Coronavirus SARS-CoV2 infection (COVID-19)

Essential Evidence

Last Updated on 2021-08-16 © 2021 John Wiley & Sons, Inc.

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Authors:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia
Mindy A. Smith, MD, MS, Clinical Professor, Department of Family Medicine, Michigan State University
Henry C. Barry, MD, MD, MS, Professor Emeritus, Michigan State University
Pete Yunyongying, MD, FACP, Associate Professor , Carle-Illinois College of Medicine, University of Illinois
John Hickner MD, MS, Professor Emeritus, University of Illinois-Chicago

Editor:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia

Overall Bottom Line

  • EDITOR'S NOTE: This topic has been made freely available and is being updated regularly. We are at times linking to preprint servers and providing direct links to articles where possible, and most of this literature has been made freely available. As preprint work becomes peer reviewed and formally published, we will update the citations. Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.
  • Suspect COVID-19 when the virus is circulating in the population and a patient reports signs and symptoms of respiratory tract infection, or less commonly fever and neurologic symptoms or thrombosis. Most common symptoms are fever, cough, myalgias, and dyspnea; loss of taste and smell are also common. Approximately 40% of all patients are asymptomatic but appear to be as infectious as symptomatic patients. B
  • Preventive measures include hand washing, surface cleaning, case isolation, quarantine of contacts for 14 days, school and university closures, and general social distancing/sheltering at home. Modeling indicates that only by doing all of these measures can the number of severe cases requiring ventilation not overwhelm hospitals.B
  • Two mRNA vaccines from Pfizer/BioNTech and Moderna have approximately 95% efficacy at preventing symptomatic disease and good safety against SARS-CoV-2. The adenovirus vectored vaccine from Johnson and Johnson/Janssen is 67% effective overall, but 74.4% in the US population that was studied. B
  • Patients can be considered cured using a test-based strategy (recovery from fever without antipyretics and without respiratory symptoms plus 2 negative PCR tests 24 hours apart). For outpatients in settings where tests are not widely available, the CDC recommends that isolation be maintained for at least 10 days after illness onset and at least 3 days (72 hours) after recovery, defined as: at least 3 days free of fever without antipyretics, 3 days without respiratory symptoms, and at least 7 days after onset of symptoms. C
  • Treatment is primarily supportive and includes monitoring oxygen saturation.
  • In patients not requiring oxygen or only requiring low-flow oxygen, remdesivir shortens the duration of hospitalization (11 vs. 15 days) and may reduce mortality slightly. 108B
  • Systemic corticosteroids have been shown in a large UK trial with 6425 patients to be highly effective at reducing mortality in patients with COVID-19 who are mechanically ventilated (NNT = 7) or who are on oxygen (NNT = 20) but not in hospitalized patients not requiring oxygen. 161 Their use also decreases the likelihood of requiring mechanical ventilation. 171B
  • Two studies have found that inhaled budesonide in outpatients with early disease have a shorter duration of symptoms and may have a lower risk of hospitalization, death, and the need for urgent visits. B
  • The monoclonal antibody bamlanivimab and the combination of casirivimab and imdevimab (Regeneron) have been given emergency use authorization for treatment of outpatients not on supplemental oxygen but at high risk for severe disease. The claimed benefit is a reduction in the risk of hospitalization or ED visit in the next 28 days from 9-10% to 3% (NNT = 3). B
  • In newly hospitalized patients not requiring mechanical ventilation, the Janus kinase inhibitor tofacitinib 10 mg twice daily reduced the composite of death or respiratory failure (18.1% vs 29.0%, p = 0.04, NNT = 9). 265B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine is not effective for severe disease, mild disease, early disease, or as post-exposure prophylaxis, and is associated with a higher risk of adverse events. 173 105A
  • The overall case fatality rate is estimated to be 0.9% and is higher in older patients and those with comorbidities. This estimate, from early in the pandemic, is likely lower now due to better treatment and ventilator management. 198 65B

Background

  • COVID-19 (coronavirus disease 2019) is a viral lower respiratory infection first reported in Wuhan City, China that has rapidly spread to become a pandemic. It is caused by novel coronavirus named 2019-nCoV and more recently SARS-CoV2.

Incidence

  • Information about incidence and the case fatality rate are evolving. Peak incidence predictions nationally and by state for the US are provided by the modeling group at the University of Washington.
  • Several other Web sites and the Johns Hopkins Coronavirus Resource Center provide detailed information on new cases, total cases, and deaths that are updated daily.
  • In a study in Los Angeles County, California, researchers invited a random sample of 1952 adult residents, 863 of whom agreed to be tested. Thirty-five (4%) individuals tested positive; after adjusting for the sensitivity and specificity of the test and population weighting they estimated 4.6% of adults had been infected, roughly a 50-fold increase in the number actually diagnosed. 113
  • In a study of 220 women admitted for delivery in New York in late March/early April 2020, all were tested and 15.4% were positive for SARS-CoV2, most of whom were asymptomatic. 60
  • A Swiss study sampled 2766 participants who were demographically similar to the overall population of the Geneva Canton for antibodies to COVID-19. After accounting for test accuracy and other factors, the range of seroprevalence during the first 4 weeks of the study ranged from 4.8% to 10.9%. Prevalence was highest in those 20 to 49 years of age, and they estimate 11.6 infections in the community for each confirmed case. 129
  • The CDC has begun a series of seroprevalence studies in 6 states, using blood specimens obtained for reasons other than COVID-19 testing (preprint server, not peer-reviewed). They used an antibody test that is 96% sensitive and 99.3% specific, and adjusted the results to account for false negatives and false positives. In the most recent report, age and sex-standardized positive rates were 1.1% in Washington, 1.9% in south Florida, 2.2% in Utah, 2.4% in Minneapolis-St. Paul, 2.7% in Missouri, 3.2% in Philadelphia, 4.9% in Connecticut, 5.8% in Louisiana, and 6.9% in the metro New York City region. Based on the number of confirmed cases, they estimate a range of 6 to 24 total cases per confirmed case, with 4 of 6 jurisdictions having 10.8 to 11.9 total cases per confirmed case. These estimates are based on data collected from mid-March to late May, so current conditions may reflect a higher seroprevalence and lower ratio of undetected to confirmed cases. 152
  • A multi-national team reported seroprevalence by country. The proportion of the population infected ranged from just over 0.0% in Asia to approximately 13% in the US (as of September 1, 2020) and over 50% in Mexico and Peru. 198
  • The rate of infection and hospitalization is higher for Black, Hispanic/Latino, and American Indian/Alaska Native than would be expected from their proportion in the general population. 168
  • Among children admitted for an ENT procedure who were asymptomatic, between 0% and 0.8% tested positive for SARS-CoV-2. 169

Other Impact

  • Based on modeling by the COVID-19 research unit at Imperial College in London early in the pandemic, the case fatality ratio is estimated to be 0.9% overall (95% credible interval 0.4% to 1.4%). It is lowest in children (0.002%) and is higher with increasing age (0.08% for 30 to 39, 0.60% for 50 to 59, 2.2% for 60 to 69, 5.1% for 70 to 79 and 9.3% for 80 and older). Estimates of the infection fatality rate .
  • The day-to-day mortality estimates are likely to change as the epidemic evolves, as there is currently incomplete case ascertainment, especially in the US, while some infected persons who will die in the subsequent 2 weeks are not yet counted in the fatality data. Data from Italy and China found similar case-fatality rates when stratified by age, with the exception of a higher rate in Italy for those 80 years and older. Since data were not reported for those 90 and older in China, this could still represent an effect of greater age in Italy within this group.
  • Undercounting deaths from COVID is likely. A report updated on September 11, 2020 estimated over 263,000 excess deaths globally. This was based on comparing current overall mortality trends in multiple countries with historical data.
  • Using excess mortality data, in New York City COVID-19 was more deadly in March through May of 2020 than the 1918 flu epidemic was during its peak months. 162
  • The CDC estimates that the US experienced 299,028 more deaths than would otherwise be expected during the period from January 26 to October 3, 2020. Surprisingly, the greatest percent increase occurred in those between 25 and 44 years of age, who had a 26.5% increase over expected deaths. For Americans between 25 and 44, 45–64, 65–74, 75–84, and 85 years of age or older, the percent increase in deaths were 27%, 14%, 24%, 22%, and 15%, respectively. The average percentage increase was 54% in Hispanic persons, 29% above average for non-Hispanic American Indian or Alaska Native persons, 33% above average for Black persons, 35% above average for those of other or unknown race or ethnicity, and 37% above average for Asian persons. Regularly updated data are available at: https://www.cdc.gov/nchs/nvss/vsrr/covid19/excess_deaths.htm. 192
  • The strongest data to date on excess deaths comes from a study of 48 US states that used federal census and mortality data. During the period from March 1 to August 1, 2020 there were 1,336,561 deaths overall, which is 225,530 more than expected. Of those, only 67% were attributed to COVID-19. Some of these deaths may not have been attributed due to unavailability of testing early in the pandemic, and were highest in states hit hard early such as New Ywork, Louisiana and Michigan. Some deaths were likely from vascular and thromboembolic causes as well, though, or neglected care for other conditions. 190

Causes of the Condition

  • The cause of COVID-19 is the novel coronavirus SARS-CoV-2.
  • Coronaviruses are enveloped, single-stranded RNA viruses that include those that caused a large-scale epidemic of severe acute respiratory syndrome (SARS) in 2002-3 and the Middle-Eastern Respiratory Syndrome (MERS), a persistent epidemic in the Arabian Peninsula since 2012. There also several widely circulating species that cause mild respiratory tract infections in humans. 74

Pathophysiology

  • COVID-19 infection ("COronaVirus Disease 2019") is caused by the novel coronarvirus SARS-CoV-2. It is the 7th coronavirus reported to cause disease in humans.
  • Like SARS-CoV, SARS-CoV-2 is in the subgenus sarbecovirus. The genome has been sequenced and it is more closely related genetically to SARS than to MERS (Middle Eastern Respiratory Syndrome). 16
  • COVID-19 appears to cause a prothrombotic state with microthrombi identified in multiple organs including the lungs, kidneys, heart, and liver, based on autopsy studies. In addition, megakaryocytes (bone marrow cells responsible for producing platelets) were found in higher than usual numbers in the lungs and heart. 146
  • Coronaviruses make use of a large envelope protein called the spike to engage host cell receptors and catalyze membrane fusion. In a recent study using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, investigators identified neutralizing cross-reactive single-domain camelid antibodies that can attach to and neutralize the viruses’ spike protein and may serve as potential therapeutic candidate for human vaccines. 83
  • Incubation period
  • The incubation period is a median of 5 days, and 97.5% who develop symptoms will do so within 11.5 days. About 1% may develop symptoms more than 14 days after exposure. 36
  • Duration of viral shedding and infectiousness
  • The median duration of viral shedding in survivors is 20 days, based on early data from Wuhan City, China. 18
  • A systematic review of 8 studies reporting on viral shedding found that 40.5% (significant heterogeneity) of patients with COVID-19 shed the virus in their stools. 128
  • Based on a series of 94 patients, researchers estimated that 44% (95% CI 25% to 69%) were infected by presymptomatic or asymptomatic index patients. Shedding declined over a median 21-day period. They estimate that patients were infectious 2.3 days prior to symptom onset (95% CI 0.8 to 3.0 days), with a peak infectiousness at 0.7 days prior to symptom onset (95% CI -0.2 to 2.0 days). 115
  • A South Korean study of 193 symptomatic and 110 asymptomatic individuals found that they tested positive for 17 to 19 days, with little difference between symptomatic and asymptomatic persons. 179
  • Among 96 consecutive patients hospitalized with COVID-19, 22 had mild disease and 74 had severe disease. The patients had daily PCR assays of sputum, saliva, blood, urine and stool. Among the 3497 samples, SARS-CoV-2 RNA was detected in 59% of the patients. The median duration of fecal shedding of SARS-CoV-2 RNA was 22 days compared with 18 days in the respiratory samples and 16 days in the serum samples. It was detected in only a single urine sample. Patients with severe disease shed virus for 1 week longer than those with mild disease (21 days vs. 14 days, respectively). 68
  • In a case-control study, compared to patients without GI symptoms, the 107 patients who had presented with GI symptoms had a longer duration of viral shedding (41 vs. 32 days). 135
  • In an Italian study that tested the entire town of Vo', persons were infectious for between 3.6 to 6.5 days, with infectiousness peaking on the day of symptom onset. 145 A Taiwanese study similarly found that persons were infectious for about 5 to 6 days. 78
  • The NBA “bubble” in Orlando, Florida that isolated all NBA players, staff and vendors during the second half of the season and playoffs provided a natural experiment for determining if those who persistently test positive with a sensitive PCR test are infectious. Of the 3,648 individuals who participated in the bubble, 36 individuals persistently tested positive after the 10 day isolation period, which began on the first day of symptoms of infection or the first positive test. The mean number of persistent positive days for these 36 individuals was 31 days. There were at least 1,480 person-days of close, direct contact among these individuals and others in the bubble and there were no documented cases of transmission. Thus, after 10 days, the likelihood of transmission appears negligible. 258
  • Mode of transmission of virus
  • It is thought that the virus is spread mainly through respiratory droplets and via aerosols, especially by those in close contact typically defined as less than 6 feet or 2 meters. However, the virus can be spread by asymptomatic persons. 27 In fact, a modeling study estimated that about 59% of all infections are spread by asymptomatic persons, 35% of whom are pre-symptomatic and 24% of whom will never become symptomatic. 227
  • In Singapore, a country where there was very careful contact tracing, researchers estimated that 10 of 157 (6.4%) locally-acquired cases were infected by someone who was presymptomatic (e.g. 1 to 3 days before symptom onset) based on contact with the presymptomatic individual and no contact with any symptomatic persons. 114 A modeling study estimated even higher rates of infection from persons with mild or asymptomatic disease, due to greater activity levels. 48
  • Researchers reported a cluster of 10 COVID-19 cases that were most likely spread from one infected person at a restaurant in Guangzhou, China. The investigators could find no other exposures to COVID-19 for the other two infected families. After careful contact tracing and assessment of the physical environment, the researchers hypothesize that the infection may have been spread by the air-conditioning unit. If so, this report has significant implications as countries open up restaurants and other business venues requiring close physical proximity. 64
  • The CDC performed a case-control study that included 154 who tested positive and 160 who tested negative. Case-patients were more likely to have reported dining at a restaurant (adjusted odds ratio [aOR] = 2.4, 95% CI = 1.5–3.8) in the 2 weeks before illness onset than controls. When the analysis was restricted to the 225 participants who did not report recent close contact with a person with known COVID-19, cases were more likely than were controls to have dined at a restaurant (aOR = 2.8, 95% CI = 1.9–4.3) or gone to a bar/coffee shop (aOR = 3.9, 95% CI = 1.5–10.1). 175
  • A series of 116 patients with COVID-19 found that coinfection was fairly uncommon, most often with rhinovirus (6.9%), RSV (5.2%) and other coronaviruses (4.3%). 58
  • Household transmission
  • A systematic review identified 44 studies of transmission within households and 10 studies of transmission within families (where not all members of the family lived in the same household). The overall estimated secondary infection rate was 16.4% in households and 17.4% among families, meaning that roughly one in six household or family contacts become infected. However, the secondary infection rates varied greatly, from a low of less than 1% in a South Korean study to a high of 45% in an Italian study. Combining the 5 US studies, 232 of 722 (32%) household contacts became infected. Spouses were at greatest risk of secondary infection, 38%. Adults were more likely to transmit infection than children, and the secondary infection rate was higher for adults (15.2%) than for children (7.9%). 234
  • In Taiwan, based on contact tracing of 2761 close contacts of 100 patients confirmed with COVID-19, there were 22 secondary infections, an attack rate of 0.7% (95% CI, 0.4%-1.0%) The attack rate was highest among the 1,818 individuals exposed within 5 days of symptom onset (1.0%) compared to those with later exposure (0 cases from 852 contacts). The rate was also highest among household contacts (4.6%) and non-household family contacts (5.3%). Contacts with only pre-symptomatic exposure had a 0.9% incidence of infection. This study suggests that isolation of infected individuals is insufficient to halt transmission of COVID-19. 78
  • A large South Korean contact tracing study found that the transmission rate was 11.8% for 10,592 household contacts of infected persons, compared to only 1.9% for non-household contacts. Transmission was lowest for young children age 0 to 9 years (5.3%), highest for older children age 10 to 19 years (18.6%), and was somewhere in between for adults, increasing with increasing age. 155
  • In a large Indian study, the risk of transmission from an index case to an exposed contact was 10.7% for high-risk contacts, who had close social contact or direct physical contact with index cases without protective measures, and 4.7% for low-risk contacts, who were in the proximity of index cases but did not meet these criteria for high-risk exposure. 189
  • Two studies examined household transmission in adults and children. In a Swiss study, adult household contacts were suspected or confirmed to have COVID-19 infection before the study child in 79% (31/39) of cases. The study child deveIoped symptoms before any other household contact in only 8% (3/39) of households. 159 In a similar international study of COVID-19 transmission in 31 household clusters from China, Singapore, South Korea, Japan and Iran, the investigators found that a child the first (index) case in only 3 of the 31 (9.7%) household clusters. (preprint server, not peer reviewed)
  • A Scottish national study found that among patient-facing healthcare workers, while the numbers were small, the risk of hospitalization was much higher for them (hazard ratio 3.3, 95% CI 2.1-5.1) as was the risk for their household members (HR 1.8, 95% CI 1.1-2.9). 197

Risk Factors

Risk Factor
Living in or traveling to an endemic area for SARS-CoV-2
Risk factors for severe COVID-19 infection include increasing age, comorbidities (diabetes, COPD, asthma, heart disease), elevated CRP, LDH, ALT or AST, decreased albumin, lymphopenia, and neutrophilia.
There is no independent association between vitamin D levels and the risk of infection with SARS-CoV-2, based on a large study that adjusted for multiple covariates.

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