Coronavirus SARS-CoV2 infection (COVID-19)

Essential Evidence

Last Updated on 2020-09-28 © 2020 John Wiley & Sons, Inc.

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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

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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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
  • Mask and isolate patients on presentation to a healthcare facility and obtain PCR from nasopharynx and oropharynx. Also test for influenza and strep throat if clinically suspected. C
  • The combination of age and CRP can be used to identify patients at low, moderate and high risk of severe illness (see Prognosis section below).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.
  • Remdesivir shortens the duration of hospitalization (11 vs. 15 days) and may reduce mortality slightly. 108B
  • 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
  • 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 infection fatality rate is estimated to be 0.5% to 0.9% and is higher in older patients and those with comorbidities. 65 As of September 24th, the Johns Hopkins Center for Health Security reports that there have been 984,813 deaths and 32,356,829 confirmed cases worldwide, 203,147 deaths and 6,997,468 confirmed cases in the US (2.9% case fatality ratio), 9,304 deaths and 151,982 confirmed cases in Canada (6.1% case fatality ratio), and 42,025 deaths and 425,765 confirmed cases in the UK (9.9% case fatality ratio). Mortality rates per 100,000 are 62.0 in the US, 25.1 in Canada, and 63.2 in the UK. These rates are higher than the true case and infected fatality rates due to the large number of undiagnosed mild and asymptomatic cases. B

Screening and Prevention

Bottom Line

  • Guidelines
  • The Johns Hopkins Center for Health Security has created guidance for state and local governments with regards to re-opening the economy.
  • CDC provides guidance for healthcare facilities and clinics.
  • The World Health Organization provides guidance regarding surveillance for SARS-CoV-2 infection in various settings.
  • Post-exposure prophylaxis
  • Researchers randomized 821 persons with a moderate-risk or high-risk exposure to someone with confirmed COVID-19 within the previous 4 days to receive HCQ or matching placebo. The primary outcome was laboratory confirmed or clinically suspected COVID-19 (testing was not yet widely available) in the next 14 days. There was no difference between groups in the primary outcome, with 49/414 (11.8%) reporting infection in the HCQ group and 58/407 (14.3%) in the placebo group (risk difference -2.4%, 95% CI -7.0 to 2.2). The findings were the same at 5, 10 and 14 days. 105
  • Vaccines
  • Multiple vaccine trials have begun initial human testing. The New York Times maintains a "Coronavirus Vaccine Tracker". As of September 25, 2020 5 vaccines were approved for limited human use, 11 were in Phase 3 trials, 14 in Phase 2 trials, and 27 in Phase 1 trials.
  • Published reports of Phase 2 trials generally report good antibody response, including evidence of both humoral and cellular immunity, with acceptable adverse effects. 154 153
  • 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
  • A variety of approaches are being used, including inactivated or weakened coronavirus, viral vector vaccines, nucleic acid vaccines (DNA and RNA), mRNA, and protein-based vaccines. These approaches are explained in a graphical article in Nature.
  • In a computational model, a vaccine must have high effectiveness (at least 60%) and high uptake (at least 75%) to single-handedly stop a pandemic. 180
  • Physical ("social") distancing
  • Frequent, adequate handwashing for 20 seconds using warm, soapy water is strongly recommended. A simple online intervention to educate patients has been evaluated and has been demonstrated to decrease transmission of respiratory tract infections in a large trial with 20,066 patients. The "GermDefence" site from this study has been adapted for COVID-19 and is freely available. 47
  • Based on modeling of COVID-19, to significantly decrease spread of the disease a combination of several measures need to be in place to avoid overwhelming hospital and ICU capacity: school and university closure, case isolation, and general social distancing of no less than 6 feet/2 meters for no more than 10 minutes.
  • Physical distancing has been broadly mandated around the world. A Cochrane review of 29 studies (10 modeling studies of COVID-19, 4 observational, and 15 modeling studies of SARS or MERS) has concluded that these measures are consistently effective in slowing the spread of an epidemic. It is most effective when implemented early and in conjunction with other measures like closing schools and restricting travel. 55
  • A comprehensive analysis determined incidence rate ratios before and after various distancing measures (school closures, workplace closures, restrictions on mass gatherings, public transportation closure and lock-down orders) were implemented in 149 countries. They found that implementation resulted in a 13% reduction in the incidence rate ratio. 156
  • A meta-analysis sponsored by WHO identified 172 observational studies of non-pharmaceutical interventions in healthcare and community settings. They found lower risk of infection with distancing (-10.2%, moderate certainty), facemask use (-14.3%, low certainty), and eye protection (-10.6%). 121
  • A Web site tracks the current status of stay-at-home orders by US state.
  • Researchers at the University of Toronto (preprint, not peer-reviewed) concluded that a 10% decrease in mobility resulted in an 11% decrease in the average daily growth rate of the epidemic.
  • Early in the outbreak in China when restrictions on public gathering and emphasis on distancing was increased, the basic reproductive number (R0 or "R naught") went from about 3.0 before public measures were put in place to only 0.3 by the time all measures were in place. R0 is the mean number of persons infected by an infected case and values less than 1 generally reflect outbreak containment. 116
  • A time series study from Harvard (preprint, not peer reviewed) found increases in doubling time that corresponded to implementation of statewide distancing measures.
  • A prospective cohort study of 144 geopolitical regions worldwide found little or no association with latitude, temperature, or relative humidity but strong associations with physical distancing, school closures, and banning mass gatherings. 86
  • A hyperlocal study in the American Journal of Preventive Medicine compared Clarke County, Georgia which had early, strict distancing with surrounding counties that implemented it later. Cases grew more quickly in surrounding counties. The doubling time also began increasing about 2 weeks earlier in Clarke County, in line with when distancing was enforced (doubling time is the number of days for cases to double, so higher is better).
  • A study applying econometric approaches to the question of whether non-pharmaceutical interventions are effective studied 1717 administrative units in six countries. Their modeling concludes that implementation of all policy measures (such as school closures, social isolation guidelines, travel bans) resulted in reductions in the rate of growth of cases, with larger reductions in Iran, China, South Korea and Italy and smaller reductions in the US and France. They estimate that these measures reduced the number of confirmed cases in those 6 countries by over 60 million, with a reduction of confirmed cases in the US by 4.8 million and total cases by 60 million (assuming that many cases were asymptomatic or never confirmed). 127
  • Contact tracing and isolation
  • Early detection and screening of contacts is important to prevent the spread of COVID-19 infection early during an outbreak. It is not feasible later. 7
  • Contacts of COVID-19 exposed individuals should quarantine for 14 days with daily monitoring for fever and other symptoms. Persons living alone should have daily virtual contact with someone who can obtain help in the event of worsening
  • Some countries such as Taiwan and Singapore had success with early and aggressive implementation of contact tracing. A report from Taiwan on 100 index cases and 2761 close contacts found a 0.7% rate of secondary infections, all occurring with exposure during the first 5 days of symptoms. Of 852 close contacts after 5 days there were no secondary infections. 78
  • An outbreak in Beijing was contained within one month using a combination of rapid response, extensive testing, quick results reporting, and comprehensive contact. 166
  • Digital approaches to contact tracing using mobile phones have been developed. 130
  • Facemasks
  • Surgical masks
  • During the 2003 SARS outbreak in Taiwan, wearing surgical face masks on entering the hospital, on hospital wards and in out-patient clinics prevented nearly all cases of SARS among healthcare workers. 75
  • None of 41 healthcare workers who had exposure to aerosol-generating procedures for at least 10 minutes at a distance of less than 2 meters of a patient with COVID-19 became ill; most (85%) were wearing a surgical mask and the remainder were wearing N95 masks. 76
  • A study of exhaled breath of patients infected with seasonal coronavirus found some evidence that surgical face masks reduce spread of both droplet particles greater than 5 microns and aerosol particles ≤5 microns in diameter.
  • A single RCT from 2015 comparing surgical masks with cloth masks with no mask found that cloth masks had the highest rates of respiratory infection. 71
  • Cloth masks
  • The CDC recommended on April 2nd, 2020 that members of the public wear home-made face masks when in a public place where appropriate physical distancing may be difficult, such as a grocery store or pharmacy. Instructions for making masks are provided. However, it is not known whether this will provide a net benefit, and concern has been expressed that it might lead to abandonment of physical distancing measures by some persons. The National Academy of Science concluded that homemade masks have a filtration rate ranging from 0% to 50%.
  • A comparison of 2-layer cotton masks also found that a surgical mask was much more effective. 63
  • However, another review of the evidence for cloth masks found very little high-level evidence of their effectiveness in other viral infections. Given what is thought to be a higher rate of asymptomatic transmission with COVID-19, these may not apply. 72
  • A Chinese study found that rigorous use of face masks and daily use of disinfectants in the home reduced transmission within a household. This is particularly relevant for households where older or vulnerable family members may reside. 104
  • A study used laser interferometry (peer reviewed but not yet in PubMed) to assess droplet spread from 14 different style masks and found that a variety of cotton or polypropylene masks provided reasonable good efficacy, but that knitted masks, bandannas, and fleece gaiters were much less effective, if at all.
  • Droplet spread
  • In a laser-base study, respiratory droplets generated during normal speech travel between 5 to 7.5 cm and ranged in size from 20 to 500 micrometers. With louder speech, droplets travel farther. Using a damp washcloth resulted in dramatic reductions in number and size of droplets as well as the distance traveled. The authors are clear to report they did not assess viral transmission. 61
  • The same team using similar methods determined that louder speech also generates thousands of oral fluid droplets per second and that in a closed, stagnant air environment the droplets linger in the air for 8 to 14 minutes. 98
  • Consistent with these in vitro experiments, a study from China determined that, among 10,980 confirmed cases, only a single cluster of two patients contracted COVID-19 outdoors (preprint server, not peer-reviewed, use caution).
  • School and university outbreaks
  • During a heatwave, students and teachers were excused from facemasks, resulting in a large outbreak in the school. It was also clear from the physical layout that distancing was not possible. Overall, 13% of students and 17% of staff tested positive, and 43% of students and 75% of staff were symptomatic. 151
  • The first large US university to return to in person instruction in early August (University of North Carolina at Chapel Hill) was forced to pivot to online instruction after 4 clusters with over 130 students in the first week of classes.
  • Surface decontamination
  • Surface decontamination using 60% or higher ethanol, 0.5% or higher hydrogen peroxide, or a dilute bleach (0.1% sodium hypochlorite) is recommended given persistence of the virus on surfaces. 45
  • Personal Protective Equipment (PPE) for healthcare workers
  • Healthcare personnel doing procedures that may generate aerosols should use a fitted respirator mask (N95) as well as face shield, gloves, and gown. (Surviving Sepsis Campaign Guidelines, 3/26/20).
  • Some studies have compared N95 masks with standard medical masks for prevention of influenza in healthcare workers. 44 43 42 They have found little difference, but in these studies poor fit and lack of compliance with N95 masks was common. These studies cannot be applied to the COVID-19 epidemic where the motivation to comply with proper fit and adhere to consistent usage is much higher than in a study of influenza prevention.
  • N95 respirators can be decontaminated and re-used in times of shortage up to 3 times, based on one study, using either UV radiation or vaporized hydrogen peroxide. Use of 70% ethanol was found to be acceptable for decontamination once, but additional decontamination with ethanol resulted in a sharp drop in mask filtration performance. 138
  • In a study of 420 healthcare workers sent to Wuhan for a 6-week period to care for COVID-19 patients (16 hours/week average in ICU), none tested positive after two weeks of quarantine upon their return home. 132
  • In a study of healthcare workers doing home visits in India, the attack rate was 12/62 (19%) prior to use of face shields and 0/50 (0%) after their use was initiated. 163
  • Measures recommended by front-line physicians based on personal experience include the following (personal communication, Hannah Ferenchick, MD, ED/critical care physician in Detroit, MI):
    • Scrubs only, no undershirts, minimize work jackets. If long hair, consider hairnet. If male, shave beard to improve N95 fit.
    • N95 for all encounters, often limited to one per shift, with surgical mask over N95 in case of soiling.
    • Eye protection (eye shield, helmet, welding glasses/goggles, and welding style face shield PLUS goggles for intubation or other high-risk procedures.
    • Phone in plastic sandwich bag.
    • Minimize objects close to patient (not taking pen/paper into rooms, minimize phone contact, try not to use own stethoscope).
    • Disinfect all workspaces prior to shift, including computer keyboard and mouse, desktop, phones, etc.
    • Do not eat with hands, do not touch face with hands while at work, throw away water bottles during shift and do not take home.
    • At work after shift: return dirty scrubs, change into clothes or clean scrubs, disinfect phone/badge/face shield/eye wear, place personal PPE in plastic bag without other objects, and disinfect personal stethoscope and place in bag without other objects.
    • Car: "Home" shoes kept in trunk, change out of "work" shoes and place in trunk, place personal PPE in trunk until next shift.
    • Home: Take off work purse, place in closet away from other clothes, disinfect phone again, wash hands and shower immediately. Some are choosing to isolate at home as well, and/or using garage to dump clothes.