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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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

  • Suspect severe coronavirus infection in persons with fever, cough, and other respiratory symptoms, or less commonly fever and neurologic symptoms or thrombosis when the virus is circulating in the community. C
  • RT-PCR of multiple specimens is the most appropriate diagnostic testing method. Testing should be carried out according to guidelines from and in consultation with public health authorities. 8B
  • Point-of-care PCR is highly specific, but sensitivity varies by manufacturer (76.8% for Abbott ID Now, 99.4% for Cepheid Xpert Xpress). 188B
  • Rapid antigen testing has much lower sensitivity (56.2%) and should only be used in symptomatic patients with higher viral loads. 188B

Differential Diagnosis

Community-acquired pneumonia caused by strep, influenza, legionella, mycoplasma, or other viruses
COPD exacerbation
Acute pulmonary edema
Interstitial lung disease
Hantavirus pulmonary syndrome
Opportunistic infections causing pneumonia-complicating HIV infection (pneumocystis carinii, histoplasmosis, or disseminated varicella pneumonia)

Diagnostic Criteria

  • The WHO R&D Blueprint Group recommends classifying patients with regards to disease severity as follows:
    • 1: Not hospitalized
    • 2: Hospitalized, not requiring supplemental oxygen
    • 3: Hospitalized, requiring supplemental oxygen
    • 4: Hospitalized requiring nasal high-flow oxygen, non-invasive mechanical ventilation, or both
    • 5: Hospitalized, requiring invasive mechanical ventilation, ECMO or both
    • 6: Death
  • The WHO defines several clinical syndromes:
    • Mild illness: uncomplicated upper RTI as well as non-specific symptoms such as fever, cough, fatigue, anorexia, myalgias, sore throat, dyspnea, nasal congestion, and headache. Rarely patients may present with diarrhea, nausea or vomiting.
    • Pneumonia (non-severe): Pneumonia but no need for supplemental oxygen and no signs of severe pneumonia. In child characterized by cough with tachypnea >60 bpm for <2 months; ≥50 bpm for 2 to 11 months; ≥40 bpm for 1 to 5 years.
    • Severe pneumonia: Adult or adolescent: fever or suspected RTI plus one of respiratory rate >30 bpm, severe respiratory distress, or O2 sat ≥93% on room air. Children with cough or difficulty breathing and at least one of O2 sat <90%, severe distress with grunting or severe retractions; inability to feed or drink, lethargy or unconsciousness, or seizures.
    • Acute respiratory distress syndrome: CXR or chest CT with bilateral opacities; respiratory failure not fully explained by cardiac failure or fluid overload; impaired oxygenation.
      • Oxygen impairment in adults: Mild ARDS: 200 mmHg <PaO2/FiO2 ≤300 mmHg (with PEEP or CPAP ≥5 cmH2O, or non-ventilated); Moderate ARDS: 100 mmHg <PaO2/FiO2 ≤200 mmHg (with PEEP ≥5 cmH2O, or non-ventilated); Severe ARDS: PaO2/FiO2 ≤100 mmHg (with PEEP ≥5 cmH2O, or non-ventilated); When PaO2 is not available, SpO2/FiO2 ≤315 suggests ARDS (including in non-ventilated patients)
      • Oxygen impairment in children (OI = oxygenation index and OSI = oxygenation Index using SpO2. Use PaO2-based metric when available. If PaO2 not available, wean FiO2 to maintain SpO2 ≤97% to calculate OSI or SpO2/FiO2 ratio): Bilevel ( NIV or CPAP) ≥5 cmH2O via full face mask: PaO2/FiO2 ≤300 mmHg or SpO2/FiO2 ≤264; Mild ARDS (invasively ventilated): 4 ≤OI <8 or 5 ≤OSI <7.5; Moderate ARDS (invasively ventilated): 8 ≤OI <16 or 7.5 ≤OSI <12.3; Severe ARDS (invasively ventilated): OI ≥16 or OSI ≥12.3.
    • Sepsis: In adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia. In children: suspected or proven infection and ≥2 age based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count. Severe sepsis in children is defined as sepsis accompanied by cardiovascular dysfunction, ARDS, or 2 or more organ dysfunctions. 181

Using the History and Physical

  • Suspect COVID-19 when the virus is circulating in the population and a patient reports signs and symptoms of respiratory tract infection. Most common symptoms are fever, cough, myalgias, and dyspnea.
  • A systematic review of 43 Chinese studies with 3600 patients reported the following frequency of symptoms: fever 83%, cough 60%, fatigue 38%, myalgias 28%, dyspnea 25%, and diarrhea 8.4% (see Table 1). 102
  • Cough is typically dry; the WHO/China report found that 67% had a dry or nonproductive cough while the remainder had a productive cough with thick phlegm.
  • In a series of 202 Italian outpatients with mild to moderate COVID-9 infection, 64% reported alteration of taste or smell, and 101 of 130 with altered taste or smell described it as moderate, severe, or very severe. 99 A Swiss study confirmed this, finding it in 62% of COVID-19 patients. Median day of onset was day 3, and it was most often moderate to severe. It was more common in younger and female patients. 100 It is thought that anosmia occurs because the coronavirus attaches to ACE2 receptors which are very common in the nasal epithelium and olfactory bulb.
  • The increased blood clotting observed in cases of COVID-19 has caused strokes (see Prognosis | Complications) and small vessel lesions presenting as swollen, discolored toes or fingers. Lesions are similar to pernio, a vascular inflammatory disorder seen in cold, moist climates. Skin lesions are thought to be present in up to 20% of cases and have been seen in symptomatic and asymptomatic patients.
  • A systematic review of 12 studies found that GI manifestations occurred in 3.9% of patients. 128
  • A study of 215 consecutive patients hospitalized for COVID-19 in China found CNS manifestations (dizziness, headache, impaired consciousness, stroke, ataxia or seizure) in 25%, while 9% had peripheral nervous system manifestations (altered taste or smell, visual impairment, neuropathic pain). 122
  • 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
  • Asymptomatic infections
  • A review identified 16 cohorts of COVID-19 positive individuals from Iceland, Italy, Greece, France, Japan, Argentina, and the United States, (including four ship outbreaks) ranging in size from 76 to 13,080 individuals. The percentage of people who tested positive but were asymptomatic at the time of testing ranged from a low of 6.3% in nursing home residents to highs 87.8% of occupants in a Boston homeless shelter, 87.9% on an obstetric service in New York City, and 96% of 3146 3,146 inmates in state prison systems in Arkansas, North Carolina, Ohio and Virginia. The three cohorts that came from representative samples of the population suggest the rate of asymptomatic infection is 40% to 45%. It appears that asymptomatic infection is more common in younger persons. 126 A study that included over 85% of persons living in the Italian town of Vo' found that 42% of infections were asymptomatic. However, asymptomatic persons were shown to spread infection and had similar viral loads to symptomatic persons. 145
  • An outbreak investigation on the USS Theodore Roosevelt found that of those who tested positive, 43% remained asymptomatic, 30% were presymptomatic, and 22% were symptomatic at the time of testing. 200
  • 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 See the Managing Special Populations section for a description of characteristics of children with the multisystem inflammatory syndrome.

Selecting Diagnostic Tests

  • PCR testing
  • Infection should be confirmed by PCR testing using a nasopharyngeal swab. The WHO provides guidance regarding how to prioritize testing when resources or supplies are limited.
  • Specimens for PCR testing should be obtained from the nasopharynx and oropharynx; if upper respiratory specimens are negative but clinical suspicion remains, obtain specimens from the lower respiratory tract as well.
  • After brief training, 530 symptomatic patients were asked to collect tongue, nasal, and mid-turbinate samples, in that order. Afterwards, trained staff collected swab samples from the nasopharynx and at least one additional location. Using the staff-collected sample as “the gold standard,” self-collected samples were 90% sensitive (one-sided 97.5% CI 78-100) for tongue samples, 94% sensitive (97.5% CI 84-100) for nasal samples, and 96% sensitive (97.5% CI 87-100) for mid-turbinate samples. 117 This study suggests that patient-collected samples are reasonably accurate and have the potential to decrease the frequency of exposing staff to potentially infectious material.
  • A review of 7 published studies evaluated the accuracy of PCR by days from symptom onset. Virus is detectable beginning 3 to 4 days following exposure, with the highest sensitivity in the first 5 days following symptom onset. 187
  • In a Chinese study of 51 patients eventually diagnosed with COVID-19, 15 (29%) had a negative PCR but positive CT at initial presentation; PCR became positive for these patients over the next 1 to 7 days. Only one patient had a positive PCR and negative CT which became positive for viral pneumonia 3 days later. 62
  • Saliva testing
  • A systematic review of studies comparing saliva with NP sampling identified 16 studies with 5922 unique patients. Overall, the risk of bias in the included studies was high for patient selection but low otherwise. Overall, the pooled sensitivity and specificity for saliva-based tests were 83% (95% credible interval [CrI] 75%-91%) and 99% (95% CrI 98%-99.8%), respectively. This was comparable to those for nasopharyngeal-based tests: 85% (95% CrI 77%-92%) and 99% (95% CrI 97.4%-99.8%), respectively. 224
  • After brief training, 530 patients were asked to collect tongue, nasal, and mid-turbinate samples, in that order. Afterwards, trained staff collected swab samples from the nasopharynx and at least one additional location. Compared with samples collected by trained staff, the patient-collected specimens had high sensitivity of 90% to 96%. 117
  • Point-of-care PCR and rapid antigen test
  • A Cochrane review of 11 studies of point of care PCR tests found 95.2% sensitivity and 98.9% specificity. However, this differed by manufacturer. The Abbott ID Now (5 studies) was only 76.8% sensitive but 99.6% specific (LR+ 192, LR- 0.23). The Cepheid Xpert XPress (6 studies) was 99.4% sensitive and 96.8% specific (LR+ 31, LR- 0.01). 188
  • A Cochrane review of 8 studies concluded that rapid antigen testing has much lower sensitivity (56%) but good specificity (99.5%) and should only be used in symptomatic patients with higher viral loads.
  • Real world evaluation of the accuracy of rapid antigen tests also found significantly lower sensitivity than manufacturer reports. One study evaluated the Abbott BinaxNOW rapid antigen in the Pima County, Arizona Health Department. In 827 symptomatic patients, 80% of whom were within 7 days of the onset of symptoms, sensitivity was 64% and specificity was 100%. In 2592 asymptomatic persons, sensitivity was only 36% while specificity was 99.8%. 212 A second study evaluated the Quidel Sofia SARS FIA test in patients at a Wisconsin urgent care center. In patients symptomatic ≤ 5 days, sensitivity was 82% and specificity 100%. However, if symptomatic >5 days, sensitivity dropped to 55% and specificity to 97.3%. 211
  • Antibody (IgG and IgM) tests
  • The FDA requires that antibody tests be at least 90% sensitive and 95% specific. These test characteristics lead to an unacceptably high false positive rate in low prevalence situations.
  • A meta-analysis identified 40 studies of IgG and/or IgM antibody tests for SARS-CoV-2. The overall risk of bias was high for almost all studies. Based on 15 studies of ELISA assays, they found the following test characteristics: sensitivity 84%, specificity 98%, LR+ 42, LR- 0.16. Based on 17 studies of lateral flow immunoassays, they found sensitivity 66%, specificity 97%, LR+ 22, LR- 0.35. Finally, based on 13 studies of chemiluminescent immunoassays they found sensitivity 98%, specificity 97% to 98%, LR+ 49, LR- 0.02. These values reflect testing 3 or more weeks following symptom onset. 150
  • A rapid systematic review from the National Academies estimates that IgM can be detected a median of 5 days after symptom onset and IgG a median of 14 days (range 10-18 days) after symptom onset.
  • An Icelandic study tracked persons who had recovered from COVID-19, and found that antibody levels persisted for at least 4 months at high levels. 177
  • In an outbreak on a fishing vessel prior to vaccine availability, of 122 persons on the boat only 3 had evidence of neutralizing antibodies prior to departure. While all tested negative prior to departure, at least one false negative occurred, and 103 of 122 were eventually infected on the voyage. However, all 3 of the persons with neutralizing antibodies due to previous infection remained uninfected. The likelihood of these 3 all being among the 19 uninfected was estimated to be 0.2%. 193
  • Other blood tests
  • In early reports of hospitalized patients in Wuhan City, lymphocytopenia was common (83%). The median white cell count was 3700 in patients with severe disease and 4900 in those with non-severe disease. The median lymphocyte count was 800 in severe disease and 1000 in non-severe disease. 15
  • C-reactive protein, d-dimer, interleukin-6, and LDH are commonly elevated. Lymphopenia and neutrophilia are commonly seen. These blood tests also serve as risk factors for poor outcomes.
  • A systematic review of 43 studies with 3600 Chinese patients found that the most common laboratory findings in patients sick enough to be admitted to hospital were elevated c-reactive protein (69%), elevated lactate dehydrogenase (52%) and elevated d-dimer (29%) (see Table 1). 102
  • Imaging
  • A systematic review of 43 studies with 3600 Chinese patients found that he most common imaging findings in patients sick enough to be admitted to hospital were ground glass opacities on chest CT (80%) and bilateral pneumonia (73%). The absence of radiographic findings was reported in 18% with mild disease and 3% with severe disease in early reports. 102 15
  • Up to half of patients may have normal CT findings in the first 2 days after onset of flu-like symptoms. Early radiologic changes include peripheral focal or multi-focal ground glass opacities. Late radiologic findings may include crazy paving (ground-glass opacity with superimposed interlobular septal thickening and intralobular septal thickening) and consolidation peaking 9 to 13 days after onset of symptoms, followed by slow clearing over the next month. 37
  • A retrospective review of CT scans in 21 Chinese patients without severe respiratory distress identified 4 stages: 1) early stage (0-4 days after onset) with ground glass opacities; 2) progressive stage (5-8 days) with rapid spread to involve multiple lobes with ground glass opacities, crazy-paving pattern, and consolidation; 3) peak stage (9-13 days) with increased findings and dense consolidation; and 4) absorption stage (14+ days) with consolidation gradually absorbed over the next month or more, with no further crazy-paving pattern. 85
  • These radiographic findings may persist for months after recovery. 17 In a study of 114 patients with severe COVID-19 pneumonia, 6-month follow-up CT showed lung fibrotic-like changes in 35%; changes were associated with older age, acute respiratory distress syndrome, longer hospital stays, tachycardia, non-invasive mechanical ventilation, and higher initial chest CT score. 245

Approach to the Patient