how to write a literature review on covid 19

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

Harapan harapan.

a Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

b Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

c Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

d Division of Infectious Diseases, AichiCancer Center Hospital, Chikusa-ku Nagoya, Japan

Amanda Yufika

e Department of Family Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

Wira Winardi

f Department of Pulmonology and Respiratory Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

g School of Medicine, The University of Western Australia, Perth, Australia

Haypheng Te

h Siem Reap Provincial Health Department, Ministry of Health, Siem Reap, Cambodia

Dewi Megawati

i Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Denpasar, Indonesia

j Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA

Zinatul Hayati

k Department of Clinical Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

Abram L. Wagner

l Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, MI 48109, USA

Mudatsir Mudatsir

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.

On December 31, 2019, the China Health Authority alerted the World Health Organization (WHO) to several cases of pneumonia of unknown aetiology in Wuhan City in Hubei Province in central China. The cases had been reported since December 8, 2019, and many patients worked at or lived around the local Huanan Seafood Wholesale Market although other early cases had no exposure to this market [1] . On January 7, a novel coronavirus, originally abbreviated as 2019-nCoV by WHO, was identified from the throat swab sample of a patient [2] . This pathogen was later renamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the Coronavirus Study Group [3] and the disease was named coronavirus disease 2019 (COVID-19) by the WHO. As of January 30, 7736 confirmed and 12,167 suspected cases had been reported in China and 82 confirmed cases had been detected in 18 other countries [4] . In the same day, WHO declared the SARS-CoV-2 outbreak as a Public Health Emergency of International Concern (PHEIC) [4] .

According to the National Health Commission of China, the mortality rate among confirmed cased in China was 2.1% as of February 4 [5] and the mortality rate was 0.2% among cases outside China [6] . Among patients admitted to hospitals, the mortality rate ranged between 11% and 15% [7] , [8] . COVID-19 is moderately infectious with a relatively high mortality rate, but the information available in public reports and published literature is rapidly increasing. The aim of this review is to summarize the current understanding of COVID-19 including causative agent, pathogenesis of the disease, diagnosis and treatment of the cases, as well as control and prevention strategies.

The virus: classification and origin

SARS-CoV-2 is a member of the family Coronaviridae and order Nidovirales. The family consists of two subfamilies, Coronavirinae and Torovirinae and members of the subfamily Coronavirinae are subdivided into four genera: (a) Alphacoronavirus contains the human coronavirus (HCoV)-229E and HCoV-NL63; (b) Betacoronavirus includes HCoV-OC43, Severe Acute Respiratory Syndrome human coronavirus (SARS-HCoV), HCoV-HKU1, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV); (c) Gammacoronavirus includes viruses of whales and birds and; (d) Deltacoronavirus includes viruses isolated from pigs and birds [9] . SARS-CoV-2 belongs to Betacoronavirus together with two highly pathogenic viruses, SARS-CoV and MERS-CoV. SARS-CoV-2 is an enveloped and positive-sense single-stranded RNA (+ssRNA) virus [16] .

SARS-CoV-2 is considered a novel human-infecting Betacoronavirus [10] . Phylogenetic analysis of the SARS-CoV-2 genome indicates that the virus is closely related (with 88% identity) to two bat-derived SARS-like coronaviruses collected in 2018 in eastern China (bat-SL-CoVZC45 and bat-SL-CoVZXC21) and genetically distinct from SARS-CoV (with about 79% similarity) and MERS-CoV [10] . Using the genome sequences of SARS-CoV-2, RaTG13, and SARS-CoV [11] , a further study found that the virus is more related to BatCoV RaTG13, a bat coronavirus that was previously detected in Rhinolophus affinis from Yunnan Province, with 96.2% overall genome sequence identity [11] . A study found that no evidence of recombination events detected in the genome of SARS-CoV-2 from other viruses originating from bats such as BatCoV RaTG13, SARS-CoV and SARSr-CoVs [11] . Altogether, these findings suggest that bats might be the original host of this virus [10] , [11] .

However, a study is needed to elucidate whether any intermediate hosts have facilitated the transmission of the virus to humans. Bats are unlikely to be the animal that is directly responsible for transmission of the virus to humans for several reasons [10] : (1) there were various non-aquatic animals (including mammals) available for purchase in Huanan Seafood Wholesale Market but no bats were sold or found; (2) SARS-CoV-2 and its close relatives, bat-SL-CoVZC45 and bat-SL-CoVZXC21, have a relatively long branch (sequence identity of less than 90%), suggesting those viruses are not direct ancestors of SARS-CoV-2; and (3) in other coronaviruses where bat is the natural reservoir such as SARS-CoV and MERS-CoV, other animals have acted as the intermediate host (civets and possibly camels, respectively). Nevertheless, bats do not always need an intermediary host to transmit viruses to humans. For example, Nipah virus in Bangladesh is transmitted through bats shedding into raw date palm sap [12] .

Transmission

The role of the Huanan Seafood Wholesale Market in propagating disease is unclear. Many initial COVID-19 cases were linked to this market suggesting that SARS-CoV-2 was transmitted from animals to humans [13] . However, a genomic study has provided evidence that the virus was introduced from another, yet unknown location, into the market where it spread more rapidly, although human-to-human transmission may have occurred earlier [14] . Clusters of infected family members and medical workers have confirmed the presence of person-to-person transmission [15] . After January 1, less than 10% of patients had market exposure and more than 70% patients had no exposure to the market [13] . Person-to-person transmission is thought to occur among close contacts mainly via respiratory droplets produced when an infected person coughs or sneezes. Fomites may be a large source of transmission, as SARS-CoV has been found to persist on surfaces up to 96 h [16] and other coronaviruses for up to 9 days [17] .

Whether or not there is asymptomatic transmission of disease is controversial. One initial study published on January 30 reported asymptomatic transmission [18] , but later it was found that the researchers had not directly interviewed the patient, who did in fact have symptoms prior to transmitting disease [19] . A more recent study published on February 21 also purported asymptomatic transmission [20] , but any such study could be limited by errors in self-reported symptoms or contact with other cases and fomites.

Findings about disease characteristics are rapidly changing and subject to selection bias. A study indicated the mean incubation period was 5.2 days (95% confidence interval [95%CI]: 4.1–7.0) [13] . The incubation period has been found to be as long as 19 or 24 days [21] , [22] , although case definitions typically rely on a 14 day window [23] .

The basic reproductive number ( R 0 ) has been estimated with varying results and interpretations. R 0 measures the average number of infections that could result from one infected individual in a fully susceptible population [24] . Studies from previous outbreaks found R 0 to be 2.7 for SARS [25] and 2.4 for 2009 pandemic H1N1 influenza [26] . One study estimated that that basic reproductive number ( R 0 ) was 2.2 (95% CI: 1.4–3.9) [13] . However, later in a further analysis of 12 available studies found that R 0 was 3.28 [27] . Because R 0 represents an average value it is also important to consider the role of super spreaders, who may be hugely responsible for outbreaks within large clusters but who would not largely influence the value of R 0 [28] . During the acute phase of an outbreak or prepandemic, R 0 may be unstable [24] .

In pregnancy, a study of nine pregnancy women who developed COVID-19 in late pregnancy suggested COVID-19 did not lead to substantially worse symptoms than in nonpregnant persons and there is no evidence for intrauterine infection caused by vertical transmission [29] .

In hospital setting, a study involving 138 COVID-19 suggested that hospital-associated transmission of SARS-CoV-2 occurred in 41% of patients [30] . Moreover, another study on 425 patients found that the proportion of cases in health care workers gradually increased by time [13] . These cases likely reflect exposure to a higher concentration of virus from sustained contact in close quarters.

Outside China, as of February 12, 2020, there were 441 confirmed COVID-19 cases reported in 24 countries [6] of which the first imported case was reported in Thailand on January 13, 2020 [6] , [31] . Among those countries, 11 countries have reported local transmission with the highest number of cases reported in Singapore with 47 confirmed cases [6] .

Risk factors

The incidence of SARS-CoV-2 infection is seen most often in adult male patients with the median age of the patients was between 34 and 59 years [20] , [30] , [7] , [32] . SARS-CoV-2 is also more likely to infect people with chronic comorbidities such as cardiovascular and cerebrovascular diseases and diabetes [8] . The highest proportion of severe cases occurs in adults ≥60 years of age, and in those with certain underlying conditions, such as cardiovascular and cerebrovascular diseases and diabetes [20] , [30] . Severe manifestations maybe also associated with coinfections of bacteria and fungi [8] .

Fewer COVID-19 cases have been reported in children less than 15 years [20] , [30] , [7] , [32] . In a study of 425 COVID-19 patients in Wuhan, published on January 29, there were no cases in children under 15 years of age [13] , [33] . Nevertheless, 28 paediatric patients have been reported by January 2020 [34] . The clinical features of infected paediatric patients vary, but most have had mild symptoms with no fever or pneumonia, and have a good prognosis [34] . Another study found that although a child had radiological ground-glass lung opacities, the patient was asymptomatic [35] . In summary, children might be less likely to be infected or, if infected, present milder manifestations than adults; therefore, it is possible that their parents will not seek out treatment leading to underestimates of COVID-19 incidence in this age group.

Pathogenesis and immune response

Like most other members of the coronavirus family, Betacoronavirus exhibit high species specificity, but subtle genetic changes can significantly alter their tissue tropism, host range, and pathogenicity. A striking example of the adaptability of these viruses is the emergence of deadly zoonotic diseases in human history caused by SARS-CoV [36] and MERS-CoV [37] . In both viruses, bats served as the natural reservoir and humans were the terminal host, with the palm civet and dromedary camel the intermediary host for SARS-CoV and MERS-CoV, respectively [38] , [39] . Intermediate hosts clearly play a critical role in cross species transmission as they can facilitate increased contact between a virus and a new host and enable further adaptation necessary for an effective replication in the new host [40] . Because of the pandemic potential of SARS-CoV-2, careful surveillance is immensely important to monitor its future host adaptation, viral evolution, infectivity, transmissibility, and pathogenicity.

The host range of a virus is governed by multiple molecular interactions, including receptor interaction. The envelope spike (S) protein receptor binding domain of SARS-CoV-2 was shown structurally similar to that of SARS-CoV, despite amino acid variation at some key residues [10] . Further extensive structural analysis strongly suggests that SARS-CoV-2 may use host receptor angiotensin-converting enzyme 2 (ACE2) to enter the cells [41] , the same receptor facilitating SARS-CoV to infect the airway epithelium and alveolar type 2 (AT2) pneumocytes, pulmonary cells that synthesize pulmonary surfactant [42] . In general, the spike protein of coronavirus is divided into the S1 and S2 domain, in which S1 is responsible for receptor binding and S2 domain is responsible for cell membrane fusion [10] . The S1 domain of SARS-CoV and SARS-CoV-2 share around 50 conserved amino acids, whereas most of the bat-derived viruses showed more variation [10] . In addition, identification of several key residues (Gln493 and Asn501) that govern the binding of SARS-CoV-2 receptor binding domain with ACE2 further support that SARS-CoV-2 has acquired capacity for person-to-person transmission [41] . Although, the spike protein sequence of receptor binding SARS-CoV-2 is more similar to that of SARS-CoV, at the whole genome level SARS-CoV-2 is more closely related to bat-SL-CoVZC45 and bat-SL-CoVZXC21 [10] .

However, receptor recognition is not the only determinant of species specificity. Immediately after binding to their receptive receptor, SARS-CoV-2 enters host cells where they encounter the innate immune response. In order to productively infect the new host, SARS-CoV-2 must be able to inhibit or evade host innate immune signalling. However, it is largely unknown how SARS-CoV-2 manages to evade immune response and drive pathogenesis. Given that COVID-19 and SARS have similar clinical features [7] , SARS-CoV-2 may have a similar pathogenesis mechanism as SARS-CoV. In response to SARS-CoV infections, the type I interferon (IFN) system induces the expression of IFN-stimulated genes (ISGs) to inhibit viral replication. To overcome this antiviral activity, SARS-CoV encodes at least 8 viral antagonists that modulate induction of IFN and cytokines and evade ISG effector function [43] .

The host immune system response to viral infection by mediating inflammation and cellular antiviral activity is critical to inhibit viral replication and dissemination. However, excessive immune responses together with lytic effects of the virus on host cells will result in pathogenesis. Studies have shown patients suffering from severe pneumonia, with fever and dry cough as common symptoms at onset of illness [7] , [8] . Some patients progressed rapidly with Acute Respiratory Stress Syndrome (ARDS) and septic shock, which was eventually followed by multiple organ failure and about 10% of patients have died [8] . ARDS progression and extensive lung damage in COVID-19 are further indications that ACE2 might be a route of entry for the SARS-CoV-2 as ACE2 is known abundantly present on ciliated cells of the airway epithelium and alveolar type II (cells (pulmonary cells that synthesize pulmonary surfactant) in humans [44] .

Patients with SARS and COVID-19 have similar patterns of inflammatory damage. In serum from patients diagnosed with SARS, there is increased levels of proinflammatory cytokines (e.g. interleukin (IL)-1, IL6, IL12, interferon gamma (IFNγ), IFN-γ-induced protein 10 (IP10), macrophage inflammatory proteins 1A (MIP1A) and monocyte chemoattractant protein-1 (MCP1)), which are associated with pulmonary inflammation and severe lung damage [45] . Likewise, patients infected with SARS-CoV-2 are reported to have higher plasma levels of proinflammatory cytokines including IL1β, IL-2, IL7, TNF-α, GSCF, MCP1 than healthy adults [7] . Importantly, patients in the intensive care unit (ICU) have a significantly higher level of GSCF, IP10, MCP1, and TNF-α than those non-ICU patients, suggesting that a cytokine storm might be an underlying cause of disease severity [7] . Unexpectedly, anti-inflammatory cytokines such as IL10 and IL4 were also increased in those patients [7] , which was uncommon phenomenon for an acute phase viral infection. Another interesting finding, as explained before, was that SARS-CoV-2 has shown to preferentially infect older adult males with rare cases reported in children [7] , [8] . The same trend was observed in primate models of SARS-CoV where the virus was found more likely to infect aged Cynomolgus macaque than young adults [46] . Further studies are necessary to identify the virulence factors and the host genes of SARS-CoV-2 that allows the virus to cross the species-specific barrier and cause lethal disease in humans.

Clinical manifestations

Clinical manifestations of 2019-nCoV infection have similarities with SARS-CoV where the most common symptoms include fever, dry cough, dyspnoea, chest pain, fatigue and myalgia [7] , [30] , [47] . Less common symptoms include headache, dizziness, abdominal pain, diarrhoea, nausea, and vomiting [7] , [30] . Based on the report of the first 425 confirmed cases in Wuhan, the common symptoms include fever, dry cough, myalgia and fatigue with less common are sputum production, headache, haemoptysis, abdominal pain, and diarrhoea [13] . Approximately 75% patients had bilateral pneumonia [8] . Different from SARS-CoV and MERS-CoV infections, however, is that very few COVID-19 patients show prominent upper respiratory tract signs and symptoms such as rhinorrhoea, sneezing, or sore throat, suggesting that the virus might have greater preference for infecting the lower respiratory tract [7] . Pregnant and non-pregnant women have similar characteristics [48] . The common clinical presentation of 2019-nCoV infection are presented in Table 1 .

Clinical symptoms of patients with 2019-nCoV infection.

Severe complications such as hypoxaemia, acute ARDS, arrythmia, shock, acute cardiac injury, and acute kidney injury have been reported among COVID-19 patients [7] , [8] . A study among 99 patients found that approximately 17% patients developed ARDS and, among them, 11% died of multiple organ failure [8] . The median duration from first symptoms to ARDS was 8 days [30] .

Efforts to control spread of COVID-19, institute quarantine and isolation measures, and appropriately clinically manage patients all require useful screening and diagnostic tools. While SARS-CoV-2 is spreading, other respiratory infections may be more common in a local community. The WHO has released a guideline on case surveillance of COVID-19 on January 31, 2020 [23] . For a person who meets certain criteria, WHO recommends to first screen for more common causes of respiratory illness given the season and location. If a negative result is found, the sample should be sent to referral laboratory for SARS-CoV-2 detection.

Case definitions can vary by country and will evolve over time as the epidemiological circumstances change in a given location. In China, a confirmed case from January 15, 2020 required an epidemiological linkage to Wuhan within 2 weeks and clinical features such as fever, pneumonia, and low white blood cell count. On January 18, 2020 the epidemiological criterion was expanded to include contact with anyone who had been in Wuhan in the past 2 weeks [50] . Later, the case definitions removed the epidemiological linkage.

The WHO has put forward case definitions [23] . Suspected cases of COVID-19 are persons (a) with severe acute respiratory infections (history of fever and cough requiring admission to hospital) and with no other aetiology that fully explains the clinical presentation and a history of travel to or residence in China during the 14 days prior to symptom onset; or (b) a patient with any acute respiratory illness and at least one of the following during the 14 days prior to symptom onset: contact with a confirmed or probable case of SARS-CoV-2 infection or worked in or attended a health care facility where patients with confirmed or probable SARS-CoV-2 acute respiratory disease patients were being treated. Probable cases are those for whom testing for SARS-CoV-2 is inconclusive or who test positive using a pan-coronavirus assay and without laboratory evidence of other respiratory pathogens. A confirmed case is one with a laboratory confirmation of SARS-CoV-2 infection, irrespective of clinical signs and symptoms.

For patients who meet diagnostic criteria for SARS-CoV-2 testing, the CDC recommends collection of specimens from the upper respiratory tract (nasopharyngeal and oropharyngeal swab) and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage) [51] . In each country, the tests are performed by laboratories designated by the government.

Laboratory findings

Among COVID-19 patients, common laboratory abnormalities include lymphopenia [8] , [20] , [30] , prolonged prothrombin time, and elevated lactate dehydrogenase [30] . ICU-admitted patients had more laboratory abnormalities compared with non-ICU patients [30] , [7] . Some patients had elevated aspartate aminotransferase, creatine kinase, creatinine, and C-reactive protein [20] , [7] , [35] . Most patients have shown normal serum procalcitonin levels [20] , [30] , [7] .

COVID-19 patients have high level of IL1β, IFN-γ, IP10, and MCP1 [7] . ICU-admitted patients tend to have higher concentration of granulocyte-colony stimulating factor (GCSF), IP10, MCP1A, MIP1A, and TNF-α [7] .

Radiology findings

Radiology finding may vary with patients age, disease progression, immunity status, comorbidity, and initial medical intervention [52] . In a study describing 41 of the initial cases of 2019-nCoV infection, all 41 patients had pneumonia with abnormal findings on chest computed tomography (CT-scan) [7] . Abnormalities on chest CT-scan were also seen in another study of 6 cases, in which all of them showed multifocal patchy ground-glass opacities notably nearby the peripheral sections of the lungs [35] . Data from studies indicate that the typical of chest CT-scan findings are bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities [7] , [8] , [20] , [30] , [32] , [53] . The consolidated lung lesions among patients five or more days from disease onset and those 50 years old or older compared to 4 or fewer days and those 50 years or younger, respectively [47] .

As the disease course continue, mild to moderate progression of disease were noted in some cases which manifested by extension and increasing density of lung opacities [49] . Bilateral multiple lobular and subsegmental areas of consolidation are typical findings on chest CT-scan of ICU-admitted patients [7] . A study among 99 patients, one patient had pneumothorax in an imaging examination [8] .

Similar to MERS-CoV and SARS-CoV, there is still no specific antiviral treatment for COVID-19 [54] . Isolation and supportive care including oxygen therapy, fluid management, and antibiotics treatment for secondary bacterial infections is recommended [55] . Some COVID-19 patients progressed rapidly to ARDS and septic shock, which was eventually followed by multiple organ failure [7] , [8] . Therefore, the effort on initial management of COVID-19 must be addressed to the early recognition of the suspect and contain the disease spread by immediate isolation and infection control measures [56] .

Currently, no vaccination is available, but even if one was available, uptake might be suboptimal. A study of intention to vaccinate during the H1N1 pandemic in the United States was around 50% at the start of the pandemic in May 2009 but had decreased to 16% by January 2010 [57] .

Neither is a treatment available. Therefore, the management of the disease has been mostly supportive referring to the disease severity which has been introduced by WHO. If sepsis is identified, empiric antibiotic should be administered based on clinical diagnosis and local epidemiology and susceptibility information. Routine glucocorticoids administration are not recommended to use unless there are another indication [58] . Clinical evidence also does not support corticosteroid treatment [59] . Use of intravenous immunoglobulin might help for severely ill patients [8] .

Drugs are being evaluated in line with past investigations into therapeutic treatments for SARS and MERS [60] . Overall, there is not robust evidence that these antivirals can significantly improve clinical outcomes A. Antiviral drugs such as oseltamivir combined with empirical antibiotic treatment have also been used to treat COVID-19 patients [7] . Remdesivir which was developed for Ebola virus, has been used to treat imported COVID-19 cases in US [61] . A brief report of treatment combination of Lopinavir/Ritonavir, Arbidol, and Shufeng Jiedu Capsule (SFJDC), a traditional Chinese medicine, showed a clinical benefit to three of four COVID-19 patients [62] . There is an ongoing clinical trial evaluating the safety and efficacy of lopinavir-ritonavir and interferon-α 2b in patients with COVID-19 [55] . Ramsedivir, a broad spectrum antivirus has demonstrated in vitro and in vivo efficacy against SARS-CoV-2 and has also initiated its clinical trial [63] , [64] . In addition, other potential drugs from existing antiviral agent have also been proposed [65] , [66] .

Control and prevention strategies

COVID-19 is clearly a serious disease of international concern. By some estimates it has a higher reproductive number than SARS [27] , and more people have been reported to have been infected or died from it than SARS [67] . Similar to SARS-CoV and MERS-CoV, disrupting the chain of transmission is considered key to stopping the spread of disease [68] . Different strategies should be implemented in health care settings and at the local and global levels.

Health care settings can unfortunately be an important source of viral transmission. As shown in the model for SARS, applying triage, following correct infection control measures, isolating the cases and contact tracing are key to limit the further spreading of the virus in clinics and hospitals [68] . Suspected cases presenting at healthcare facilities with symptoms of respiratory infections (e.g. runny nose, fever and cough) must wear a face mask to contain the virus and strictly adhere triage procedure. They should not be permitted to wait with other patients seeking medical care at the facilities. They should be placed in a separated, fully ventilated room and approximately 2 m away from other patients with convenient access to respiratory hygiene supplies [69] . In addition, if a confirmed COVID-19 case require hospitalization, they must be placed in a single patient room with negative air pressure – a minimum of six air changes per hour. Exhausted air has to be filtered through high efficiency particulate air (HEPA) and medical personnel entering the room should wear personal protective equipment (PPE) such as gloves, gown, disposable N95, and eye protection. Once the cases are recovered and discharged, the room should be decontaminated or disinfected and personnel entering the room need to wear PPE particularly facemask, gown, eye protection [69] .

In a community setting, isolating infected people are the primary measure to interrupt the transmission. For example, immediate actions taken by Chinese health authorities included isolating the infected people and quarantining of suspected people and their close contacts [70] . Also, as there are still conflicting assumptions regarding the animal origins of the virus (i.e. some studies linked the virus to bat [71] , [72] while others associated the virus with snake [73] ), contacts with these animal fluids or tissues or consumption of wild caught animal meet should be avoided. Moreover, educating the public to recognize unusual symptoms such as chronic cough or shortness of breath is essential therefore that they could seek medical care for early detection of the virus. If large-scale community transmission occurs, mitigating social gatherings, temporary school closure, home isolation, close monitoring of symptomatic individual, provision of life supports (e.g. oxygen supply, mechanical ventilator), personal hand hygiene, and wearing personal protective equipment such as facemask should also be enforced [74] .

In global setting, locking down Wuhan city was one of the immediate measure taken by Chinese authorities and hence had slowed the global spread of COVID-19 [74] . Air travel should be limited for the cases unless severe medical attentions are required. Setting up temperature check or scanning is mandatory at airport and border to identify the suspected cases. Continued research into the virus is critical to trace the source of the outbreak and provide evidence for future outbreak [74] .

Conclusions

The current COVID-19 pandemic is clearly an international public health problem. There have been rapid advances in what we know about the pathogen, how it infects cells and causes disease, and clinical characteristics of disease. Due to rapid transmission, countries around the world should increase attention into disease surveillance systems and scale up country readiness and response operations including establishing rapid response teams and improving the capacity of the national laboratory system.

Competing interests

The authors declare that they have no competing interests.

Ethical approval

Not required.

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

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

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

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

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

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

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

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

Conclusions

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

Peer Review reports

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

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

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

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

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

Methodology

Research question.

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

Study design

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

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

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

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

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

Eligibility criteria

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

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

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

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

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

Information sources

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

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

Study selection

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

Data collection process

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

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

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

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

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

Quality assessment in individual reviews

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

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

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

Synthesis of results

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

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

Managing overlapping systematic reviews

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

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

PRISMA flow diagram

Characteristics of included reviews

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

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

Population and study designs

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

Systematic review findings

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

A meta-analysis of the prevalence of mortality

Clinical symptoms

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

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

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

Therapeutic possibilities

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

Laboratory and radiological findings

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

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

Quality of evidence in individual systematic reviews

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Availability of data and materials

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

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Acknowledgments

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

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

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

Dónal P. O’Mathúna

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

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

Thilo Caspar von Groote

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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

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

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

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

Introduction

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

Epidemiology and Pathophysiology

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

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

Clinical Manifestation

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

Respiratory

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

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

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

ENT (Ear, Nose, and Throat)

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

Cardiovascular

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

Gastrointestinal

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

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

Neurological

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

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

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

Musculoskeletal

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

Hematological

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

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

Endocrine and Reproductive

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

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

Clinical Presentation in Specific Population

In children.

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

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

In Pregnant Women

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

In Immuno-Compromised Population

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

Multisystem Involvement in COVID-19

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

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

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

Association Between Clinical Presentations, COVID-19 Severity and Prognosis

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

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

Author Contributions

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

Conflict of Interest

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

Acknowledgments

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

Abbreviations

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

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

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

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

Reviewed by:

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

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

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• Published: 16 May 2022

A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection

• David A. Jamison Jr. 1   na1 ,
• S. Anand Narayanan   ORCID: orcid.org/0000-0002-9783-5711 1 , 2   na1 ,
• Nídia S. Trovão   ORCID: orcid.org/0000-0002-2106-1166 1 , 3 ,
• Joseph W. Guarnieri 1 , 4 ,
• Michael J. Topper 1 , 5 ,
• Pedro M. Moraes-Vieira   ORCID: orcid.org/0000-0002-8263-786X 1 , 6 , 7 , 8 ,
• Viktorija Zaksas   ORCID: orcid.org/0000-0001-7916-4902 1 , 9 ,
• Keshav K. Singh   ORCID: orcid.org/0000-0002-0047-8616 1 , 10 ,
• Eve Syrkin Wurtele 1 , 11 &
• Afshin Beheshti   ORCID: orcid.org/0000-0003-4643-531X 1 , 12 , 13   na2  

European Journal of Human Genetics volume  30 ,  pages 889–898 ( 2022 ) Cite this article

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• Viral infection

COVID-19, the disease caused by SARS-CoV-2, has claimed approximately 5 million lives and 257 million cases reported globally. This virus and disease have significantly affected people worldwide, whether directly and/or indirectly, with a virulent pathogen that continues to evolve as we race to learn how to prevent, control, or cure COVID-19. The focus of this review is on the SARS-CoV-2 virus’ mechanism of infection and its proclivity at adapting and restructuring the intracellular environment to support viral replication. We highlight current knowledge and how scientific communities with expertize in viral, cellular, and clinical biology have contributed to increase our understanding of SARS-CoV-2, and how these findings may help explain the widely varied clinical observations of COVID-19 patients.

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Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants

Cong Sun, Chu Xie, … Mu-Sheng Zeng

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Sibei Lei, Xiaohua Chen, … Ke Men

Introduction

As of November 21st, 2021, over 257 million cases of coronavirus disease 2019 (COVID-19) have been reported, and more than 5 million lives claimed globally [ 1 ]. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Development of vaccines against SARS-CoV-2 provide a major step forward in reducing COVID-19’s impact. However, the pandemic is ongoing, and the continued viral transmission allows for accumulation of mutations in the viral genome, which can provide advantages in replication, immune escape, increased transmissibility, or diagnostic detection failure [ 2 ]. With the quickly evolving SARS-CoV-2 variants and the slow rate of vaccination globally, it is critical to fully understand this novel virus and disease.

Coronaviruses are named as such because the S proteins resemble a halo or corona on scanning electron microscope imagery [ 3 ]. SARS-CoV-2 belongs to the genus Betacoronavirus. Of the human Betacoronavirus, including OC43, HKU1, SARS-CoV-1, and Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) [ 4 ]. SARS-CoV-2 bears the highest genetic sequence similarity to SARS-CoV-1 [ 5 ]. Accordingly, COVID-19, caused by SARS-CoV-2, resembles SARS, caused by SARS-CoV-1, in many ways, but with some important differences [ 6 ]. Key characteristics of SARS-CoV-1 and 2 include: 1) a positive-sense RNA virus with a large genome of ~30 kilobases; 2) a large, enveloped virus containing a helical nucleocapsid with the virus’s genetic code, with an exterior studded in several spike proteins that facilitate the infection of host cells), and 3) similar genomic structures. The first 2/3 of both genomes encodes for two macro polypeptides pp1a/pp1b (see Fig.  1 ). Pp1a/pp1b are auto-proteolytically processed to generate 16 non-structural proteins (NSP).

Structural elements of the virus, including the spike protein, envelope, membrane, and internal components such as the viral single-stranded RNA and nucleocapsid proteins (above). SARS-CoV-2 genome components (below).

The main virus-specific functions of the SARS-CoV-2 NSPs are: NSP1 - cellular mRNA degradation, global translation inhibition; NSP2 - cell cycle progression disruption; NSP3 - formation of double-membrane vesicles (DMVs; SARS-CoV-2 protease); NSP4 - formation of DMVs; NSP5 - main SARS-CoV-2 protease; NSP6 - formation of DMVs, NSP7 - replication complex; NSP8 – primase; NSP9 - RNA binding protein; NSP10 - cofactor of NSP14 & NSP16; NSP11 - unknown, NSP12 - RNA-dependent RNA polymerase; NSP13 - RNA helicase, 5ʹ phosphatase, NSP14 - N7-MTase, 3ʹ-5ʹ exonuclease; NSP15 – endonuclease; and NSP16–2ʹ-O-MTase, mRNA capping.

The remaining 1/3 of the SARS-CoV-2 genome encodes for the structural proteins S (spike), E (envelope), M (membrane), and N (nucleocapsid), and several open reading frames (ORFs; (3a, 6, 7a, 7b, 8, 9b, and 10) [ 7 ]. The S protein binds the host cell receptor, which for SARS-CoV-1/2 is the human angiotensin-converting enzyme 2 (hACE2) (see Fig.  2 and Supplementary Table  1 ). These proteins share homology and function with SARS-CoV-1.

Structural interactions between the virus and target cell, including the viral spike protein, ACE2-receptor, TMPRSS2 reaction to cleave and begin the viral intracellular internalization (above, A ), and consequent signal transduction pathways stimulated by the virus as it hijacks pathways to turn the infected cell into a SARS-CoV-2 producing factory (below, B ).

There are two notable differences between SARS-CoV-1 and SARS-CoV-2. First is the presence of the ORF8 polypeptide found in SARS-CoV-2 but not in SARS-CoV-1. SARS-CoV-1 has a 29 nucleotide (nt) deletion (del) which splits it into ORF8a and ORF8b. Second, SARS-CoV-2 contains a gene encoding a novel orphan protein, ORF10, which is not present in SARS-CoV-1 [ 7 ].

SARS-CoV-2’s evolutionary rate has been estimated to be around 9’×’10 −4 substitutions per site per year [ 8 ], while also having a high transmissibility, large portion of asymptomatic cases [ 9 ], large pool of susceptible hosts to replicate in [ 10 , 11 ], and on-going environmental pressures (e.g., low vaccination rates and changes in policies allowing human carriers to continue to transmit the virus), which have allowed SARS-CoV-2 to accumulate mutation in its genome.

Mutations have been detected in all parts of the viral genome, including in the leader 5ʹ untranslated region (UTR), orf1ab (NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, and NSP14), spike, ORF3a, ORF8, nucleocapsid, and ORF10 [ 8 ]. These genomic changes have been shown to influence viral immune evasion, inflammasome interaction, helicase, exonuclease proofreading mechanism, the activity of the RNA-dependent RNA polymerase (RdRp) and thereby viral replication, infectivity, and cell release [ 12 ].

Mutations associated with the spike are of particular interest, as they influence human-to-human transmission, as well as human-to-animal passage. Within the spike, mutations tend to fall into four general classes, those that affect the receptor-binding domain (RBD), which are of importance because some may provide both immune escape or a fitness advantage, as well as facilitate reverse zoonotic events. There are some mutations that occur in the N-terminal domain (NTD), which is the portion most exposed on the virus surface. There is evidence for immune selection in this region, and preliminary evidence that at least one of these changes (delH69/delV70) could improve fitness [ 13 ]. Mutations in or near the furin cleavage site, and several groupings close to the D614G mutation, possibly affect infection efficiency and can also be important for neutralizing antibodies.

This large SARS-CoV-2 genome diversity has been categorized by different nomenclature systems, describing variants of varied public health interest or concern. Pango lineages B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) have been classified as “variants of concern” (VOC) because they present mutations that have been shown to impact diagnostics, treatments, or vaccines, conferring increased transmissibility and increased disease severity. The impact of these mutations highlights the need for further research not only on the mechanisms of SARS-CoV-2 intracellular processes, but also how the extracellular environment may lead to further spread of the virus and subsequent public health burden.

The SARS-CoV-2 virus can exert physiological effects by directly infecting cells and via intercellular signaling by the infected cells. In this review, we provide insight into SARS-CoV-2 infection and intracellular host responses (targets, pathways, networks, biological processes, and functional adaptations) to viral invasion. We emphasize a canonical set of reactions induced by SARS-CoV-2, which we have organized for the reader’s consideration. However, there is tremendous variation in cellular responses to SARS-CoV-2, depending on factors including the cell type, organ type, metabolic and physiological context, patient genetics, individual clinical characteristics (e.g., age, sex, comorbidities), and stage/severity in the COVID-19 disease.

This is the first of a three-part comprehensive series of linked reviews on SARS-CoV-2 covering: intracellular effects (present study); extracellular consequences (review 2); and current and potential therapeutics (review 3). This review and the two that will follow aim to provide a foundational understanding of the current knowledge on SARS-CoV-2, from basic biology to clinical outcome and therapy avenues, that highlight future areas of research and could help inform public health interventions across the world.

Infected tissue and cell types

SARS-CoV-2 targets the nasal cavity and lungs; however, the detailed cellular tropism remains unclear, and likely varies among individuals. Furthermore, there is increased variability of viral cellular tropism with the emergent SARS-CoV-2 variants, which include Alpha, Beta, Gamma, Epsilon, Eta, Iota, Kappa, 1.617.3, Mu, Zeta, and in particular, Delta and Omicron, as well as the various lineages of each variant [ 14 ]. This is related with SARS-CoV-2’s mutation ability affecting its antigenic phenotype to circumvent immunity. The spike protein mediates attachment of the virus to host cell-surface receptors and fusion between virus and cell membranes; it is also the principal target for neutralizing antibodies generated following infection, and is the component for both mRNA and adenovirus-based vaccines [ 15 ]. Several studies have contributed to the current understanding of how mutations in the SARS-CoV-2 spike protein affect neutralization and emergence of new strains, which include studies of traditional escape mutation, targeted characterization of particular mutations, and wider investigations of large numbers of circulating variants [ 16 ]. These are active areas of research, in particular given the continued emergence of new lineages of new variants. A study of human, bat, non-human primate, and mouse cell lines showed various cell types were susceptible to the virus. These included pulmonary, intestinal, hepatic, renal, and neuronal, with cell lines expressing the hACE-2 receptor (hACE-2) having a generally greater viral load [ 17 ]. Although cell lines do not reflect physiological conditions, this research indicates that SARS-CoV-2 can infect many cell types, and that hACE-2 provides a critical entry mechanism [ 18 ]. Epithelial, vascular endothelial, pancreas, and mucosal cell types can all be infected by the virus [ 19 , 20 , 21 ].

Several investigations have employed 3D organoid cultures to simulate more physiological conditions than cell cultures [ 22 ]. In one such study, lung and colonic organoid models showed SARS-CoV-2 infection was reduced when various SARS-CoV-2 entry inhibitors were applied [ 22 ]. Another study illustrated the flexibility of different organoid models, such as pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons from human pluripotent stem cells, and adult primary cells (human islets, hepatocyte, and cholangiocytes) to test viral effects such as cytokine production, gene expression, and other physiological responses. The resultant data correlated well with some patient autopsy samples [ 22 ] indicating organoids provide a valuable disease modeling tool [ 18 ].

In one study of post-mortem patients, immunohistochemistry and immunofluorescence revealed viral antigen (spike protein) in pneumocytes and hyperplastic cells around the bronchioles, mucosal epithelia, submucosal glands, gland ducts of the trachea, glands of the small intestine, distal tubules and collecting ducts of the kidneys, islets of Langerhans, glands and intra-islet ducts of the pancreas, and vascular tissues of the brain and heart [ 23 ]. Few viral antigens were present in the large intestine and renal proximal tubules, and none in the liver. A follow-up colocalization analysis showed ACE2 and viral antigen in the lung, trachea, small intestine, kidney, pancreas, and heart. In the brain, ACE2-expressing cells were detected, but they were negative for the viral antigen [ 23 ]. Endothelial cells of multiple organs were infected, supporting the clinical observations of endotheliitis in some COVID-19 patients.

Single-cell RNA sequencing (scRNA-seq) demonstrated ACE2 receptor expression was primarily restricted to lung pneumocytes, gut absorptive enterocytes, and nasal mucosa goblet secretory cells [ 24 ]. In general, the distribution of ACE2 receptors may in part explain the systemic diversity and range of SARS-CoV-2’s effects. Further research into infection of these cell types versus others in mucosal barrier organs will be important to determine cell-types that serve as initial entry ways for the virus into the body.

Human autopsy studies [ 21 ] have shown that SARS-CoV-2 infects multiple organs including lungs, pharynx, liver, nasal mucosa, trachea, intestines, skin, pancreas, kidney, brain, and heart. A study of 27 patients showed multi-organ tropisms (lung, pharynx, heart, liver, brain, and kidneys), with the highest levels of SARS-CoV-2 copies per cell, as detected by in situ hybridization and indirect immunofluorescence, in the respiratory tract, and lower levels in the kidneys, liver, heart, and brain [ 21 ]. Transcriptional profiling of nasopharyngeal swabs, patient autopsy, and body-wide tissues (e.g. heart, liver, lung, kidney, and lymph nodes), provided further evidence of the physiologically systemic effects of SARS-CoV-2 [ 24 ].

These studies suggest that the virus has a varying range of expression within each organ, which may be influenced by levels of the ACE2-receptor and related entry factors (Transmembrane protease, serine-2 [TMPRSS2], transferrin receptor protein 1 [TRFC1], cluster of differentiation 4 [CD4], and neuropilin-1 [NRP1]) within each organ-type [ 24 ]. This further highlights the varied organ and tissues that are capable of being infected by the virus, and the resultant wide-range of patient symptoms.

The physiological status of the individual significantly affects COVID-19 morbidity and mortality [ 25 , 26 ]. Notably, patients with pre-existing conditions of obesity, hypertension, and diabetes have a less favorable disease outcome, likely in part due to the elevated levels of inflammation and metabolic disturbances associated with those conditions [ 25 ]. Conversely, SARS-CoV-2 infection may exacerbate pre-existing conditions, leading to more severe COVID-19 outcome [ 27 ].

SARS-CoV-2 Receptors – Angiotensin Converting Enzyme-2 (ACE2)

The cellular surface receptor ACE2, a key regulator of the Renin-Angiotensin Aldosterone System (RAAS). It is speculated to be the primary SARS-CoV-2 viral target for entry. SARS-CoV-2 is thought to infect multiple organs in part due to the widespread distribution, expression, and polymorphisms of ACE2 [ 28 , 29 ].

ACE2’s molecular function in the human RAAS pathway is to cleave Angiotensin I to produce Angiotensin 1–9, and break down Angiotensin II into Angiotensin 1–7. RAAS moderates blood pressure and osmolarity by means of hormonal feedback control. In response to binding of ACE2 to the ACE2 receptor (ACE2R), blood vessels vasoconstrict. This process is mediated by G-protein-signaling, activating phospholipase C and increasing cytosolic Ca 2+ concentrations. ACE2 also plays an important role in inactivating Des-Arg9-Bradykinin (DABK), a bradykinin involved in inflammation. This inactivation promotes C-X-C motif chemokine 5 (CXCL5), macrophage inflammatory protein-2 (MIPS2), keratinocytes-derived chemokine (KC), and tumor necrosis factor-〈 (TNF-α) activity, drawing leukocytes into the affected tissues [ 30 ].

Decreased ACE2 receptor expression can have detrimental effects. Computational models of COVID-19 suggest the role of a bradykinin storm in the pathophysiology of the disease. In this model, the Kallikrein-Kinin and Renin-Angiotensin-Aldosterone Systems are integrated, with cross-talk mediated by the degradation of bradykinin by ACE and prolylcarboxypeptidase [ 31 ]. This behavior makes the SARS-CoV-2 spike protein behave akin to an ACE-inhibiting drug [ 32 ]. Thus, disruption of ACE2 expression from SARS-CoV-2 binding can lead to altered tissue function and exacerbate disease.

The ~600-kDa trimeric S proteins can bind to ACE2 through the RBD required for membrane fusion (see Fig.  2 ). The binding initiates viral internalization, with the cleavage of S1/S2 inducing a conformational change from prefusion into post-fusion. S1 consists of the NTD, the RBD, and subdomain 1 and 2 (SD1 and SD2). S2 contains the hydrophobic fusion peptide and is responsible for the viral and cell membrane fusion [ 33 ]. SARS-CoV-2 S-protein shows varying states of conformational shifts of the RBD site progressing towards proteolytic processing, making the viral RBD more accessible to ACE2, with the cleavage at the S1/S2 leading towards RBD open confirmation and viral internalization [ 33 , 34 ]. The S- and RBD-viral sites are notable for affecting transmission and disease severity, and variants have been shown to accumulate mutations at these sites leading to increased S- and RBD affinity with ACE2 [ 35 ]. Understanding the biology of the SARS-CoV-2 surface interactions will help elucidate how the virus can invade multiple organ systems and cell types.

Calcium Ion (Ca 2+ ) Signaling

The calcium ion (Ca 2+ ) is essential for many aspects of cellular physiology and viral replication. Experimental data on the relation between Ca 2+ signaling and SARS-CoV-2 infection and replication is sparse. However, studies of other coronaviruses (e.g., SARS-CoV-1, MERS-CoV) have reported that these viruses utilize Ca 2+ for host fusion [ 36 ]. The fusion protein (FP) of MERS-CoV binds to one Ca 2+ ion, while the SARS-CoV-2 spike (S) protein has two FP domains, FP1 and FP2, and binds to two Ca 2+ ions for host cell entry [ 37 ]. SARS-CoV-2 appears to affect cellular function by altering the host Ca 2+ homeostasis in ways that promote viral infection and reproduction (see Fig.  3 ). One mechanism is through disruption of calcium channels and pumps (e.g., voltage-gated calcium channels (VGCCs), receptor-operated calcium channels, store-operated calcium channels, transient receptor-potential ion channels, and Ca 2+ -ATPase) [ 28 , 37 ]. This leads to increased intracellular Ca 2+ concentrations, resulting in virus-induced cell lysis [ 28 , 37 ]. The interaction between the virus and VGCCs may also promote virus-host cell fusion for entry [ 28 ].

Structural elements of the virus, including the spike protein, envelope, membrane, and internal components such as the viral single-stranded RNA and nucleocapsid proteins (above).

Viroporins, transmembrane pore-forming proteins that alter membrane permeability to ions including Ca 2+ by forming membrane channels, are a characteristic of a diversity of virus. SARS-CoV-1/2 each encode viroporins. SARS-CoV-1 encodes for three viroporin proteins ORF3a, E and ORF8b, which alter ion homeostasis within the cell, and have important roles in pathogenesis and promoting viral fitness. SARS-CoV-2 encodes two of these viroporin proteins, E and ORF3a; however, the ORF8 protein of SARS-CoV-2 is highly divergent from SARS-CoV-1 ORF8b and lacks the viroporin sequence of SARS-CoV-1 ORF8b.

The E and ORF3a proteins of coronaviruses impact Ca 2+ homeostasis in the host, by acting as calcium ion channels, enhancing the virion’s entry and replication potential [ 38 ]. The SARS-CoV-2-E protein is a 76 amino acid (aa) integral membrane protein with one transmembrane domain (TMD) that allows the E protein to form protein-lipid channels in membranes that promote permeability to Ca 2+ ions. The SARS-CoV-2-ORF3a protein is 274 aa in length, harbors three helical TMD, and is a Na + or Ca 2+ ion channel protein. The alteration of Ca 2+ homeostasis by SARS-COV-1-E and SARS-COV-2-E proteins promotes SARS-CoV-1/2 fitness and elicits the production of chemokines and cytokines, contributing to pathogenesis. Ion channel activity modulation by the SARS-CoV-1-ORF3a protein also modulates viral release [ 39 ]. Therefore, when SARS-CoV-2 infects the human body, the resultant dysregulation of Ca 2+ homeostasis may contribute to morbidity and mortality. COVID-19 patients have been noted to have low serum calcium levels overall [ 40 ].

We speculate that Ca 2+ dysregulation could lead to increased cellular oxidative stress and shifts in metabolic activity. Low Ca 2+ may also be coupled with viral infection and internalization through the ACE2R, which synergizes with Ca 2+ signaling pathways. Understanding these reverberations will increase our insight into the basic biology of the effects of SARS-CoV-2 infection on the various organ systems.

Intracellular signaling

Viral infection and hijacking of cell-surface receptors begin to trigger activation of multiple intracellular pathways in addition to Ca 2+ signaling. As infection proceeds, SARS-CoV-2 manipulates, or totally reprograms, the normal metabolism and signaling of the host cell, optimizing the molecular environment to enable the viral replication cycle. This involves interfering with signaling pathways that regulate processes of DNA repair and replication, immune response, transcription, metabolism, cell cycle, and apoptosis [ 39 ].

SARS-CoV-2 infection alters phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), Type I and III interferon, transforming growth factor-β (TGF-β), Toll-like receptors (TLR), and nuclear factor kappa-light chain enhancer (NF-κB) pathways. These pathways are dysregulated in the setting of SARS-CoV-2 to antagonize host antiviral responses and are vital for viral replication, entry, propagation, and/or apoptosis/viral release. For instance, severe COVID-19 is characterized by an inflammatory profile dominated by NF-κB activity [ 41 ]. The SARS-CoV-2-encoded NSP13 and Open Reading Frame 9c (ORF9c) proteins can interact directly with elements of the transducin-like enhancer (TLE) family of proteins and thus regulate the NF-κB inflammatory response [ 42 ]. While broad activation of NF-κB is induced by a variety SARS-CoV-2-encoded products, Open Reading Frame 7a (ORF7a) specifically is a potent stimulator of NF-κB associated proinflammatory chemo- and cytokines, which are elevated in the presence of severe COVID-19. NF-κB plays a similar role in other coronavirus infections.

Host antiviral immunity requires an optimal and coordinated response to control viral infections; this immunity is mediated by several host sensors, notably pattern recognition receptors (PRR). PRRs identify damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively). SARS-CoV-2 infects the cell via the endosomal compartment, and may activate TLRs, such as TLR4, resulting in increased NF-κB activity and expression [ 42 , 43 ]. The MyD88-mediated TRIF activation of TLR downstream pathways triggers the nuclear translocation of NF-κB, IFN regulatory factor 3 (IRF-3), and IFN regulatory factor 7 (IRF-7), resulting in the expression of innate immunity proinflammatory cytokines (interleukin-1 [IL-1], interleukin-6 [IL- 6], TNF-α) and interferons (IFNs). Continuous activation of TLR can increase MyD88 and Interleukin-1β (IL-1β), which then can further activate NF-κB [ 43 ]. RNA viruses are detected by several sensors, such as TLRs 3, 7 and 8. TLR3 recognizes double stranded RNA, while TLR7 and TLR8 single stranded RNA. In addition to ssRNA and dsRNA, viral proteins can act as PAMPS and potentiate inflammatory signaling through the stimulation of surface TLRs. Interestingly, in SARS-CoV-2, TLR2 is a critical mediator of envelope protein detection and driver of pathogenesis through inflammatory process augmentation [ 44 ]. Some individuals with severe COVID-19 have mutations in genes associated with type I and III IFN pathways [ 45 ]. Ten percent of individuals that progress to severe COVID-19 pneumonia display elevated amounts of neutralizing antibodies against type I IFN-α2 and IFN-ω [ 46 ]; these antibodies are not present in healthy or asymptomatic individuals. Of note, albeit TLR3 activation is critical for viral clearance, TLR3 hyperactivation can lead to a cytokine storm and the subsequent severe COVID-19. Other receptors are also involved in SARS-CoV-2 recognition, such as the proteins of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5). Once inside the cell, double strand viral RNA can be recognized by RIG-I/MDA5, thus initiating an antiviral response through mitochondrial antiviral signaling (MAVS). MAVS activated the downstream pathways, IκB kinase α/β (IKK) and TBK1/IKKε, leading to translocation of NF-κB and/or IRF3 into the nucleus and induction of genes involved with innate antiviral immunity and the subsequent induction of IFN-stimulated genes (ISGs).

Inhibition of IFNs and ISGs is a tactic used by several viruses to evade host antiviral responses [ 47 ], and SARS-CoV-2-mediated IFNs and ISGs dysregulation appears to be an important strategy used by this virus to replicate and disrupt immune homeostasis. Furthermore, therapies with type I and III IFNs alone or combined with other drugs suppressed SARS-CoV-2, ameliorating COVID-19 disease [ 48 ].

The cytokine TGF-β triggers the Janus kinases (JAKs) / signal transducer and activator of transcription (STAT) proteins (JAK/STAT) pathway in certain contexts, while suppressing it in others [ 49 ]. It has been proposed that SARS-CoV-2 proteins, particularly NSP1 and ORF6, may dysregulate STAT1 and STAT3, leading to a positive feedback loop where coagulopathy triggers TLR4 via PAI-1 binding, circularly activating STAT; for this reason, therapeutic targeting of the Janus kinase pathway has been proposed [ 50 ].

The innate immune response is a first step to protecting against pathogens, which stimulate the interferon signaling pathway and expression of IFN-I, leading to an antiviral cellular response [ 51 ]. Coronaviruses have developed mechanisms to hinder IFN-expression and reduce the production of IFN. This suppression has been shown to correlate with disease severity and mortality [ 52 ]. This holds true for SARS-CoV-2, with recent studies showing that viral proteins ORF6, ORF8, and nucleocapsid being potent inhibitors of the IFN-I signaling pathway [ 53 ].

Metabolic adaptations

Viruses rely on host cell machinery to propagate, promoting anabolism for generation of macromolecules needed for virion replication and assembly (see Fig.  2 ). Consequently, viral proteins (see Supplementary Table  1 ) affect intracellular pathways, leading to subsequent adaptations by the cellular metabolism where the mitochondria plays a central role.

We reported recently through study of COVID-19 patient samples (i.e., nasopharyngeal swab samples, various organs from autopsy COVID-19 samples, murine lung tissues, and various organs from hamsters being infected with SARS-CoV-2) that heavy suppression occurs of mitochondrial functions in various organs [ 54 ]. Specifically, in the course of SARS-CoV-2 infection, the virus blocks the transcription of discrete groups of mitochondrial genes from major bioenergetic organs, while upregulation occurs in others as a compensatory mechanism to rescue the damage occurring in the major bioenergetic organs. This demonstrated a dynamic evolution of mitochondrial gene expression and cellular energetics as the virus progresses from one organ to the next. Transcriptomic changes in the nasopharyngeal infected samples revealed that during initial SARS-CoV-2 infection, nDNA coded mitochondrial genes are blocked and the co-inhibited genes were found to group together as components of preassembly modules of the mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II, III, IV and V. At the time of death for COVID-19 patients, we showed virtually all mitochondrial function were inhibited in the heart, suggesting cardiac mitochondrial dysfunction in longer term COVID-19 pathology. In addition, mTOR signaling and the integrated stress response were highly dysregulated throughout all organs. Lastly, mitochondrial inhibition was shown to activate HIF-1α and its target genes shifting cellular metabolism away from catabolism and towards viral synthesis. Our results indicate that manipulation of mitochondrial function may be an important approach for mitigating the severity of COIVID-19.

SARS-CoV-2 infection of human monocytes [ 55 ] and human pulmonary alveolar epithelial (HPAEpiC) cells [ 56 ] induced mitochondrial reactive oxygen species (mROS) production, increased HIF-1α protein levels and upregulated expression of HIF-1α target genes [ 57 ]. The stability of hypoxia inducible factor-1α (HIF-1α) during a SARS-CoV-2 infection was shown to increase the production of pro-inflammatory cytokines and SARS-CoV-2 replication [ 55 , 56 , 57 ]. The expression of ORF3a in human embryonic kidney 293 T-antigen cells (HEK293T) cells increased the stability of HIF-1α and induced mROS production, which is an activator of HIF-1α. Together these results suggest that ORF3a induces mROS production to activate HIF-1α, which in turn triggers a shift in cellular metabolism to favor glycolysis, resulting in increased viral replication and transcription of pro-inflammatory cytokines.

Following host cell infection, the SARS-CoV-2 replication/transcription complex synthesizes ~30 kb viral genomes as well as the subgenomic RNAs required to encode for viral structural and mechanistic proteins. Between 1–5 h post-infection, the percentage of coronavirus-encoded protein per total cellular protein translation may increase by as much as 20,000 times, with the fraction of viral to cellular RNA ultimately reaching as high as 90% intracellularly [ 58 ]. To accommodate this huge shift towards viral replication, there is certainly a requirement of a shift in cellular metabolism to accommodate for viral synthesis. An investigation of SARS-CoV-2 metabolism during the initial 48-hours post viral infection showed that amino acid availability and synthesis are altered, de novo purine synthesis intermediates are accumulated, intracellular glucose and folate are depleted, and lactate levels are elevated [ 59 ]. This suggests a viral strategy of upregulating purine metabolism at the post-translational level to coincide with the shutting off of the majority of host proteins at translation levels.

Virus-infected cells also commonly exhibit the Warburg effect - increased glycolytic metabolism in the presence of inadequate oxygen for oxidative phosphorylation - to supply reducing equivalents and precursors for macromolecule biosynthesis, and to support generation of ATP needed for also increasing nucleotide and lipid biosynthesis. Metabolic shifts include dysregulated Ca 2+ signaling and increased mitochondrial generation of ROS. How SARS-CoV-2 induces host cell nucleotide metabolism remains unanswered.

Mitochondrial metabolism and function are highly impacted in multiple ways. With the shift towards glycolysis, there is a reduction in oxidative phosphorylation affecting the mitochondria and its function. SARS-CoV-2 may interact with the mitochondria to destabilize its oxidative phosphorylation capacity. Coronavirus replication requires the formation of double-membrane vesicles (DMVs) derived from endoplasmic reticulum (ER). These DMVs serve as a site for viral replication and help conceal the virus from host cellular defenses. Interestingly, mitochondrial stress is known to induce mitochondria-derived vesicles (MDVs) that communicate with the ER. It is conceivable that SARS-CoV-2 disruption of mitochondrial function results in the induction of (double-membrane) MDVs. SARS-CoV-2 RNA present in the mitochondria induces mitochondrial dysfunction. Increased DMVs can provide opportunity for viruses to hide and replicate [ 60 ].

SARS-CoV-2 and all subgenomic RNAs are enriched in the host mitochondria, and viral genome’s 5ʹ - and 3ʹ -UTRs contain distinct mitochondrial localization signals [ 61 ], indicating that the viral RNA may hijack the mitochondria, an interesting hypothesis for experimental validation [ 61 ]. Other recent studies have mapped physical interactions of SARS-CoV-2 encoded proteins with mitochondrial localized proteins. These interactions include: NSP8 interaction with mitochondrial ribosomal protein s2 (MRPS2), mitochondrial ribosomal protein s5 (MRPS5), mitochondrial ribosomal protein s25 (MRPS25), and mitochondrial ribosomal protein s27 (MRPS27) ribosomal proteins; ORF9c interaction with mitochondrial NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 1 (NDUFAF1) and NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 9 (NDUFB9); ORF10 interaction with TIMM8; and NSP7 interaction with mitochondrial NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 2 (NDUFAF2). NDUFAF1, NDUFAF2, NDUFB9, and NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 10 (NDUFA10) are all key players in the assembly of complex I, and NDUFA10 is suggested as being one of the master regulators of the SARS-CoV-2 pathology [ 7 ]. Interactions were also observed between viral M protein and ATPase Na + /K + Transporting Subunit Beta 1 (ATP1B1), ATPase H + Transporting V1 Subunit A (ATP6V1A), acyl-coenzyme A dehydrogenase (ACADM), Alpha-aminoadipic semialdehyde synthase (AASS), Peptidase, Mitochondrial Processing Subunit Beta (PMPCB), Pitrilysin Metallopeptidase 1 (PITRM1), Coenzyme Q8B (COQ8B), and Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA); these proteins are each components of critical mitochondrial metabolic pathways. SARS-CoV-2-encoded ORF9b protein interacts and localizes with Translocase Of Outer Mitochondrial Membrane 70 (TOMM70) [ 7 ], a mitochondrial import receptor important for transporting proteins into mitochondria and, more importantly, in modulating anti-viral cellular defense pathways [ 62 ]. These mitochondrial interactions offer glimpses of the viral effect on glycolytic and oxidative phosphorylation pathways and the potential side effects.

Another example of COVID-19’s mitochondrial-related impacts is the over-production of cellular ROS [ 63 ]. ROS and reactive nitrogen species have diverse functions in biological systems; oxidatively attacking pathogens, regulating cell proliferation, and key signaling functions [ 64 ]. However, dysregulation of ROS is implicated in many diseases, including the hyper-inflammatory late phase of COVID-19 [ 65 ]. As a part of normal redox metabolism, superoxide radicals are converted into hydrogen peroxide by the action of superoxide dismutase. The hydrogen peroxide is subsequently broken down into water by glutathione peroxidase. During COVID-19, isoforms of enzymes, including glutathione peroxidase and thioredoxin reductase, may be directly targeted and proteolyzed by the SARS-CoV-2 protease, Mpro.

SARS-CoV-2 is thought to suppress the ROS-associated Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor that regulates the expression of antioxidant proteins that protect against oxidative damage. Dysregulation of the Nrf2 pathway will exacerbate the pro-oxidative stress caused by the virus [ 66 ]. SARS-CoV-2 may suppress the accumulation of the selenoprotein transcripts, which are crucial for the correct functioning of Phospholipid hydroperoxide glutathione peroxidase (GPX4) and mitochondria function [ 67 ]. This redox impairment would lead to a buildup of hydrogen peroxide, which could trigger inflammation by promoting the activity of the mitogen-activated protein kinase (MAPK), NF-κB, and the nuclear NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome [ 68 ].

Due to the multiple effects of SARS-CoV-2 that alter cellular metabolic and oxidative states, there are multiple directions to deplete NAD+, loss of cellular ATP and reduced Poly-ADP-ribose polymerase (PARP) activity, each of which have cytotoxic effects of their own [ 69 ]. In general, NADPH, synthesized from NAD+, is necessary for many key redox reactions; a reduced level of NADPH could play a mechanistic role in cellular metabolic changes from SARS-CoV-2 infection.

SARS-CoV-2 mediated reduction in ATP and nitric oxide signaling induces cell stress

Cellular metabolism adapts to the alterations induced by SARS-CoV-2 infection of the cell (see Fig.  4 ). These adaptations depend on the cell and tissue type. Here, we focus on ATP signaling, which is relevant to epithelial cells, and nitric oxide (NO) signaling, which tends to be perturbed in endothelial cells [ 70 ]. Activation of each pathway at low levels provides protection to the host.

Metabolic pathways and shifts that lead to cellular dysregulation and viral activation to lead towards viral replication (above).

ATP production from oxidative phosphorylation, glycolysis, and other pathways is critical to support cellular physiology, but this molecule also has signaling properties, which can be particularly beneficial in epithelial cells [ 70 ]. Perturbations in ATP generation induced by the virus in epithelial cells [ 71 ] can lead to ATP release from the apical or basolateral spaces, and subsequent extracellular ATP signaling [ 72 ]. It can stimulate P2 receptors on neighboring epithelial cells to activate signal transduction pathways and alter cellular function in adjacent cells even if they are not infected, thus priming naive host cells for confrontation with the virus [ 71 , 72 ].

In the endothelium, nitric oxide directly affects mitochondrial metabolism through interaction with cytochrome C, providing cytoprotection against free radicals. However, reduction of NO bioavailability, due to the increased oxidative stress state caused by SARS-CoV-2-elevated superoxides, results in the formation of peroxynitrites (ONOO-). The reduced NO diffusion to neighboring vascular smooth muscle may impair vascular function [ 73 ]. Peroxynitrite also causes injury to the mitochondria and reduces ATP synthesis, with all of the concomitant negative effects. Therefore, loss of NO bioavailability has major cellular consequences, inducing shifts in multiple enzymatic pathways, cell injury, and death.

Like ATP, NO acts as a biological signaling molecule. This dissolved gas rapidly diffuses across cell membranes and regulates various functions across the body [ 73 ]. The vascular endothelium is the predominant cellular source of NO production, and it plays a critical role in maintaining cardiovascular function. Factors that reduce endothelial NO production (increased oxidative stress, changes in NO synthase synthesis) negatively affect endothelial function [ 73 ]. The cascade of inflammation and oxidative stress triggered by COVID-19 leads to the formation of superoxide free radicals, impairing biological processes and increasing cytotoxicity in the host cells [ 74 ]. The instantaneous reaction of superoxide and NO yields ONOO-, a powerful, cytotoxic nitrating agent. This reaction effectively destroys the NO, rendering it unavailable for its normal regulatory purposes. Thus, the downregulation of NO bioavailability is thought to be a central factor in the severity of COVID-19-associated endotheliitis and the onset of endothelial dysfunction [ 75 ].

The causative agent of the COVID-19 the pandemic, SARS-CoV-2, has caused loss of incomes, economic crises, morbidities, and loss of life worldwide. Here, we describe the virus and review state-of-the-art information about the processes it utilizes to enter and reprogram the human host machinery. We detail research on early infection using evidence from patient samples, organoids and cells, and non-human animal studies. Each of these has limitations but taken together provide unique observational and mechanistic insight on SARS-CoV-2 infection.

COVID-19 is a pleiotropic condition. Viral insults and subsequent cellular metabolic adaptations differ in the context of cell-type, genotype and environmental influences. Thus, much of what we have presented applies to specific cell types and contexts, and we have attempted to cover these contexts.

Key avenues of future research on SARS-CoV-2 infection and propagation include: 1) defining the mechanisms of how the virus enters cells, and the protein and receptor molecules that are critical to this process; 2) elucidating the dynamics of how protein machinery is captured and retrofitted for viral purposes in a cell-specific manner; 3) understanding how the host genetics and environment can affect the ability of the virus to infect; 4) understanding the impact of SARS-CoV-2 on glycolysis and oxidative phosphorylation; and 5) revealing how the mitochondria adapts to ultimately shift its physiology from steady-state.

In the best-case scenario for the SARS-CoV-2 virus, infection leads to a cascade of intracellular adaptations in which multiple networks are remodeled, from transcription to metabolism to signal transduction, shifting the invaded host cell from its original physiology into a SARS-CoV-2 replication system, and causing the emission of new viral particles and signaling molecules. The subsequent disease events will reverberate across the body’s cells and organs. This will be the subject of our Part 2 review (in preparation).

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Acknowledgements

The opinions expressed in this article are those of the authors and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

This work was supported by supplemental funds for COVID-19 research from Translational Research Institute of Space Health through NASA Cooperative Agreement NNX16AO69A (T-0404) to AB, and by a NASA Space Biology Postdoctoral Fellowship (80NSSC19K0426) to SAN. MJT is a recipient of The Evelyn Grollman Glick Scholar Award and supported by research funding from The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Van Andel Research Institute through the Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by AACR, and Specialized Program of Research Excellence (SPORE) program, through the National Cancer Institute (NCI), grant P50CA254897.

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These authors contributed equally: David A. Jamison and S. Anand Narayanan.

This author jointly supervised this work: Afshin Beheshti.

Authors and Affiliations

COVID-19 International Research Team, Medford, MA, USA

David A. Jamison Jr., S. Anand Narayanan, Nídia S. Trovão, Joseph W. Guarnieri, Michael J. Topper, Pedro M. Moraes-Vieira, Viktorija Zaksas, Keshav K. Singh, Eve Syrkin Wurtele & Afshin Beheshti

Department of Nutrition & Integrative Physiology, Florida State University, Tallahassee, FL, USA

• S. Anand Narayanan

Fogarty International Center, National Institutes of Health, Bethesda, MD, USA

Nídia S. Trovão

Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Joseph W. Guarnieri

Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Michael J. Topper

Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil

Pedro M. Moraes-Vieira

Obesity and Comorbidities research Center (OCRC), University of Campinas, Campinas, SP, Brazil

Experimental Medicine Research Cluster, University of Campinas, Campinas, Brazil

Center for Translational Data Science, University of Chicago, Chicago, IL, USA

Viktorija Zaksas

Department of Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Keshav K. Singh

Center for Metabolic Biology, Bioinformatics and Computational Biology, and Genetics Development, and Cell Biology, Iowa State University, Ames, IA, USA

Eve Syrkin Wurtele

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

• Afshin Beheshti

KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA, USA

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Conceptualization: DAJ; Writing – Original Draft: DAJ, SN; Writing – Review and Editing: AB, ESW, KKS, JWG, MJT, VZ, PMMV, DAJ, SN, NST. Visualization: DAJ, SN, JWG; Supervision: AB; Funding Acquisition: AB.

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Jamison, D.A., Anand Narayanan, S., Trovão, N.S. et al. A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet 30 , 889–898 (2022). https://doi.org/10.1038/s41431-022-01108-8

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Older adults’ experiences during the COVID-19 pandemic: a qualitative systematic literature review

• Elfriede Derrer-Merk   ORCID: orcid.org/0000-0001-7241-0808 1 ,
• Maria-Fernanda Reyes-Rodriguez   ORCID: orcid.org/0000-0002-2645-5092 2 ,
• Laura K. Soulsby   ORCID: orcid.org/0000-0001-9071-8654 1 ,
• Louise Roper   ORCID: orcid.org/0000-0002-2918-7628 3 &
• Kate M. Bennett   ORCID: orcid.org/0000-0003-3164-6894 1  

BMC Geriatrics volume  23 , Article number:  580 ( 2023 ) Cite this article

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Relatively little is known about the lived experiences of older adults during the COVID-19 pandemic. We systematically review the international literature to understand the lived experiences of older adult’s experiences during the pandemic.

Design and methodology

This study uses a meta-ethnographical approach to investigate the included studies. The analyses were undertaken with constructivist grounded theory.

Thirty-two studies met the inclusion criteria and only five papers were of low quality. Most, but not all studies, were from the global north. We identified three themes: desired and challenged wellbeing; coping and adaptation; and discrimination and intersectionality.

Overall, the studies’ findings were varied and reflected different times during the pandemic. Studies reported the impact of mass media messaging and its mostly negative impact on older adults. Many studies highlighted the impact of the COVID-19 pandemic on participants' social connectivity and well-being including missing the proximity of loved ones and in consequence experienced an increase in anxiety, feeling of depression, or loneliness. However, many studies reported how participants adapted to the change of lifestyle including new ways of communication, and social distancing. Some studies focused on discrimination and the experiences of sexual and gender minority and ethnic minority participants. Studies found that the pandemic impacted the participants’ well-being including suicidal risk behaviour, friendship loss, and increased mental health issues.

The COVID-19 pandemic disrupted and impacted older adults’ well-being worldwide. Despite the cultural and socio-economic differences many commonalities were found. Studies described the impact of mass media reporting, social connectivity, impact of confinement on well-being, coping, and on discrimination. The authors suggest that these findings need to be acknowledged for future pandemic strategies. Additionally, policy-making processes need to include older adults to address their needs. PROSPERO record [CRD42022331714], (Derrer-Merk et al., Older adults’ lived experiences during the COVID-19 pandemic: a systematic review, 2022).

Peer Review reports

Introduction

In March 2020 the World Health Organisation declared a pandemic caused by the virus SARS-CoV2 (COVID-19) [ 1 ]. At this time 118,000 cases in 114 countries were identified and 4,291 people had already lost their lives [ 2 ]. By July 2022, there were over 5.7 million active cases and over 6.4 million deaths [ 2 ]. Despite the effort to combat and eliminate the virus globally, new variants of the virus are still a concern. At the start of the pandemic, little was known about who would be most at risk, but emerging data suggested that both people with underlying health conditions and older people had a higher risk of becoming seriously ill [ 3 ]. Thus, countries worldwide imposed health and safety measures aimed at reducing viral transmission and protecting people at higher risk of contracting the virus [ 4 ]. These measures included: national lockdowns with different lengths and frequencies; targeted shopping times for older people; hygiene procedures (wearing masks, washing hands regularly, disinfecting hands); restricting or prohibiting social gatherings; working from home, school closure, and home-schooling.

Research suggests that lockdowns and protective measures impacted on people’s lives, and had a particular impact on older people. They were at higher risk from COVID-19, with greater disease severity and higher mortality compared to younger people [ 5 ]. Older adults were identified as at higher risk as they are more likely to have pre-existing conditions including heart disease, diabetes, and severe respiratory conditions [ 5 ]. Additionally, recent research highlights that COVID-19 and its safety measures led to increased mental health problems, including increased feelings of depression, anxiety, social isolation, and loneliness, potentially cognitive decline [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Other studies reported the consequences of only age-based protective health measures including self-isolation for people older people (e.g. feeling old, losing out the time with family) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].

Over the past decade, the World Health Organisation (WHO) has recognised the importance of risk communication within public health emergency preparedness and response, especially in the context of epidemics and pandemics. Risk communication is defined as “the real-time exchange of information, advice and opinions between experts or officials, and people who face a threat (hazard) to their survival, health or economic or social well-being” ([ 31 ], p5). This includes reporting the risk and health protection measurements through media and governmental bodies. Constructing awareness and building trust in society are essential components of risk communication [ 32 ]. In the context of the pandemic, the WHO noted that individual risk perception helped to prompt problem-solving activities (such as wearing face masks, social distancing, and self-isolation). However, the prolonged perception of pandemic-related uncertainty and risk could also lead to heightened feelings of distress and anxiety [ 31 , 33 ], see also [ 34 , 35 , 36 , 37 ].

This new and unprecedented disease provided the ground for researchers worldwide to investigate the COVID-19 pandemic. To date (August 2022), approximately 8072 studies have been recorded on the U.S. National Library of Medicine ClinicalTrials.gov [ 38 ] and 12002 systematic reviews have been registered at PROSPERO, concerning COVID-19. However, to our knowledge, there is little known about qualitative research as a response to the COVID-19 pandemic and how it impacted older adults’ well-being [ 39 ]. In particular, little is known about how older people experienced the pandemic. Thus, our research question considers: How did older adults experience the COVID-19 pandemic worldwide?

We use a qualitative evidence synthesis (QES) recommended by Cochrane Qualitative and Implementation Methods Group to identify peer-reviewed articles [ 40 ]. This provides an overview of existing research, identifies potential research gaps, and develops new cumulative knowledge concerning the COVID-19 pandemic and older adults’ experiences. QES is a valuable method for its potential to contribute to research and policy [ 41 ]. Flemming and Noyes [ 40 ] argue that the evidence synthesis from qualitative research provides a richer interpretation compared to single primary research. They identified an increasing demand for qualitative evidence synthesis from a wide range of “health and social professionals, policymakers, guideline developers and educationalists” (p.1).

Methodology

A systematic literature review requires a specific approach compared to other reviews. Although there is no consensus on how it is conducted, recent systematic literature reviews have agreed the following reporting criteria are addressed [ 42 , 43 ]: (a) a research question; (b) reporting database, and search strategy; (c) inclusion and exclusion criteria; (d) reporting selection methods; (e) critically appraisal tools; (f) data analysis and synthesis. We applied these criteria in our study and began by registering the research protocol with Prospero [ 44 ].

The study is registered at Prospero [ 44 ]. This systematic literature review incorporates qualitative studies concerning older adults’ experiences during the COVID-19 pandemic.

Search strategy

The primary qualitative articles were identified via a systematic search as per the qualitative-specific SPIDER approach [ 45 ]. The SPIDER tool is designed to structure qualitative research questions, focusing less on interventions and more on study design, and ‘samples’ rather than populations, encompassing:

S-Sample. This includes all articles concerning older adults aged 60 +  [ 1 ].

P-Phenomena of Interest. How did older adults experience the COVID-19 pandemic?

D-Design. We aim to investigate qualitative studies concerning the experiences of older adults during the COVID-19 pandemic.

E-Evaluation. The evaluation of studies will be evaluated with the amended Critical Appraisal Skills Programme CASP [ 46 ].

R-Research type Qualitative

Information source

The following databases were searched: PsychInfo, Medline, CINAHL, Web of Science, Annual Review, Annual Review of Gerontology, and Geriatrics. A hand search was conducted on Google Scholar and additional searches examined the reference lists of the included papers. The keyword search included the following terms: (older adults or elderly) AND (COVID-19 or SARS or pandemic) AND (experiences); (older adults) AND (experience) AND (covid-19) OR (coronavirus); (older adults) AND (experience) AND (covid-19 OR coronavirus) AND (Qualitative). Additional hand search terms included e.g. senior, senior citizen, or old age.

Inclusion and exclusion criteria

Articles were included when they met the following criteria: primary research using qualitative methods related to the lived experience of older adults aged 60 + (i.e. the experiences of individuals during the COVID-19 pandemic); peer-reviewed journal articles published in English; related to the COVID-19 pandemic; empirical research; published from 2020 till August 2022.

Articles were excluded when: papers discussed health professionals’ experiences; diagnostics; medical studies; interventions; day-care; home care; or carers; experiences with dementia; studies including hospitals; quantitative studies; mixed-method studies; single-case studies; people under the age of 60; grey literature; scoping reviews, and systematic reviews. We excluded clinical/care-related studies as we wanted to explore the everyday experiences of people aged 60 + . Mixed-method studies were excluded as we were interested in what was represented in solely qualitative studies. However, we acknowledge, that mixed-method studies are valuable for future systematic reviews.

Meta-ethnography

The qualitative synthesis was undertaken by using meta-ethnography. The authors have chosen meta-ethnography over other methodologies as it is an inductive and interpretive synthesis analysis and is uniquely “suited to developing new conceptual models and theories” ([ 47 ], p 2), see also [ 48 ]. Therefore, it combines well with constructivist grounded theory methodology. Meta-ethnography also examines and identifies areas of disagreements between studies [ 48 ].

This is of particular interest as the lived experiences of older adults during the COVID-19 pandemic were likely to be diverse. The method enables the researcher to synthesise the findings (e.g. themes, concepts) from primary studies, acknowledging primary data (quotes) by “using a unique translation synthesis method to transcend the findings of individual study accounts and create higher order” constructs ([ 47 ], p. 2). The following seven steps were applied:

Getting started (identify area of interest). We were interested in the lived experiences of older adults worldwide.

Deciding what was relevant to the initial interest (defining the focus, locating relevant studies, decision to include studies, quality appraisal). We decided on the inclusion and exclusion criteria and an appropriate quality appraisal.

Reading the studies. We used the screening process described below (title, abstract, full text)

Determining how the studies were related (extracting first-order constructs- participants’ quotes and second-order construct- primary author interpretation, clustering the themes from the studies into new categories (Table 3 ).

Translating the studies into one another (comparing and contrasting the studies, checking commonalities or differences of each article) to organise and develop higher-order constructs by using constant comparison (Table 3 ). Translating is the process of finding commonalities between studies [ 48 ].

Synthesising the translation (reciprocal and refutational synthesis, a lines of argument synthesis (interpretation of the relationship between the themes- leads to key themes and constructs of higher order; creating new meaning, Tables 2 , 3 ),

Expressing the synthesis (writing up the findings) [ 47 , 48 ].

Screening and Study Selection

A 4-stage screening protocol was followed (Fig.  1 Prisma). First, all selected studies were screened for duplicates, which were deleted. Second, all remaining studies were screened for eligibility, and non-relevant studies were excluded at the preliminary stage. These screening steps were as follows: 1. title screening; 2. abstract screening, by the first and senior authors independently; and 3. full-text screening which was undertaken for almost all papers by the first author. However, 2 papers [ 9 , 23 ] were assessed independently by LS, LR, and LMM to avoid a conflict of interest. The other co-authors also screened independently a portion of the papers each, to ensure that each paper had two independent screens to determine inclusion in the review [ 49 ]. This avoided bias and confirmed the eligibility of the included papers (Fig.  1 ). Endnote reference management was used to store the articles and aid the screening process.

Prisma flow diagram adapted from Page et al. [ 50 ]. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 372, n71. https://doi.org/10.1136/bmj.n71 )

Data extraction

After title and abstract screening, 39 papers were selected for reading the full article. 7 papers were excluded after the full-text assessment (1 study was conducted in 2017, but published in 2021; 2 papers were not fully available in English, 2 papers did not address the research question, 1 article was based on a conference abstract only, 1 article had only one participant age 65 +).

The full-text screening included 32 studies. All the included studies, alongside the CASP template, data extraction table, the draft of this article, and translation for synthesising the findings [ 47 , 48 ] were available and accessible on google drive for all co-authors. All authors discussed the findings in regular meetings.

Quality appraisal

A critical appraisal tool assesses a study for its trustworthiness, methodological rigor, and biases and ensures “transparency in the assessment of primary research” ([ 51 ], p. 5); see also [ 48 , 49 , 50 , 51 , 52 , 53 ]. There is currently no gold standard for assessing primary qualitative studies, but different authors agreed that the amended CASPS checklist was appropriate to assess qualitative studies [ 46 , 54 ]. Thus, we use the amended CASP appraisal tool [ 42 ]. The amended CASP appraisal tool aims to improve qualitative evidence synthesis by assessing ontology and epistemology (Table 1 CASP appraisal tool).

A numerical score was assigned to each question to indicate whether the criteria had been met (= 2), partially met (= 1), or not met (= 0) [ 54 ]; see also [ 55 ]. The score 16 – 22 are considered to be moderate and high-quality studies. The studies scored 15 and below were identified as low-quality papers. Although we focus on higher-quality papers, we did not exclude papers to avoid the exclusion of insightful and meaningful data [ 42 , 48 , 52 , 53 , 54 , 55 , 56 , 57 ]. The quality of the paper was considered in developing the evidence synthesis.

We followed the appraisal questions applied for each included study and answered the criteria either ‘Yes’, ‘Cannot tell’, or ‘No’. (Table 1 CASP appraisal criteria). The tenth question asking the value of the article was answered with ‘high’ of importance, ‘middle’, or low of importance. The new eleventh question in the CASP tool concerning ontology and epistemology was answered with yes, no, or partly (Table 1 ).

Data synthesis

The data synthesis followed the seven steps of Meta-Ethnography developed by Noblit & Hare [ 58 ], starting the data synthesis at step 3, described in detail by [ 47 ]. This encompasses: reading the studies; determining how the studies are related; translating the studies into one another; synthesis the translations; and expressing synthesis. This review provides a synthesis of the findings from studies related to the experiences of older adults during the COVID-19 pandemic. The qualitative analyses are based on constructivist grounded theory [ 59 ] to identify the experiences of older adults during the COVID-19 pandemic (non-clinical) populations. The analysis is inductive and iterative, uses constant comparison, and aims to develop a theory. The qualitative synthesis encompasses all text labelled as ‘results’ or ‘findings’ and uses this as raw data. The raw data includes participant’s quotes; thus, the synthesis is grounded in the participant's experience [ 47 , 48 , 60 , 61 ]. The initial coding was undertaken for each eligible article line by line. Please see Table 2 Themes per author and country. Focused coding was applied using constant comparison, which is a widely used approach in grounded theory [ 61 ]. In particular, common and recurring as well as contradicting concepts within the studies were identified, clustered into categories, and overarching higher order constructs were developed [ 47 , 48 , 60 ] (Tables 2 , 3 , 4 ).

We identified twenty-seven out of thirty-two studies as moderate-high quality; they met most of the criteria (scoring 16/22 or above on the CASP; [ 54 ]. Only five papers were identified as low qualitative papers scoring 15 and below [ 71 , 73 , 74 , 86 , 91 ]. Please see the scores provided for each paper in Table 4 . The low-quality papers did not provide sufficient details regarding the researcher’s relationship with the participants, sampling and recruitment, data collection, rigor in the analysis, or epistemological or ontological reasoning. For example, Yildirim [ 91 ] used verbatim notes as data without recording or transcribing them. This article described the analytical process briefly but was missing a discussion of the applied reflexivity of using verbatim notes and its limitations [ 92 ].

This systematic review found that many studies did not mention the relationship between the authors and the participant. The CASP critical appraisal tool asks: Has the relationship between the researcher and participants been adequately considered? (reflecting on own role, potential bias). Many studies reported that the recruitment was drawn from larger studies and that the qualitative study was a sub-study. Others reported that participants contacted the researcher after advertising the study. One study Goins et al., [ 72 ] reported that students recruited family members, but did not discuss how this potential bias impacted the results.

Our review brings new insights into older adults’ experiences during the pandemic worldwide. The studies were conducted on almost all continents. The majority of the articles were written in Europe followed by North America and Canada (4: USA; 3: Canada, UK; 2: Brazil, India, Netherlands, Sweden, Turkey 2; 1: Austria, China, Finland, India/Iran, Mauritius, New Zealand, Serbia, Spain, Switzerland, Uganda, UK/Ireland, UK/Colombia) (see Fig.  2 ). Note, as the review focuses on English language publications, we are unable to comment on qualitative research conducted in other languages see [ 72 ].

Numbers of publications by country

The characteristics of the included studies and the presence of analytical themes can be found in Table 4 . We used the following characteristics: Author and year of publication, research aims, the country conducted, Participant’s age, number of participants, analytical methodology, CASP score, and themes.

We identified three themes: desired and challenged wellbeing; coping and adaptation; discrimination and intersectionality. We will discuss the themes in turn.

Desired and challenged wellbeing

Most of the studies reported the impact of the COVID-19 pandemic on the well-being of older adults. Factors which influenced wellbeing included: risk communication and risk perception; social connectivity; confinement (at home); and means of coping and adapting. In this context, well-being refers to the evidence reported about participants' physical and mental health, and social connectivity.

Risk perception and risk communication

Politicians and media transmitted messages about the response to the pandemic to the public worldwide. These included mortality and morbidity reports, and details of health and safety regulations like social distancing, shielding- self-isolation, or wearing masks [ 34 , 35 , 36 , 37 ]. As this risk communication is crucial to combat the spread of the virus, it is also important to understand how people perceived the reporting during the pandemic.

Seven studies reported on how the mass media impacted participants' well-being [ 23 , 67 , 68 , 70 , 72 , 81 , 85 ]. Sangrar et al. [ 68 ] investigated how older adults responded to COVID-19 messaging: “My reaction was to try to make sure that I listen to everything and [I] made sure I was aware of all the suggestions and the precautions that were being expressed by various agencies …”. (p. 4). Other studies reported the negative impact on participants' well-being of constant messaging and as a consequence stopped watching the news to maintain emotional well-being [ 3 , 67 , 68 , 70 , 72 , 81 , 85 ]. Derrer-Merk et al. [ 23 ] reported one participant said that “At first, watching the news every day is depressing and getting more and more depressing by the day, so I’ve had to stop watching it for my own peace of mind” (p. 13). In addition, news reporting impacted participants’ risk perception. For example, “Sometimes we are scared to hear the huge coverage of COVID-19 news, in particular the repeated message ‘older is risky’, although the message is useful.” ([ 81 ], p5).

• Social connectivity

Social connectivity and support from family and community were found in fourteen of the studies as important themes [ 9 , 62 , 66 , 67 , 68 , 75 , 76 , 77 , 78 , 79 , 80 , 83 , 84 , 90 ].

The impact of COVID-19 on social networks highlighted the diverse experiences of participants. Some participants reported that the size of social contact was reduced: “We have been quite isolated during this corona time” ?([ 80 ], p. 3). Whilst other participants reported that the network was stable except that the method of contact was different: “These friends and relatives, they visited and called as often as before, but of course, we needed to use the telephone when it was not possible to meet” ([ 77 ], p. 5). Many participants in this study did not want to expand their social network see also [ 9 , 77 , 78 , 79 ]. Hafford-Letchfield et al. [ 76 ] reported that established social networks and relationships were beneficial for the participants: “Covid has affected our relationship (with partner), we spend some really positive close time together and support each other a lot” (p. 7).

On the other hand, other studies reported decreases of, and gaps in, social connectedness: “I couldn’t do a lot of things that I’ve been doing for years. That was playing competitive badminton three times a week, I couldn’t do that. I couldn’t get up early and go volunteer in Seattle” [ 9 , 67 , 75 ]. A loss of social connection with children and grandchildren was often mentioned: “We cannot see our grandchildren up close and personal because, well because they [the parents] don’t want us, they don’t want to risk our being with the kids … it’s been an emotional loss exacerbated by the COVID thing” ([ 68 ] p.10); see also [ 9 , 67 , 78 ]. On the contrary, Chemen & Gopalla [ 66 ] note that those older adults who were living with other family members reported that they were more valued: “Last night my daughter-in-law thanked me for helping with my granddaughter” (p.4).

Despite reports of social disconnectedness, some studies highlighted the importance of support from family members and how support changed during the COVID-19 pandemic [ 9 , 62 , 81 , 83 , 90 ]. Yang et al. [ 90 ] argued that social support was essential during the Lockdown in China: “N6 said: ‘I asked my son-in-law to take me to the hospital” (p. 4810). Mahapatra et al. [ 81 ] found, in an Indian study, that the complex interplay of support on different levels (individual, family, and community) helped participants to adapt to the new situation. For example, this participant reported that: “The local police are very helpful. When I rang them for something and asked them to find out about it, they responded immediately” (p. 5).

Impact of confinement on well being

Most articles highlighted the impact of confinement on older adults’ well-being [ 9 , 62 , 63 , 65 , 67 , 69 , 70 , 72 , 75 , 77 , 78 , 79 , 81 , 82 , 83 , 85 , 89 , 90 ].

Some studies found that participants maintained emotional well-being during the pandemic and it did not change their lifestyle [ 79 , 80 , 82 , 83 , 89 , 92 ]: “Actually, I used this crisis period to clean my house. Bookcases are completely cleaned and I discarded old books. Well, we have actually been very busy with those kind of jobs. So, we were not bored at all” ([ 79 ], p. 5). In McKinlay et al. [ 82 ]’s study, nearly half of the participants found that having a sense of purpose helped to maintain their well-being: “You have to have a purpose you see. I think mental resilience is all about having a sense of purpose” (p. 6).

However, at the same time, the majority of the articles (12 out of 18) highlighted the negative impact of confinement and social distancing. Participants talked of increased depressive feelings and anxiety. For example, one of Akkus et al.’s [ 62 ] participants said: “... I am depressed; people died. Terrible disease does not give up, it always kills, I am afraid of it …” (p. 549). Similarly, one of Falvo et al.’s [ 67 ] participants remarked: “I am locked inside my house and I am afraid to go out” (p. 7).

Many of the studies reported the negative impact of loneliness as a result of confinement on participants’ well-being including [ 69 , 70 , 72 , 78 , 79 , 90 , 93 ]. Falvo et al. [ 67 ] reported that many participants experienced loneliness: “What sense does it make when you are not even able to see a family member? I mean, it is the saddest thing not to have the comfort of having your family next to you, to be really alone” (p. 8).

Not all studies found a negative impact on loneliness. For example, a “loner advantage” was found by Xie et al. ([ 82 ], p. 386). In this study participants found benefits in already being alone “It’s just a part of who I am, and I think that helps—if you can be alone, it really is an asset when you have to be alone” ([ 82 ], p. 386).

Bundy et al. [ 80 ] investigated loneliness from already lonely older adults and found that many participants did not attribute the loneliness to the pandemic: “It’s not been a whole lot, because I was already sitting around the house a whole lot anyway ( …). It’s basically the same, pretty well … I’d pretty well be like this anyway with COVID or without COVID” (p. 873) (see also [ 83 ]).

A study from Serbia investigated how the curfew was perceived 15 months afterward. Some participants were calm: “I realized that … well … it was simply necessary. For that reason, we accepted it as a measure that is for the common good” ([ 70 ], p.634). Others were shocked: “Above all, it was a huge surprise and sort of a shock, a complete shock because I have never, ever seen it in my life and I felt horrible, because I thought that something even worse is coming, that I even could not fathom” ([ 70 ], p. 634).

The lockdowns brought not only mental health issues to the fore but impacted the physical health of participants. Some reported they were fearful of the COVID-19 pandemic: “... For a little while I was afraid to leave, to go outside. I didn’t know if you got it from the air” ([ 75 ]. p. 6). Another study reported: “It’s been important for me to walk heartily so that I get a bit sweaty and that I breathe properly so that I fill my lungs—so that I can be prepared—and be as strong as possible, in case I should catch that coronavirus” ([ 77 ], p. 9); see also [ 70 , 78 , 82 , 85 ].

Coping and adaptation

Many studies mentioned older adults’ processes of coping and adaptation during the pandemic [ 63 , 64 , 68 , 69 , 72 , 75 , 79 , 81 , 85 , 87 , 88 , 89 , 90 ].

A variety of coping processes were reported including: acceptance; behavioural adaptation; emotional regulation; creating new routines; or using new technology. Kremers et al. [ 79 ] reported: “We are very realistic about the situation and we all have to go through it. Better days will come” (p. e71). Behavioural adaptation was reported: “Because I’m asthmatic, I was wearing the disposable masks, I really had trouble breathing. But I was determined to find a mask I could wear” ([ 68 ], p. 14). New routines with protective hygiene helped some participants at the beginning of the pandemic to cope with the health threat: “I am washing my hands all the time, my hands are raw from washing them all the time, I don't think I need to wash them as much as I do but I do it just in case, I don’t have anybody coming in, so there is nobody contaminating me, but I keep washing” ([ 69 ], p. 4391); see also [ 72 ]. Verhage et al. [ 87 ] reported strategies of coping including self-enhancing comparisons, distraction, and temporary acceptance: “There are so many people in worse circumstances …” (p. e294). Other studies reported how participants used a new technology: “I have recently learned to use WhatsApp, where I can make video phone calls.” ([ 88 ], p. 163); see also [ 89 ].

Discrimination -intersectionality (age and race/gender identity)

Seven studies reported ageism, racism, and gender discrimination experienced by older adults during the pandemic [ 23 , 63 , 67 , 70 , 76 , 84 , 88 ].

Prigent et al. [ 84 ], conducted in a New Zealand study, found that ageism was reciprocal. Younger people spoke against older adults: “why don’t you do everyone a favour and drop dead you f******g b**** it’s all because of ones like you that people are losing jobs” (p. 11). On the other hand, older adults spoke against the younger generation: “Shame to see the much younger generations often flout the rules and generally risk the gains made by the team. Sheer arrogance on their part and no sanctions applied” (p.11). Although one study reported benevolent ageism [ 23 ] most studies found hostile ageism [ 23 , 63 , 67 , 70 , 76 , 84 ]. One study from Canada exploring 15 older adult’s Chinese immigrants’ experiences reported racism as people around them thought they would bring the virus into the country. The negative impact on existing friendships was told by a Chinese man aged 69 “I can tell some people are blatantly despising us. I can feel it. When I talked with my Caucasian friends verbally, they would indirectly blame us for the problem. Eventually, many of our friendships ended because of this issue” ([ 88 ], p161). In addition, this study reported ageism when participants in nursing homes felt neglected by the Canadian government.

Two papers reported experiences of sexual and gender minorities (SGM) (e.g. transgender, queer, lesbian or gay) and found additional burdens during the pandemic [ 63 , 76 ]. People experienced marginalisation, stereotypes, and discrimination, as well as financial crisis: “I have faced this throughout life. Now people look at me in a way as if I am responsible for the virus.” ([ 63 ], p. 6). The consequence of marginalisation and ignorance of people with different gender identities was also noted by Hafford- Letchfield et al. [ 76 ]: “People have been moved out of their accommodation into hotels with people they don't know …. a gay man committed suicide, community members know of several that have attempted suicide. They are feeling pretty marginalised and vulnerable and you see what people are writing on the chat pages” (p.4). The intersection of ageism, racism, and heterosexism and its negative impact on people’s well-being during the pandemic reflects additional burden and stressors for older adults.

This systematic literature review is important as it provides new insights into the lived experiences of older adults during the COVID-19 pandemic, worldwide. Our study highlights that the COVID-19 pandemic brought an increase in English-written qualitative articles to the fore. We found that 32 articles met the inclusion criteria but 5 were low quality. A lack of transparency reduces the trustworthiness of the study for the reader and the scientific community. This is particularly relevant as qualitative research is often criticised for its bias or lack of rigor [ 94 ]. However, their findings are additional evidence for our study.

Our aim was to explore, in a systematic literature review, the lived experiences of older adults during the COVID-19 pandemic worldwide. The evidence highlights the themes of desired and challenged wellbeing, coping and adaptation, and discrimination and intersectionality, on wellbeing.

Perceived risk communication was experienced by many participants as overwhelming and anxiety-provoking. This finding supports Anwar et al.’s [ 37 ] study from the beginning of the pandemic which found, in addition to circulating information, that mass media influenced the public's behaviour and in consequence the spread of disease. The impact can be positive but has also been revealed to be negative as well. They suggest evaluating the role of the mass media in relation to what and how it has been conveyed and perceived. The disrupted social connectivity found in our review supports earlier studies that reported the negative impact of people’s well-being [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ] at the beginning of the pandemic. This finding is important for future health crisis management, as the protective health measures such as confinement or self-isolation had a negative impact on many of the participants’ emotional wellbeing including increased anxiety, feelings of depression, and loneliness during the lockdowns. As a result of our review, future protective health measures should support people’s desire to maintain proximity with their loved ones and friends. However, we want to stress that our findings are mixed.

The ability of older adults to adapt and cope with the health crisis is important: many of the reported studies noted the diverse strategies used by older people to adapt to new circumstances. These included learning new technologies or changing daily routines. Politicians and the media and politicians should recognise both older adults' risk of disease and its consequences, but also their adaptability in the face of fast-changing health measures. This analysis supports studies conducted over the past decades on lifespan development, which found that people learn and adapt livelong to changing circumstances [ 95 , 96 , 97 ].

We found that discrimination against age, race, and gender identity was reported in some studies, in particular exploring participants’ experiences with immigration backgrounds and sexual and gender minorities. These studies highlighted the intersection of age and gender or race and were additional stressors for older adults and support the findings from Ramirez et al. [ 98 ] This review suggests that more research should be conducted to investigate the experiences of minority groups to develop relevant policies for future health crises.

Our review was undertaken two years after the pandemic started. At the cut-off point of our search strategy, no longitudinal studies had been found. However, in December 2022 a longitudinal study conducted in the USA explored older adult’s advice given to others [ 99 ]. They found that fostering and maintaining well-being, having a positive life perspective, and being connected to others were coping strategies during the pandemic [ 100 ]. This study supports the results of the higher order constructs of coping and adaptation in this study. Thus, more longitudinal studies are needed to enhance our understanding of the long-term consequences of the COVID-19 pandemic. The impact of the COVID-19 restrictions on older adults’ lives is evident. We suggest that future strategies and policies, which aim to protect older adults, should not only focus on the physical health threat but also acknowledge older adults' needs including psychological support, social connectedness, and instrumental support. The policies regarding older adult’s protections changed quickly but little is known about older adults’ involvement in decision making [ 100 ]. We suggest including older adults as consultants in policymaking decisions to ensure that their own self-determinism and independence are taken into consideration.

There are some limitations to this study. It did not include the lived experiences of older adults in care facilities or hospitals. The studies were undertaken during the COVID-19 pandemic and therefore data collection was not generally undertaken face-to-face. Thus, many studies included participants who had access to a phone, internet, or email, others could not be contacted. Additionally, we did not include published papers after August 2022. Even after capturing the most commonly used terms and performing additional hand searches, the search terms used might not be comprehensive. The authors found the quality of the papers to be variable, and their credibility was in question. We acknowledge that more qualitative studies might have been published in other languages than English and were not considered in this analysis.

To conclude, this systematic literature review found many similarities in the experiences of older adults during the Covid-19 pandemic despite cultural and socio-economic differences. However, we stress to acknowledge the heterogeneity of the experiences. This study highlights that the interplay of mass media reports of the COVID-19 pandemic and the policies to protect older adults had a direct impact on older adults’ well-being. The intersection of ‘isms’ (ageism, racism, and heterosexism) brought an additional burden for some older adults [ 98 ]. These results and knowledge about the drawbacks of health-protecting measures need to be included in future policies to maintain older adults’ well-being during a health crisis.

Availability of data and materials

The systematic literature review is based on already published articles. And all data analysed during this study are included in this manuscript. No additional data was used.

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Elfriede Derrer-Merk contributed to the design, analysis, and writing the draft. Maria-Fernanda Rodriguez-Reyes contributed to the analysis, revised the draft, and approved the submission. Laura K. Soulsby contributed to the analysis, revised the draft, and approved the submission. Louise Roper contributed to the analysis, revised the draft, and approved the submission. Kate M. Bennett contributed to the design, analysis, writing the draft, and approved the submission.

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Derrer-Merk, E., Reyes-Rodriguez, MF., Soulsby, L.K. et al. Older adults’ experiences during the COVID-19 pandemic: a qualitative systematic literature review. BMC Geriatr 23 , 580 (2023). https://doi.org/10.1186/s12877-023-04282-6

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Advancing social justice, promoting decent work

Ilo is a specialized agency of the united nations, how the covid-19 pandemic is changing business: a literature review.

To better support our constituents, we need to understand the on-going changes caused by Covid -19. This paper is structured around three main elements: the workforce; the workspace; and wellbeing. We hope this will help employer and business membership organizations as well as individual businesses, achieving stronger recoveries, greater resilience and growth.

A Step-by-Step Guide to Writing a Stellar Literature Review (with Help from AI)

Table of contents

Aren’t all of us mini versions of Sherlock Holmes when browsing data and archives for a research piece? As we go through the process, a comprehensive literature review is an essential toolkit to make your research shine.

A literature review consists of scholarly sources that validate the content. Its primary objective is to offer a concise summary of the research and to let you explore relevant theories and methodologies. Through this review, you can identify gaps in the existing research and bridge them with your contribution. 

The real challenge is how to write an excellent literature review. Let’s learn.

What is the purpose of a literature review?

A literature review is an introduction to your research. It helps you put your perspective to the table, along with a summary of the theme.

What does my literature review communicate?

• Explanation of your research: how the information was collected, the research method, the justification of the chosen data sources, and an overview of the data analysis.
• Framework: the journey from where the concept began and how it is presented.
• Connects the previous and current research: 

It presents the broader scope of your research by connecting it to the existing data and debates and underlining how your content fits the prevailing studies. 

In an era of information overload, a literature review must be well-structured. 

Let’s learn all about the structure and style of a literature review that’ll help you strengthen your research.

Literature review– structure and style

Begin with a question and end it with the solution– the key to structuring a literature review. It resembles an essay’s format, with the first paragraph introducing the readers to the topic and the following explaining the research in-depth.

The conclusion reiterates the question and summarizes the overall insights of your research. There’s no word count restriction. —it depends on the type of research. For example, a dissertation demands lengthy work, whereas a short paper needs a few pages. 

In a literature review, maintaining high quality is vital, with a focus on academic writing style. Informal language should be avoided in favor of a more formal tone. 

The content avoids contractions, clearly differentiating between previous and current research through the use of past and present tense. Wordtune assists in establishing a formal tone, enhancing your work with pertinent suggestions. This AI-powered tool ensures your writing remains genuine, lucid, and engaging. 

The option of refining the tonality offers multiple possibilities for rephrasing a single sentence. Thus, pick the best and keep writing.

Get Wordtune for free > Get Wordtune for free >

Your friendly step-by-step guide to writing a literary review (with help from AI)

Do you find it challenging to begin the literature review? Don’t worry! We’re here to get you started with our step-by-step guide.

1. Narrow down the research scope

Simply begin with the question: What am I answering through my research?

Whether it’s cooking or painting, the real challenge is the prep-up for it rather than performing the task. Once you’re done, it smoothly progresses. Similarly, for your literature review, prepare the groundwork by narrowing down the research scope.

Browse and scoop out relevant data inclining well with your research. While you can’t cover every aspect of your research, pick a topic that isn’t too narrow nor too broad to keep your literature review well-balanced. 

2. Hunt relevant literature

The next question: Does this data align with the issue I’m trying to address?

As you review sources of information, hunt out the best ones. Determine which findings help in offering a focused insight on your topic. The best way to pick primary sources is to opt for the ones featured in reliable publications. You can also choose secondary sources from other researchers from a reasonable time frame and a relevant background.

For example, if your research focuses on the Historical Architecture of 18th-century Europe, the first-hand accounts and surveys from the past would hold more weight than the new-age publications. 

3. Observe the themes and patterns in sources

Next comes: What is the core viewpoint in most of the research? Has it stayed constant over time, or have the authors differed in their points of view?

Ensure to scoop out the essential aspects of what each source represents. Once you have collected all this information, combine it and add your interpretations at the end. This process is known as synthesis.

Synthesize ideas by combining arguments, findings and forming your new version.

4. Generate an outline

The next question: How can I organize my review effectively? When navigating multiple data sources, you must have noticed a structure throughout the research. Develop an outline to make the process easier. An outline is a skeletal format of the review, helping you connect the information more strategically.

Here are the three different ways to organize an outline– Chronologically, Thematically, or by Methodology.You can develop the outline chronologically, starting from the older sources and leading to the latest pieces. Another way of organizing is to thematically divide the sections and discuss each under the designated sub-heading.

You can even organize it per the research methods used by the respective authors. The choice of outline depends on the subject. For example, in the case of a science paper, you can divide the information into sections like introduction, types of equipment, method, procedure, findings, etc. In contrast, it’s best to present it in divisions based on timelines like Ancient, Middle Ages, Industrial revolutions, etc., for a history paper.

If you’re confused about how to structure the data, work with Wordtune. 

With the Generate with AI feature, you can mention your research topic and let Wordtune curate a comprehensive outline for your study.

Having a precise prompt is the key to getting the best results.

5. Start filling!

Your next question must be: Am I ready to compose all the parts of the literature review?

Once you’re ready with the basic outline and relevant sources, start filling in the data. Go for an introductory paragraph first to ensure your readers understand the topic and how you will present it. Ensure you clearly explain the section in the first sentence.

However, if beginning from the first paragraph seems intimidating, don’t worry! Add the main body content to the sub-headings, then jump to the introduction. 

Add headings wherever possible to make it more straightforward and guide your readers logically through different sources. Lastly, conclude your study by presenting a key takeaway and summarizing your findings. To make your task easier, work with Wordtune. It helps align your content with the desired tone and refine the structure.

6. Give attention to detail and edit

The last question: Am I satisfied with the language and content written in the literature review? Is it easy to understand?

Once you’re done writing the first draft of a literature review, it’s time to refine it. Take time between writing and reading the draft to ensure a fresh perspective. It makes it easier to spot errors when you disconnect from the content for some time. Start by looking at the document from a bird's eye to ensure the formatting and structure are in order. 

After reviewing the content format, you must thoroughly check your work for grammar, spelling, and punctuation. One of the best approaches to editing and proofreading is to use Wordtune . It helps simplify complex sentences, enhance the content quality, and gain prowess over the tonality.

The dos and don’ts of writing a literature review

Writing a stellar literature review requires following a few dos and don'ts. Just like Sherlock Holmes would never overlook a hint, you must pay attention to every minute detail while writing a perfect narrative. To help you write, below are some dos and don'ts to remember.

Composing a literature review demands a holistic research summary, each part exhibiting your understanding and approach. As you write the content, make sure to cover the following points:

• Keep a historical background of the field of research. Highlight the relevant relation between the old studies and your new research.
• Discuss the core issue, question, and debate of your topic.
• Theories lay the foundation of research. While you’re writing a literature review, make sure to add relevant concepts and ideas to support your statements.
• Another critical thing to keep in mind is to define complex terminologies. It helps the readers understand the content with better clarity. 

Examples of comprehensive literature reviews

Aren’t good examples the best way to understand a subject? Let’s look into a few examples of literature reviews and analyze what makes them well-written.

1. Critical Thinking and Transferability: A Review of the Literature (Gwendolyn Reece)

An overview of scholarly sources is included in the literature review, which explores critical thinking in American education. The introduction stating the subject’s importance makes it a winning literature review. Following the introduction is a well-defined purpose that highlights the importance of research.

As one keeps reading, there is more clarity on the pros and cons of the research. By dividing information into parts with relevant subheadings, the author breaks a lengthy literature review into manageable chunks, defining the overall structure.

Along with other studies and presented perspectives, the author also expresses her opinion. It is presented with minimal usage of ‘I,’ keeping it person-poised yet general. Toward the conclusion, the author again offers an overview of the study. A summary is further strengthened by presenting suggestions for future research as well. 

2. The Use of Technology in English Language Learning: A Literature Review

This literature review is thematically organized on how technology affects language acquisition. The study begins with an introduction to the topic with well-cited sources. It presents the views of different studies to help readers get a sense of different perspectives. After giving these perspectives, the author offers a personalized opinion.

One of the critical aspects that makes this a good literature review is a dedicated paragraph for definitions. It helps readers proceed further with a clear understanding of the crucial terminologies. There’s a comparison of the modern and previous studies and approaches to give an overall picture of the research.

Once the main body is composed, the author integrates recommendations for action-based tips. Thus, the literature review isn’t just summarizing the sources but offering actions relevant to the topics. Finally, the concluding paragraph has a brief overview with key takeaways.

Wordtune: your writing buddy!

A literature review demands the right balance of language and clarity. You must refine the content to achieve a formal tone and clear structure. Do you know what will help you the most? Wordtune !. 

The real-time grammar checker leaves no scope for errors and lets you retain precision in writing. This writing companion is all you need for stress-free working and comprehensive literature review development.

Let the narrative begin

A literary review isn't just about summarizing sources; it's about seamlessly bringing your perspective to the table. Always remember to set a narrative for added interest and a brilliant composition. With structure and style being the pillars of a stellar literature review, work with Wordtune to ensure zero compromises on the quality.

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A literature review of the economics of COVID-19

Affiliation.

• 1 Department of Economics University of Ottawa Ottawa Ontario Canada.
• PMID: 34230772
• PMCID: PMC8250825
• DOI: 10.1111/joes.12423

The goal of this piece is to survey the developing and rapidly growing literature on the economic consequences of COVID-19 and the governmental responses, and to synthetize the insights emerging from a very large number of studies. This survey: (i) provides an overview of the data sets and the techniques employed to measure social distancing and COVID-19 cases and deaths; (ii) reviews the literature on the determinants of compliance with and the effectiveness of social distancing; (iii) mentions the macroeconomic and financial impacts including the modelling of plausible mechanisms; (iv) summarizes the literature on the socioeconomic consequences of COVID-19, focusing on those aspects related to labor, health, gender, discrimination, and the environment; and (v) summarizes the literature on public policy responses.

Keywords: COVID‐19; coronavirus; economic impact; lockdowns; social impact.

© 2021 John Wiley & Sons Ltd.