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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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


Bottom Line

  • Overall prognosis
  • Approximately 85% to 90% experience a mild illness, while 10% to 15% experience severe disease requiring hospitalization, including 5% who require ICU admission. 54 22
  • In a report of the initial 41 confirmed cases of COVID-19 in Wuhan, China, days from illness onset to dyspnea in 21 patients was 8 days (5.0-13.0) and to ARDS, occurring in 11 patients, was 9 days (8.0-14.0). 41
  • Viral shedding persisted a median of 20 days in hospitalized patients who recovered, and as long as 37 days. 18
  • Mortality
  • Mortality was very high early in the pandemic. In a retrospective cohort study of 191 adults hospitalized in Wuhan, China with confirmed COVID-19 infections who had been discharged or had died by January 31, 2020, 72% were discharged and 28% died as inpatients. 18
  • The mortality estimates have changed as the pandemic evolved. This is due in part to incomplete case ascertainment, underreporting of deaths, the evolution of newer strains, and of course changes in therapy. For example, a study comparing monthly rates among hospitalized patients at a large New York medical center found that the case fatality ratio decreased from 25.6% in March to 7.6% in August, after adjusting for patient factors and severity of illness on admission. 196
  • Based on modeling by the COVID-19 research unit at Imperial College in London, the infected 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 30-39, 0.60% for 50-59, 2.2% for 60-69, 5.1% for 70-79 and 9.3% for 80 and older). Mortality is also higher in those with comorbidities such as hypertension, diabetes and chronic cardiopulmonary conditions. It is important to note that any estimates of fatality ratios during a pandemic will be in accurate and should be considered preliminary.
  • The same group published a more detailed and updated report on March 30, 2020. They provide updated estimates of the infection fatality ratio (IFR, deaths/all infections including mild and asymptomatic) and the case fatality ratio (CFR, deaths/symptomatic or confirmed infections). They estimate a mean duration from symptom onset to death of 18 days, and for survivors the time from symptom onset to hospital discharge of 25 days. They do a good job of trying to adjust for biases in the data due to oversampling of severe cases early in a pandemic, failure to adjust for age, and the lag between case identification and death. The overall IFR is estimated to be 0.66%, and the overall CFR 1.38%. The CFR increases from 0.06% for those in their 20’s to 0.15% in their 30’s, 0.30% in their 40’s, 1.3% in their 50’s, 4.0% in their 60’s, 8.6% in their 70’s, and 13.4% for those 80 and older. The proportion hospitalized increased from 1% for patients in their 20’s to 4% in their 40’s to 12% in their 60’s. 65
  • A registry study of 8 million admissions to 1030 US hospitals of non-pregnant adults age 18 to 34 years found 3222 admissions, of whom 21% required intensive care, 10% mechanical ventilation, and 2.7% died. 185
  • A Canadian retrospective cohort study found that compared with ancestral strains, N501Y-positive variants (Alpha/B.1.17, Beta/B.1.351 and Gamma/P.1) were associated with a 52% (95% CI 42%-63%) increase in the likelihood of hospitalization, an 89% (95% CI 67%-117%) increase in the risk of ICU admission, and a 51% (95% CI 30%-78%) in mortality. The Delta variant was associated with a 108% (95% CI 78%-140%) increase in the risk of hospitalization, 235% (95% CI 160%-331%) increase in the risk of ICU admission, and 133% (95% CI 54%-231%) increase in the risk of death 271.
  • It is known that some variants appear to spread more easily, such as the B.1.1.7 ("UK variant"). It appears to be transmitted about 40% faster than the original strain in the US, and may become the dominant strain in the US. 216 In one analysis, 384 of 2,583 deaths were due to the B.1.1.7 strain, and the relative hazard of death within 28 days was 1.35 (95% CI 1.08-1.68). Another case-control analysis of community testing data linked to mortality data found a mortality hazard ratio of 1.91 (95% CI 1.35-2.71). In a matched cohort analysis of 14,939 people infected with the B. strain compared to 15,555 infected with the original strain, there were 104 deaths (0.2%) compared to 65 deaths (0.1%), a mortality ratio of 1.65 (95% CI 1.21-2.25). However, in a hospital based study, the risk of death from the B.1.1.7 strain was not statistically increased (odds ratio 0.63 (95% CI 0.20-1.69), though this small study could not exclude an excess mortality of up to 69%. 215
  • Morbidity
  • A VA study compared outcomes for patients hospitalized with COVID-19 with those for patients hospitalized with seasonal influenza in the 3 previous years. After adjusting for potential known confounders, those with COVID-19 were more likely to experience complications such as acute kidney injury (37.2% vs. 29.0%; OR 1.5, 95% CI 1.4-1.7), severe septic shock (8.8% vs. 2.4%; OR 4.0, 95% CI 3.4-4.8), pulmonary embolism (3.2% vs. 2.1%; OR 1.5, 95% CI 1.2-1.9), and arrhythmias and sudden cardiac death (3.8% vs. 2.2%; OR 1.8, 95% CI 1.4-2.2). More COVID-19 died (18.6% vs. 5.3%; HR 5.0, 95% CI 4.4-5.6), required mechanical ventilation (15.0% vs. 4.2%; HR 4.0, 95% CI 3.5-4.5), and were in intensive care units (36.8% vs. 18.6%; HR 2.4, 95% CI 2.3-2.6). 235
  • Prognosis in subgroups
  • In the UK, standardized mortality rates were less than 1.0 in whites and were higher in persons of Black African (SMR 3.2), Black Caribbean (2.2), Pakistani (3.3), Indian (1.7), and Bangladeshi (2.4) origin. 103
  • A study comparing mortality rates for Black and white patients in Louisiana found that after adjusting for severity at presentation, age, comorbidities and socioeconomic factors there was no difference in case fatality ratios. 107 A second larger study in a US 92 hospital system similarly found no difference in mortality after adjusting for age, sex, insurance status, comorbidity, neighborhood deprivation, and site of care (HR for Black vs. white 0.93, 95% CI 0.83-1.09). 164
  • A study compared mortality in Black and white patients hospitalized in different hospitalis for COVID-19. After fully adjusting the analysis, they found no difference in outcomes between Black and white patients in the same hospital or health system. However, they also concluded that Black patients are more likely to be hospitalized in hospitals with higher overall mortality rates. 267
  • A study of 800 patients with active cancer, of whom one third were not receiving active treatment, found no association between active therapy and mortality. As in other populations, age and comorbidities increased the risk of death. 106
  • The CDC summarized over 1.7 million cases and over 100,000 deaths due to COVID-19 from January 22 through May 30, 2020 in the MMWR. The CDC had sufficient information on 287,320 individuals regarding chronic diseases. Cardiovascular disease was present in 32% of cases, diabetes in 30% and chronic lung disease in 18%. Of all 1.7 million patients reported to the CDC during this time period, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU and 71,116 (5%) died. The hospitalization rate was six times higher among patients with a chronic disease (45.4% vs. 7.6%) and the death rate was twelve times higher (19.5% vs. 1.6%).
  • Persistence of symptoms ("Long COVID" or "Long hauler syndrome")
  • In an Italian study, patients who had been hospitalized for COVID-19 but now met criteria for discontinuing quarantine were invited to attend a COVID-19 follow-up clinic. Of 179 eligible patients, 143 agreed to participate and were still PCR negative. Patients were a mean of 60 days post symptom onset, and 32% reported 1 or 2 symptoms and 55% reported 3 or more persistent symptoms; fully 44% reported a clinically significant decline in a quality-of-life scale compared to their pre-COVID-19 state. The most common post-COVID-19 symptoms at follow-up were fatigue (53%), dyspnea (43%), joint pain (28%), chest pain (22%), cough (17%), and anosmia (16%). 144
  • A Michigan study identified 1250 patients with COVID-19 discharged from 38 Michigan hospitals between March 16 and July 1, 2020. Within 60 days of discharge, 84 patients died and 189 patients were re-hospitalized. Of patients alive 60 days after discharge, 488 completed a post-discharge telephone survey. Cardiopulmonary symptoms (such as cough and dyspnea) were reported by 33% of patients, and 13% of patients had persistent loss of taste or smell. This study from Michigan hospitals confirms that roughly 30% of patients hospitalized with COVID-19 infection will have persistent symptoms for at least 2 months. 201
  • A Chinese study identified 2469 patients who had been hospitalized in Wuhan City and discharged early in the pandemic, and was able to follow-up with 1733 of them a median of just over 6 months later. Of the 1,655 participants who completed the survey, 67% reported at least one symptom at follow-up. The most common symptoms were fatigue or muscle weakness (63%), sleep difficulties (26%), pain or discomfort (27%), and anxiety or depression (23%). Twenty-three percent performed under the lower limit of normal for the 6-minute walk test, and 53% had at least one abnormal lung CT pattern. 226
  • Using national healthcare databases, this research team identified nearly 54,000 persons hospitalized in the United Kingdom with COVID who were discharged alive by August 31, 2020 and another group from the general population who were exactly matched based on age group, sex, ethnicity, region of residence, living circumstances (level of deprivation), body mass index group, and several comorbid conditions. During the follow-up period, the hospitalized patients were more likely than the matched controls to die (12.3% vs. 1.7%) to have been hospitalized (29.4% vs. 9.2%), and to have newly diagnosed respiratory disease (21.5% vs. 0.8%). 253
  • These authors used a federated electronic health record database in the United States that house data on 81 million patients in 62 different health care organizations. In the 6 months after diagnosis, 33.6% of patients with COVID had a subsequent diagnosis of any neurologic or psychiatric illness. These were more frequent among those hospitalized (38.7%), who were in ICUs (46.4%), and those with encephalopathy (62.3%). Compared with the persons with influenza, the patients with COVID were more likely to have subsequent care for any of the 14 neurologic or psychiatric conditions (HR 1.44; 95% CI 1.40-1.47) or for a new diagnosis (HR 1.78; 95% CI 1.68-1.89). These were also higher than in persons with any respiratory illness (HR 1.16; 95% CI 1.14-1.17 for any diagnosis; 1.32; 95% CI 1.27-1.36 for a new diagnosis). 254
  • Persistent symptoms can occur in patients with mild or asymptomatic infection as well. Swedish researchers compared 323 healthcare workers with mild or asymptomatic infection with 1072 who were not infected. They identified patients with persistent anosmia, fatigue, ageusia, dyspnea, sleeping disorder, headache, palpitations, impaired concentration, myalgias, or memory impairment rated as moderate to severe. Any moderately severe or worse symptom was present more often in the seropositive patients at 2 months (26% vs. 8.9%), 4 months (21.4% vs. 7.2%), and 8 months (14.9% vs. 3.4%). The most common persistent symptoms at 8 months were anosmia (9.0%), fatigue (4.0%), ageusia (3.7%), and dyspnea (1.9%). Symptoms did appear to decline over time. 255
  • A systematic review of 57 studies with 250,351 individuals, 80% of home were sick enough to be hospitalized, found that 54% still had COVID related symptoms 6 months later. The most frequent specific issues were chest imaging abnormalities in 62%, difficulty concentrating in 24%, generalized anxiety disorder in 30%, general functional impairments in 44%, and fatigue or muscle weakness in 38%. 283
  • Reinfection
  • The first known case of re-infection was reported in August 2020 of a 33-year-old man who became ill with COVID-19 4½ months after his initial infection; this second illness was milder. Viral sequencing of the two viruses did not match.
  • A UK study of 1265 healthcare workers with a positive PCR test for SARS-CoV-2 found that antibodies persisted at least 6 months, and only 2 individuals had a subsequent positive PCR test and could be said to have been reinfected. 231
  • A larger Danish study found 0.65% of persons infected during the first surge of the virus in that country were reinfected during the second surge, and they estimate that previous infection confers approximately 80% protection. 251
  • A meta-analysis of case reports found few reports of reinfection. 247
  • Prognostic risk scores
  • Laboratory tests that are risk factors for severe disease or death in COVID-19 include elevated c-reactive protein, lactate dehydrogenase, procalcitonin, d-dimer and neutrophils, and decreased leukocyte count.
  • A study in 1340 hospitalized patients at 6 US medical centers identified 3 key risk factors: age 50 to 65 years (3 points), age >65 years (5 points), respiratory rate >= 30/minute, and O2 saturation <93% (2 points). Mortality was 0.8% in the group with <2 points, 11.4% if 2 to 5 points, and 40% if >5 points. 269 Prospective validation is underway.
  • A clinical prediction rules developed and validated in China incorporates 10 predictor variables to predict critical illness in hospitalized COVID-19 patients. The area under the ROC curve was 0.88 in both derivation and validation groups. An online version is available. 94
  • A risk score from an English consortium studying hospitalized patients includes age, sex, comorbidities, respiratory rate, O2 saturation, Glasgow Coma Scale, BUN, and CRP to place patients into 4 risk groups with increasing mortality: 1.2%, 9.9%, 31.4%, and 61.5%. 176
  • Based on early data from Wuhan City, China, adverse risk factors for mortality include increasing age (OR 1.1 per year, 95% CI 1.03-1.17), a higher SOFA score, d-dimer greater than 1 mcg/L on admission, and comorbidities including hypertension, diabetes, and cardiopulmonary disease. 18 A second series of 201 patients from Wuhan City found that neutrophilia, lymphopenia, elevated LCH, increasing age, elevated c-reactive protein, and low albumin were risk factors for progression to ARDS. 20
  • Complications
  • ARDS is the most important complications of infection with SARS-CoV-2.
  • A study in Lombardy region of Italy compared rates of out of hospital cardiac arrest from 2/21/20 to 3/31/20 with the same period in 2019. There were 362 cases in 2020 compared with only 229 in 2019, a 58% increase. 93
  • Cardiovascular complications
  • Stroke complicated COVID-19 in 5.9% of patients in Wuhan, China. These patients were older, had more cardiovascular co-morbidities, and more severe pneumonia. In the US, stroke accompanying COVID-19 infection is now being reported in young and middle-aged patients, many of whom were otherwise healthy.
  • A case series reported findings regarding 5 persons with SARS-CoV-2 infection who presented during a 2-week period with a large vessel stroke (7 times the usual rate of stroke in persons under age 50 years). Their ages ranged from 33 to 49 years; 2 were healthy, one had hypertension and hyperlipidemia, one had undiagnosed diabetes, and one had diabetes and a history of mild stroke. The vessels involved include the middle cerebral artery in three, posterior cerebral artery in one, and internal carotid artery in one. All were treated with antiplatelet therapy, one with TPA, and 4 with clot retrieval. All but one experienced at least some improvement in their symptoms, and 3 had been discharged at the time the article was written. D-dimer levels were significantly elevated in three patients. 67
  • A retrospective cohort study in New York compared the incidence of ischemic stroke in influenza patients between 2016 and 2018 (0.2%) with that in COVID-19 patients (1.6%), with an adjusted odds ratio of 7.6 (95% CI 2.3-25.2). 136
  • Another study in US professional athletes in 6 leagues identified 789 with a positive test for COVID-19; all but 12 were men, who apparently don't follow instructions well. Approximately 42% had no symptoms. Thirty (3.8%) had an abnormal cardiac test: 6 (0.8%) had elevated troponin levels; 10 (1.3%) had abnormal ECGs; and 20 (2.5%) had an abnormal echocardiogram. Most (27 of the 30 or 90%) of these athletes underwent cMRI and 15 underwent both cMRI and stress echocardiograms. Among the 3 who didn’t undergo cMRI, their stress tests were normal. Five of the 27 tested had abnormal cMRIs: 3 had myocarditis and 2 had pericarditis. All five were held out of sports participation. The remaining 25 were allowed to return to play and, so far, none have experienced any cardiac events. 208
  • Thrombotic complications
  • Investigators studied the incidence of thrombotic complications of all 184 ICU patients with COVID-19 pneumonia hospitalized at 3 Dutch academic medical centers. 31% of the patients had thrombotic complications, including 27% with venous thromboembolism and 3.7% with arterial thrombotic events. Pulmonary embolism was the most frequent complication (25% of all patients). The investigators recommend that all patients with COVID-19 admitted to the ICU receive thrombosis prophylaxis. This is consistent with the observation that high levels of d-dimer are associated with a worse prognosis. 69
  • A consecutive series of 3334 patients with COVID-19 hospitalized between March 1 and April 17, 2020 at NYU Langone Health Center was studied, of whom 829 were in the ICU and 2505 were not in the ICU. During this period most patients received thromboprophylaxis. Rates of PE were 6.2% in the ICU and 2.2% on the ward; for deep vein thrombosis rates were 9.4% in the ICU and 2.0% on the ward. Rates of stroke were 3.7% in the ICU and 0.9% on the ward, and for myocardial infarction were 13.9% in the ICU and 7.3% on the ward. These rates appear to be higher than with other respiratory infections. 167
  • A second study of 449 patients in Wuhan, China with severe COVID-19 found no difference in overall 28-day mortality. However, they did find an association between anticoagulant use and lower mortality in those with an elevated sepsis induced coagulopathy score (40% vs. 64%, p = 0.03, NNT = 4).
  • A case series from Bergamo, Italy reported an outbreak of Kawasaki-like disease in children. They compared 19 children diagnosed prior to 2/17/20 with 10 diagnosed since that time. The monthly incidence since 2/17/20 was 30x higher than previously, and children were older (mean 7.5 vs. 3.0 years) and sicker (more with shock, cardiac involvement, and need for adjunctive corticosteroids). 92

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