Coronavirus SARS-CoV2 infection (COVID-19)

Essential Evidence

Last Updated on 2022-01-07 © 2022 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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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
  • • The most appropriate diagnostic test is RT-PCR of multiple specimens carried out according to guidelines. 9 Point-of-care PCR is highly specific, but sensitivity varies by manufacturer; rapid antigen testing has much lower sensitivity (56.2%) and should only be used in symptomatic patients with higher viral loads. 188B
  • Preventive measures include hand washing, surface cleaning, face masks, case isolation, quarantine of contacts for 14 days, school and university closures, social distancing, and sheltering at home. The most effective available face mask should be used when in indoor public spaces to prevent spread. 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. Vaccine effectiveness for the delta variant is about 87% to 90% overall, but lower among the immunocompromised and elderly. Boosters increase protection about 10-fold and are recommended at least 6 months after the second dose of vaccine. B
  • 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 are 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 171B
  • Two studies have found that use of inhaled budesonide in outpatients with early disease results in a shorter duration of symptoms and possibly a lower risk of hospitalization, death, and the need for urgent visits.B
  • A single RCT enrolling 1497 high risk outpatients with symptomatic COVID-19 compared fluvoxamine with placebo and reported a reduced likelihood of hospitalization (11% vs. 16%, NNT = 20, 95% CI 12-61).B 281
  • 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. A systematic review found an NNT of 21 to 24 to prevent hospitalization. 280B
  • 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 (HCQ) 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
  • 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.Data support that after 10 days, the likelihood of transmission appears negligible. C
  • The overall case fatality rate is estimated to be between 0.5% and 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

Screening and Prevention

Bottom Line

  • Multiple interventions employed simultaneously (e.g., masks, distancing, contact tracing, quarantine, immunization) provide the greatest likelihood of reducing the spread of COVID-19 in a community (the so-called "Swiss Cheese" model of prevention).
  • 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.
  • Vaccines
  • 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.
  • Two mRNA vaccines from Pfizer/BioNTech and Moderna have approximately 95% efficacy against symptomatic disease and good safety. The adenovirus vectored vaccine from Johnson and Johnson/Janssen is 67% overall, but 74.4% in the US population that was studied. The Oxford -AstraZeneca vaccine was also approximately 67% effective overall. The efficacy should not be directly compared because the different vaccines were studied in different populations, at different times during the pandemic, and when different variant strains were or were not circulating.
  • Pfizer BioNTech vaccine
  • A total of 37,706 persons were randomized to the Pfizer BioNTech mRNA vaccine or placebo and had at least 2 months follow-up. There were a similar number of withdrawals between dose 1 and 2, about 300, and somewhat more in the placebo group after dose 2 (95 vs. 48). Only 2.6% were found to have antibodies due to a prior infection, and results presented below are for all patients who received 2 doses of vaccine regardless of prior infection. Participants were 49.4% female, with a mean age of 50 years. By age group, 58% were 16 to 55 years, 42% were older than 55 years, and 21% were older than 65 years. The population was fairly representative by race and ethnicity of the US as a whole, with 83% white, 9.3% Black, 4.3% Asian, and 28% Hispanic or Latinx. Efficacy was approximately 95% regardless of age, race, or ethnicity. With regards to safety, injection site pain, fatigue, and headache were common but generally mild. 205 The vaccine is equally effective in adolescents age 12 to 15 years (efficacy 100%, 95% CI 75%-100%). 263
  • An Israeli study matched vaccinated and unvaccinated patients, and found that the Pfizer-BioNTech vaccine was 92% effective at preventing any infection, 94% at preventing symptomatic infection, 87% for preventing hospitalization, and 92% for preventing severe COVID-19. 210
  • A Kaiser Permanente study in California compared about 1 millionfully vaccinated members with 2 million unvaccinated members. While there was some waning of efficacy against infection, there was no waning in the protection against hospitalization. The authors report the vaccine’s overall effectiveness against hospitalization for COVID was 93% against delta variants and 95% against other strains. 278
  • An Israeli study compared fully vaccinated persons who had and had not received a 3rd "booster" dose of the Pfizer BioNTech vaccine. They found that the risk of any infection was much higher in the un-boosted group (adjusted risk ratio 11.3, 95% CI 10.4-12.3), as was the risk of severe infection (aRR 19.5, 95% CI 12.9-29.5). There was no added protection during the first week after the booster, and the protection rose to substantial levels about 12 to 16 days after the booster was given. 276
  • Moderna vaccine
  • The mRNA-1273 SARS-CoV-2 vaccine developed by Moderna was the second of two messenger-RNA vaccines to be approved by the FDA for emergency use, approved in December of 2020. This randomized, placebo controlled trial, the basis for approval of this vaccine, enrolled 30,420 individuals. Participants were each given two injections 28 days apart of either the vaccine or placebo. Starting 14 days after the second injection, symptomatic COVID-19 infection occurred in 185 participants in the placebo group and in 11 participants in the vaccinated group. Therefore, the vaccine efficacy for preventing symptomatic COVID-19 infection was 94.1% (95% CI 89.3%- 96.8%).
  • The results were similar in subgroups such as those who had evidence of infection at baseline (2.2% of participants) and those 65 years and older. Results were similar 14 days after the first dose, indicating early protection even before the second dose was administered. There were 30 severe COVID infections, all in the placebo group, showing a high level of protection against severe COVID disease. About 84% of participants had local reactions including swelling, redness and pain, to the first injection and 89% did after the second injection. 204
  • Johnson and Johnson (Janssen) vaccine
  • The vaccine was developed using a replication incompetent adenovirus encoded with a variant of the SARS-CoV-2 spike protein; this is a traditional vaccine development approach. The vaccine was evaluated in a racially and ethnically diverse group of 43,783 adults, with data for efficacy are reported for 39,058 adults. Efficacy was 66.9% (95% CI 59.0%-73.4%) overall for preventing confirmed moderate to severe COVID-19 occurring at least 14 days after vaccination. Efficacy was similar for older and younger patients. Efficacy did vary by region, though, with 74.4% efficacy seen in the US, 64.7% in Latin America, and only 52.0% in South Africa, likely due to the South African variant. For prevention of severe/critical COVID-19, the vaccine had 76.7% overall efficacy. Results were similar for prevention of cases that required hospitalization, ICU admission, mechanical ventilation, or ECMO (75.0%) although numbers are small and confidence intervals are broad. All 7 deaths attributed to COVID-19 occurred in the placebo group and were in South Africa; there were fewer all-cause deaths as well in the vaccine group in those vaccinated at least 14 days before (3 vs. 15). Like the Pfizer and Moderna vaccines, side effects included mild and transient injection site pain (49%), headache (39%), fatigue (38%), and myalgias (33%). 285
  • Oxford-AstraZeneca vaccine
  • This vaccine was studied in 17,177 patients in the UK, Brazil, and South Africa and 67% effectiveness for symptomatic infection. The vaccine had 63% effectiveness in those receiving 2 standard doses, and 80.7% effective (95% CI 62.1%-90.2%) for those who received the low dose for the initial injection. Interestingly, efficacy was higher with a longer interval between the first and second vaccination: 82.4% when the second injection was given more than 12 weeks after the first injection compared to 54.9% when the second injection was given less than 6 weeks after the first injection. To find out if the initial dose provided some protection, they analyzed the effectiveness of the first dose starting 22 days after the initial injection. The first dose was 76% effective from day 22 to day 90 in preventing symptomatic infections, though it was not effective in preventing asymptomatic infections during this time period. 203 A pooled analysis of randomized trial data from early 2021 found that the AstraZeneca vaccine was 67% effective for preventing symptomatic COVID, 100% effective at preventing hospitalizations, and that modeling suggested greater effectiveness with a 3 month interval between doses. 203
  • Vaccine adverse effects
  • A study using a registry of 10,162,227 vaccine eligible persons compared adverse events that occurred 1 to 21 days after vaccination with adverse events that occurred in vaccinated individuals 22 to 42 days after vaccination. They studied 23 adverse events including acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome and found no significant difference for any of them between vaccinated and unvaccinated persons. 274
  • A study in US military personnel (largely young men) found that the incidence of myocarditis with immunization was approximately 4 to 5 cases per 100,000 immunizations. 249
  • A linked dataset from 40 hospitals found that the incidence of myocarditis following mRNA vaccine administration was approximately 1 per 100,000 vaccinated persons, and of pericarditis was 1.8 per 100,000. 272
  • An Israeli study found the risk of myocarditis was 2.7 per 100,000 vaccinated persons. 273
  • Cerebral venous sinus thrombosis (CVST) with thrombocytopenia is a rare complication of the Janssen/Johnson & Johnson vaccine. Based on voluntarily reported data from VAERS, after 7 million doses 12 patients were identified with CVST. Most were age 18 to 39 years, and 7 had at least one risk factor for CVST (obesity, hypothyroidism, or combined oral contraceptive use). The patients became symptomatic between 6 and 15 days of the vaccine and were hospitalized between 2 and 14 days from onset of symptoms. Eleven of the 12 presented with headache and one developed a headache later. Eight of the 12 had additional venous thromboses (e.g., portal vein, internal jugular, etc.) and 7 had intracerebral hemorrhages. All of the patients were hospitalized, 10 to intensive care. At the time of publication, 5 patients were still in the hospital, 3 died, and 4 were discharged to home. The true incidence is likely higher due to the voluntary nature of VAERS reporting. 259
  • CVST was also observed in patients who received the Oxford-AstraZeneca vaccine at a rate of 2.5/100,000 vaccinations in excess of that observed in the general population (RR 20, 95% CI 8.1-42). Thromboembolic events were also slightly more common (11 excess events/100,000 vaccinations). 260
  • Based on voluntary reporting through the CDC VAERS system, anaphylaxis to the Pfizer-BioNTech vaccine occurs once in every 200,000 doses, 207 and to the Moderna vaccine in 1 in 400,000 doses. 206
  • However, a study that tracked 64,900 employees at Mass General Brigham hospital in Boston found a higher rate of 1 per 4,056 doses delivered. 250
  • 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
  • Vaccines and variants
  • A CDC presentation on the Delta variant was leaked to the press. It reports that the risk of infection among vaccinated persons compared to unvaccinated is 21 vs. 177 /100,000, for hospitalization was 0.1 vs. 2.52/100,000, and for mortality 0.04 vs. 0.96/100,000. Vaccine effectiveness for the Delta variant is 87% to 90% overall. However, for immunocompromised persons, the efficacy of vaccines is lower at 59% to 80%. There is also a lower effectiveness in the elderly; for example in long term care facilities the effectiveness was 70% to 75%.
  • The CDC also reported that the R0 (reproductive number, indicating the average number of new infections generated by an infectious person) for the delta variant is 5 to 10, compared with 1.5 to 3 for the ancestral strain. It causes a higher viral load and is detectable longer.
  • A case-control study in the UK found that efficacy of the Pfizer BioNTech and Oxford Astra Zeneca vaccines was good against the delta variant. 270
  • Post-exposure and pre-exposure prophylaxis
  • Hydroxychloroquine (HCQ) is not effective for post or pre-exposure prophylaxis. In an RCT with 821 persons with a moderate-risk or high-risk exposure to someone with confirmed COVID-19, there was no difference between groups in the primary outcome of infection. The findings were the same at 5, 10 and 14 days. 105
  • A small RCT randomized 132 healthcare workers to HCQ 600 mg daily or placebo. After 8 weeks, 4 persons in each group had confirmed cases of COVID-19, indicating no benefit. Adverse effects were more common in the HCQ group (NNTH = 6). 186
  • Non-Pharmaceutical Inverventions (NPI)
  • 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
  • Frequent, adequate handwashing for 20 seconds using warm, soapy water is strongly recommended. A simple online intervention to educate patients has been evaluated and was 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
  • A CDC study compared COVID-19 cases and deaths during the 1 to 20 days prior to implementation of bans on indoor dining and found steady increases in cases at 1 to 100 days after bans were relaxed and deaths at 61 to 100 days after relaxation in counties allowing on-premises dining. Those increases were not seen in counties that did not open up indoor dining.
  • 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 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 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
  • Mask mandates by governments
  • A CDC study compared COVID-19 cases and deaths during the 1 to 20 days prior to implementation of the policies, and periods after the policies were or were not enacted. They used multivariate analysis to adjust for other kinds of bans such as bans on gatherings and stay at home orders, and various combinations of mask and restaurant policies. They found consistent and steady reductions in cases and deaths in counties that implemented mask mandates, and steady increases in cases at 1 to 100 days after implementation and deaths at 61 to 100 days after implementation in counties allowing on-premises dining.
  • A CDC study reported on Kansas counties with and without a mask mandate. By August 17–23, 2020, the 7-day rolling average COVID-19 incidence had decreased by 6% to 16 cases per 100,000 among mask-mandated counties and increased by 100% to 12 per 100,000 among counties without a mask mandate. 240
  • 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 or 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
  • 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 of participants wearing 3-layer cloth masks found no evidence of oxygen desaturation: 96.1% before, 96.5% while wearing, and 96.3% after. 199
  • A randomized trial in Denmark found that 3-layer surgical type masks were not effective in preventing COVID19 infection in the wearer. The infection rate, however, was very low in both groups and the study was underpowered: it could not exclude a relative effectiveness of up to 46%. Importantly, they also did not study if face masks prevented spread of COVID-19 from infected individuals to others which is the primary benefit. Therefore, based on other studies, the recommendation stands to use the most effective available face mask to prevent spread stands. 202
  • School and university outbreaks
  • A cluster randomized trial in English schools and colleges compared two strategies: 1) 10 days of isolation after COVID-19 exposure, or 2) daily lateral flow testing with the exposed student remaining in class as long as they tested negative. During the 10-week period following randomization, the researchers tracked absences due to COVID and the rate of COVID transmission. There was no statistically significant difference in the rate of symptomatic lab-confirmed infections in the control group (59.1 per 100,000 per week) and intervention group (61.8 per 100,000 per week). Additionally, the rate of absenteeism by students and staff was low and not significantly different between the groups (1.6% vs. 1.3%). 282
  • 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.
  • The CDC compared three kinds of counties: counties with a college or university holding in-person instruction, counties with a college or university holding online instruction only, and counties without a college or university. They compared several key metrics during the 21 days prior to the start of classes and the 21 days following the start of classes. Not surprisingly, incidence increased 56% in counties with in-person instruction, and decreased in non-university and remote instruction counties. Test positivity rates increased in in person instruction counties and decreased in remote instruction and non-university counties. 229
  • Surface decontamination
  • The virus can also remain on surfaces like cardboard (up to 24 hours) and steel or plastic (up to 72 hours). However, it is not known how long before the level of viral pathogen on the surface is below the amount needed to cause human infection, nor the effect of environmental factors on duration. 28
  • 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
  • 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.
  • 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), all were provided with PPE (protective suits, masks, gloves, goggles, face shields, and gowns) and 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