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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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

Management of Special Populations


  • To date, studies have found no evidence of the virus in breastmilk or amniotic fluid samples. 2524
  • Two case series of 10 and 38 births respectively found no evidence of infection by PCR in the infants. Vertical transmission of infection therefore seems unlikely. 3938
  • WHO interim guidance recommends that mother and infant be allowed to remain together and have skin to skin contact, regardless of whether they or their infant have COVID-19 infection.
  • A study 215 pregnant women who delivered in New York in late March or early April 2020 found that 13.5% were SARS-CoV2-positive but asymptomatic, and 1.9% were SARS-CoV2 positive and symptomatic. 60
  • A study in a single UK hospital compared rates of stillbirth, preterm birth, cesarean delivery, or NICU admissions during the pandemic and during the same period one year before. Rates of stillbirth were significantly higher during the pandemic (6.98 vs.1.19 per 1000 births, p <0.05). The cause is not known, but the authors hypothesized it could be due to asymptomatic COVID-19 infection, worse prenatal care, or thrombotic complications affecting the placenta. The other outcomes did not increase during the pandemic. 160
  • A systematic review concluded that pregnant women less likely to manifest COVID-19 symptoms but more likely to need intensive care than non-pregnant women. 173
  • From December 14, 2020 to February 28, 2021, 35,691 pregnant women enrolled in the CDC v-safe voluntary reporting system for COVID-19 immunizations, which is a part of the Vaccine Adverse Event Reporting System. Of these women, 3958 enrolled in the v-safe pregnancy registry, which follows pregnant women until delivery. 827 women had a completed pregnancy at the time of this report. There were 724 live births (including 12 sets of multiple pregnancy) (86.1%), 104 spontaneous abortions (12.6%) and 1 stillbirth (0.1%). Ninety-six of the 104 spontaneous abortions occurred before 13 weeks gestation. Adverse events among the 724 live-born infants were preterm birth (9.4%), small size for gestational age (3.2%), and major congenital anomalies (2.2%); no neonatal deaths were reported. Although there is no parallel control group, these proportions of adverse outcomes are similar to pregnancy outcomes recorded in other studies prior to the COVID pandemic. 257
  • A cohort study from late 2021 compared the outcomes of pregnancy in pregnant women infected with COVID-19 during pregnancy with a matched control group of pregnant women enrolled immediately after each infected woman was identified. Women with a COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR] 1.76; 95% CI 1.27-2.43), severe infections (RR 3.38; 95% CI 1.63-7.01), intensive care unit admission (RR 5.04; 95% CI 3.13-8.10), maternal mortality (RR 22.3; 95% CI 2.88-172), preterm birth (RR 1.59; 95% CI 1.30-1.94), severe neonatal morbidity index (RR 2.66; 95% CI 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95%CI, 1.66-2.75). Asymptomatic women with a COVID-19 diagnosis were at higher risk only for maternal morbidity (RR 1.24; 95% CI 1.00-1.54) and preeclampsia (RR 1.63; 95% CI 1.01-2.63). Eleven of the women (1.6%) with COVID-19 infection died and one of the women without infection died. 277

Infants and Children

  • Infants and children generally have milder illness and a milder clinical presentation. In one series of 171 children with confirmed infection with COVID-19, 41% had fever, and 16% had no signs or symptoms. Only 3 required ICU support, all of whom had serious comorbidities (hydronephrosis, leukemia, and intussusception). 29
  • In an Italian case series of 100 childhood cases presenting to pediatric emergency departments, only 54% presented with fever, 44% with cough and 11% with shortness of breath. Mortality ranged from 0% to 0.6% in the Italian study and 4 other studies summarized by the authors. 81
  • A case series from China Table 1 identified 2,143 cases, of which 731 (34.2%) were laboratory confirmation cases and 1,412 (65.8%) suspected cases. Cases were initially identified based on clinical signs and symptoms and exposure history. The median age was 7 years. More cases were boys (56.6%) than girls (43.4%). Of the confirmed cases, 12.9% were asymptomatic, 43.1% mild, 41% moderate, 2.5% severe and 0.4% critical. Severe and critical cases were more prevalent in those under 1 year of age. On average, children were less severely ill compared to adult cases. 73
  • In a series of 1987 children in Alberta, Canada testing positive for COVID-19, 36% were asymptomatic at the time of testing. Cough (24.5%) and runny nose (19.3%) were the most common symptoms, but these symptoms did not distinguish between children with COVID-19 and children with other health conditions (LR+ 0.96, LR- 0.87). Anosmia/ageusia was the symptom most highly associated with a positive SARS-CoV-2 test, (LR+ 7.3). Next was nausea/vomiting, (LR+ 5.5). Headache and fever were weakly associated with COVID-19 infection, (LR+ 2.5 and 1.7 respectively). The combination of anosmia/ageusia, nausea/vomiting and headache was highly associated with COVID-19 infection with a positive LR of 66. 237
  • A CDC report in MMWR of pediatric hospitalizations in 14 states from 3/1/20 to 7/25/20 found a rate of 8 hospitalizations/100,000 children. Highest rate was <2 years (25/100,000) and was much higher for Hispanic and Black children (16.4 and 10.5 per 100,000, respectively, compared to non-Hispanic White children (2.1 per 100,000). One in 3 hospitalized children required intensive care.
  • In a study of 91 children with COVID-19 identified by contact tracing in South Korea, 2% remained asymptomatic, 60% had respiratory symptoms, and 55% had non-specific systemic symptoms. Viral shedding was 14 to 20 days, longer in those who were more symptomatic. 170
  • Based on a systematic review of cross-sectional and contact tracing studies, children and adolescents appear to be less likely to become infected following exposure than adults (OR 0.56, 95% CI 0.37-0.85) and also less likely to transmit infection to adults. Given the heterogeneity in the data these results should be interpreted cautiously. 184
  • Multisystem inflammatory syndrome in children (MIS-C)
  • A case series from Bergamo, Italy reported an outbreak of an inflammatory disorder in children that is similar to Kawasaki disease. 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
  • This syndrome is now referred to as multisystem inflammatory syndrome in children (MIS-C). Five case series describe the characteristics of children with this syndrome. Overall, 381 children were included in these studies, 115 (30%) were black, 276 (72%) had lab-confirmed COVID-19, and 143 (38%) also met criteria for Kawasaki Disease. Overall, 88% had gastrointestinal symptoms, 53% had nausea or vomiting and 58% had abdominal pain. Rash occurred in 60% of the children and desquamation, only reported in two studies, occurred in 7 of 28 (25%). Two-hundred twelve (56%) had redness or swelling of the lips or mucous membranes. Coronary artery dilation occurred in 11% of the children, myocardial dysfunction in 32% and shock in 34%. Only three of the studies reported chest radiograph data; 101 of the 224 (45%) were abnormal.
  • A systematic review identified 8 studies (6 in Europe, 2 in the US) of children with MIS-C, most of whom met Kawasaki diagnostic criteria or had cardiac involvement. Even in these relatively severely affected groups, mortality was 2%. Overall, 87% of children had gastrointestinal symptoms, 73% had skin or mucocutaneous symptoms, and 71% reported cardiovascular symptoms. The spectrum of symptoms in children with milder and less obvious disease is likely to be quite different than what is reported in these studies. At least 75% of the children in each study had elevated C-reactive protein, interleukin-6, and fibrinogen levels.
  • Using data on 281 children hospitalized with COVID-19, researchers found that obesity (OR 3.4, 95% CI 1.3-9.1), hypoxia on admission (OR 4.0, 95% CI 1.1-14) and bilateral pulmonary infiltrates (OR 3.7, 95% CI 1.5-9.3) were significant predictors of severe disease requiring ICU stay. The authors also report that the following factors were most strongly associated with development of MIS-C: lower absolute lymphocyte count (OR 8.3 per unit decrease in 109 cells/L; 95% CI 2.3-33) and higher levels of C-reactive protein (OR 1.06 per unit increase in mg/dL; 95% CI 1.0-1.1). 252
  • The American College of Rheumatology proposed guidelines for managing MIS-C late 2020. While the panel’s strength of confidence in the recommendations ranged from moderate to high, the underlying evidence is still in evolution. 241
    • Children with fever, COVID-19 infection, and at least two of rash, GI symptoms, conjunctivitis, edema of hands/feet, oral mucosal changes, conjunctivities, lymphadenopathy, or neurologic symptoms should be investigated for MIS-C.
    • For cardiac management, the guideline recommends serial monitoring of abnormal cardiac biomarkers (e.g., BNP, troponin T levels), performing electrocardiograms at least every 48 hours, performing follow-up echocardiograms at least every 1-2 weeks and 4-6 weeks after presentation, performing cardiac MRI after 2 to 6 months in those with signs of cardiac dysfunction and cardiac CT if there is a suspicion of distal coronary artery aneurysms if the arteries are not well seen on ultrasound.
    • The panel also recommends intravenous immune globulin and/or glucocorticoids as first line treatment followed by anakinra.
    • Low-dose aspirin is recommended for at least four weeks unless the platelet count is less than 80,000 per microliter. They also provide guidance on when to use anticoagulants such as enoxaparin or warfarin.
    • Finally, in addition to the use of glucocorticoids or anakinra, the guideline also recommends using tocilizumab in children with signs of hyperinflammation (acute respiratory distress syndrome, shock/cardiac dysfunction, substantially elevated LDH, d-dimer, IL-6, IL-2R, CRP, and/or ferritin levels, and depressed lymphocyte count, albumin levels, and/or platelet count).