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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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


Bottom Line

  • Overall prognosis
  • Approximately 85% experience a mild illness, while 15% experience a 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
  • 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
  • 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 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). 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. 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
  • These estimates are likely to change as the epidemic evolves, as there is currently incomplete case ascertainment, especially in the US, and likely underreporting of deaths as well. 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.
  • Based on data from the 10 influenza pandemics over the past 250 years, a report from the National Academies of Sciences concludes that a second peak wave occurred approximately 6 months after emergence of the virus in the human population regardless of when it first emerged in the northern hemisphere.
  • 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 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
  • 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
  • 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.
  • Biomarkers and risk factors
  • 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 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
  • Among 5700 consecutive hospitalized patients with COVID-19 in New York, the median age was 63 years, 60% were men, 34% had diabetes, and 42% were obese. At the time of admission, only 28% were receiving supplemental oxygen and only 31% were febrile. At the end of the study period, 21% had died, 14% required ICU care, of 12% mechanical ventilation (of whom 88% died). 66
  • A systematic review warned that many of the prognostic modeling studies are of poor methodologic quality. They concluded that increasing age, male sex, CRP, LDH, and lymphopenia are the most widely reported risk factors for poor prognosis. 53
  • 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
  • In a study at Ohio State University, all athletes with COVID-19 were referred for cardiac MRI, echocardiogram, ECG, and troponin, and 27 agreed to participate. Twelve (46%) had mild symptoms and the remainder were asymptomatic. None had ECG evidence of myocarditis or elevated troponin I levels, and none had echocardiographic or MRI evidence of abnormal ventricular enlargement or dysfunction. Four athletes (15%), all male, however, had MRI evidence of myocarditis. Additionally, 12 athletes (46%) had late gadolinium enhancement, indicative of past myocardial injury or perhaps part of the athlete's heart syndrome. 174
  • 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
  • An observational study compared survival for 2773 in patients with COVID-19 who did and did not receive anticoagulation while hospitalized, adjusting for age, comorbidities including atrial fibrillation, and several other potential confounders. Overall 28% received systemic anticoagulation. They found no difference between groups with regards to mortality, but they did find that those who received anticoagulation were more likely to receive mechanical ventilation, but also were more likely to survive it. This study likely suffers from extensive unmeasured confounding and confounding by indication; a clinical trial is needed. 88
  • 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