 53 ].

3.2.4. Other Nursing Care and rehabilitation of COVID-19 patients

As the number of new COVID-19 infections is increasing daily, nurses must isolate patients and prevent virus spread when transferring these patients between wards. Nurses must consider five principles when transferring patients; these include recognizing patients in the acute phase of the disease, the nurses’ safety, protecting others, availability of emergency treatment measures, and the possibility of infecting others after the patient’s transfer is completed. During patient transfer, a physician or nurse who can manage emergency conditions should accompany the patient. The patient needs constant monitoring of blood pressure, pulse, pulse oximetry, and CO2 levels and may require a defibrillator. Nurses must wear N95 masks and PPE to ensure their safety, and the patients must wear surgical masks, if possible. During patient transport, a specific route must be planned, and after the transfer, the route must be disinfected and the nurses’ protective clothing replaced [ 54 ].

With the increasing spread of the COVID-19 pandemic and the high number of patients admitted to the ICU, patients who survive and are discharged from the ICU need rehabilitation. Rehabilitation is a vital part of patient-centered care in response to the COVID-19 crises and plays an essential role in accelerating recovery after discharge from the ICU [ 55 ]. These patients may develop post-ICU syndrome and complications that may include immobility, venous thromboembolism, delirium [ 56 ], depression [ 57 ], post-traumatic stress disorder (PTSD) [ 58 ], and anxiety [ 59 ]. Rehabilitation should be done in short-term, medium, and long-term programs for patients and their families. Maintaining an active relationship between nurses and patients’ families plays an essential role in providing adequate care during the rehabilitation process. After discharge from the ICU, patients may be negatively impacted by prolonged use of sedatives, immobility, mechanical ventilation, and delirium, and may depend on personal and daily care from HCW. Many surviving COVID-19 patients need to be admitted to a rehabilitation centre to improve their functioning and be prepared to re-enter society [ 55 ].

3.3. Nurses’ experiences in the Care of Patients with COVID-19

Paying attention to nurses’ experiences in the COVID-19 pandemic can provide the best foundation for better crisis management in the future. Nurses’ experiences during the Covid-19 Pandemic can be evaluated in various positive and negative dimensions. Nurses’ negative experiences were usually related to difficulties in coping with increased work and family demands during the pandemic. As the pandemic ravages the world, management issues were among the most critical negative experiences of nurses. These include nursing staff shortages, long shifts, scarcity of resources, and PPE shortages [ 60 , 61 ]. Long shifts in the hospital, being away from family, and end-of-life care can cause emotional problems among nurses and other HCW [ 62 , 61 ]. In two qualitative studies from Turkey [ 63 ] and Iran [ 64 ], nurses experienced various psychological distress during the care of COVID-19 patients.

In contrast, nurses’ positive experiences resulted from the nursing profession’s positive contributions during the COVID-19 pandemic. Nurses’ spoke of positive comments and more respect from other people for their sacrifices. This pandemic has led to a better appreciation of the nursing profession’s contributions in managing complex public health problems and patient recovery. These positive developments have provided new opportunities for developing the nursing profession [ 61 ]. Strengthening the spirit of cooperation, pride in oneself as a committed nurse, strengthening self-confidence in caring for patients, and public support for nurses and other HCW, have been other positive experiences of nurses during the COVID-19 pandemic [ 60 ].

3.4. Nursing management during the COVID-19 Pandemic

As the COVID-19 crisis continues, nurse managers must make quick, creative, practical, and useful decisions and use appropriate methods to engage patients and their families during the disease process. Nursing personnel administrators must provide the appropriate emotional and physical support for nurses to enable them to meet the increased expectations placed on them [ 65 ]. Nurse managers should also develop management plans to provide high quality, safe, and cost-effective care [ 66 ]. The main aspects in human resource management during this crisis include: clarifying human resource structures, standardizing communication procedures, securing an adequate number of HCW and other staff, restricting high-risk procedures/behaviours, and developing flexible shifts for nurses [ 67 ]. Creating positive interactions between patients, families, and nurses to provide care can play a vital role in managing COVID-19 [ 65 ]. Appropriate instruction and interaction after discharge to provide relevant patients’ care needs such as medication adherence, diet, psychological counseling, and observance of care standards are necessary and can be achieved by Tele-nursing. Tele-nursing improves the quality of care and treatment outcomes, controls treatment costs, reduces the need for emergency room visits, and encourages patient and family involvement in care decisions to achieve a high self-management level [ 68 ].

3.5. Nurses’ barriers to caring for patients with COVID-19

There are several barriers for nurses in caring for COVID-19 patients. Most important of these are limited and ambiguous information about COVID-19 and inadequate support for HCW, such as a lack of facilities and PPE. Also, concerns about their family safety and emotional and psychological stress were other barriers reported by nurses as they cared for COVID-19 patients [ 69 ].

3.6. Ethical Challenges in the Care of Patients with COVID-19

With the spread of COVID-19, many patients are admitted into hospitals for care. Lack of sufficient medical equipment, PPE, nursing and medical staff shortages, and bedding have created ethical challenges for nurses and other HCW [ 70 ]. Due to insufficient and inadequate medical resources, medical staff had to impose restrictions on Italy’s patient care [ 70 ]. For example, younger people may be preferred for admission into ICU and mechanical ventilation [ 71 ] over older patients. In the United States, do-not-attempt-resuscitate (DNAR) has been recommended for some patients due to a shortage of respiratory support devices, ICU spaces, and PPE [ 72 ]. Another challenge in patients with COVID-19 is cardiopulmonary resuscitation (CPR) [ 73 ]. It may take up to 10 minutes to enter the patient’s room, remove the clothing, and prepare to resuscitate the patient. The same delay in CPR reduces the possibility of survival of a patient with COVID-19 by up to 10%. The lack of sufficient equipment and medical personnel, the implementation or non-implementation of CPR on patients over 80 who have undergone cardiac arrest are considered some of the major ethical challenges [ 71 ] encountered during the care of COVID-19 patients. Therefore, resource allocation during a pandemic should be based on the maximum use of limited resources, the equitable treatment of different individuals, and resource prioritization of care according to how critical the patients’ needs are [ 74 ].

4. Conclusion

The global prevalence of COVID-19 requires nurses’ active participation as the most extensive and primary professionals at the forefront of the fight against the pandemic. The fight against COVID-19 requires a combination of care based on scientific evidence, education and information sharing, public health, and sound policy. Nurses have a pivotal role in caring for patients with COVID-19. Providing comprehensive nursing care of the highest quality, supported by experience and research, can successfully reduce patients’ length of hospital stay, reduce morbidity and mortality rates of the disease, and promote patients’ recovery rate. As the COVID-19 crisis rages on, nurse managers should also develop management plans to provide high-quality, safe, and cost-effective care to patients while ensuring that nursing staff is protected while caring for patients.

Acknowledgments

The authors thank Professor Stefano Bambi for his insightful comments on earlier versions of this manuscript.