Investigations

1st investigations to order

Test
Result
Test

Order a RT-PCR for SARS-CoV-2 in patients with suspected infection whenever possible (see the Criteria section).[369]

Base decisions about who to test on clinical and epidemiologic factors.[369] Consult local health authorities for guidance as testing priorities depend on local recommendations and available resources.

In the UK, testing is recommended in: (1) people in the community with symptoms of new continuous cough, high temperature, or altered sense of smell/taste; (2) people requiring hospital admission and who have clinical or radiologic evidence of pneumonia, or acute respiratory distress syndrome, or influenza-like illness, or altered sense of smell/taste in isolation or in combination with any other symptoms.[367][408]

In the US, testing is recommended in: (1) people with symptoms, even if they are mild; (2) people who are asymptomatic and have been in close contact (less than 6 feet [2 meters] for a total of 15 minutes or more over a 24-hour period) with a person with documented infection; (3) people who are asymptomatic and have not been in close contact for at least 15 minutes with a person with documented infection only if required by a healthcare provider or public health official.[409] 

The American Academy of Pediatrics recommends testing children with symptoms consistent with COVID-19, children in close contact with an individual with probable or confirmed infection, and children scheduled for an invasive medical procedure. The decision to test does not differ by the age of the child. Testing is not recommended for other illnesses that lack shared symptoms (e.g., urinary tract infection, cellulitis), or for children exposed to close contacts of infected individuals unless those contacts go on to test positive themselves.[410]

The optimal specimen for testing depends on the clinical presentation and the time since symptom onset. The World Health Organization recommends upper respiratory specimens (nasopharyngeal and/or oropharyngeal swabs) for early-stage infections, especially asymptomatic or mild cases, and lower respiratory specimens (sputum and/or endotracheal aspirate or bronchoalveolar lavage in patients with more severe respiratory disease) for later-stage infections or patients in whom there is a strong suspicion for infection and their upper respiratory tract specimen test was negative. Other specimens (e.g., nasal mid-turbinate swab, anterior nares swab, nasopharyngeal/nasal wash/aspirate, saliva, fecal) may be recommended in some circumstances; consult local guidance.[369][415]

A positive RT-PCR result confirms SARS-CoV-2 infection (in the context of the limitations associated with RT-PCR testing). If the result is negative, and there is still a clinical suspicion of infection (e.g., an epidemiologic link, typical x-ray findings, absence of another etiology), resample the patient and repeat the test. A positive result confirms infection. If the second test is negative, consider serologic testing (see below).[369]

The pooled sensitivity has been estimated to be 87.8%, with the specificity estimated to be in the range of 87.7% to 100%.[419]

Interpret test results with caution. Evidence for the use of RT-PCR in the diagnosis of COVID-19 is still emerging, and uncertainties about its efficacy and accuracy remain.[419] It is not fully understood whether a positive result always represents infectious virus.[420] Interpreting the result depends on the accuracy of the test itself, and the pre- and post-test probabilities of disease.[422] When the pretest probability is low, positive results should be interpreted with caution, and ideally a second specimen tested for confirmation.[423] The lower the prevalence of disease in a given population, the lower the post-test probability.[424] False-positive results can be caused by a laboratory error or a cross-reaction with antibodies formed by current and past exposure to seasonal human coronavirus infections (e.g., common cold), and are more likely when the prevalence of disease is moderate to low.[426][427] Preliminary estimates of the false-positive rate in the UK are in the range of 0.8% to 4%.[428] False-negative rates of between 2% and 29% have been reported.[422]

Also collect nasopharyngeal swabs to rule out influenza and other respiratory infections according to local guidance. It is important to note that coinfections can occur, and a positive test for a non-COVID-19 pathogen does not rule out COVID-19.[2][418] When SARS-CoV-2 and influenza viruses are cocirculating, test for both viruses in all hospitalized patients with acute respiratory illness, and only test for influenza virus in outpatients with acute respiratory illness if the results will change clinical management of the patient.[3] A single-test multiplex assay to diagnose infection caused by influenza A, influenza B, and SARS-CoV-2 is available in the US.[480]

Result

positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA; may be positive for influenza A and B viruses and other respiratory pathogens

Test
Result
Test

Order in patients with severe illness.

Recommended in patients with respiratory distress and cyanosis.

Clinicians should be aware that patients with COVID-19 can develop "silent hypoxia": their oxygen saturations can drop to low levels and precipitate acute respiratory failure without the presence of obvious symptoms of respiratory distress. Only a small proportion of patients have other organ dysfunction, meaning that after the initial phase of acute deterioration, traditional methods of recognizing further deterioration (e.g., National Early Warning Score 2 [NEWS2] scores) may not help predict those patients who go on to develop respiratory failure.[400]

Result

may show low oxygen saturation (SpO₂ <90%)

Test
Result
Test

Order in patients with severe illness as indicated to detect hypercarbia or acidosis.

Recommended in patients with respiratory distress and cyanosis who have low oxygen saturation (SpO₂ <90%). 

Result

may show low partial oxygen pressure

Test
Result
Test

Order in patients with severe illness.

Lymphopenia, leukocytosis, thrombocytopenia, decreased eosinophils, decreased hemoglobin, and high neutrophil-to-lymphocyte ratio are significantly associated with severe disease, and may be useful for predicting disease progression. Severe cases are more likely to present with lymphopenia and thrombocytopenia, but not leukopenia.[481]

Elevated red blood cell distribution width (at admission and increasing during hospitalization) has been associated with a significantly increased risk of mortality in hospitalized patients.[482]

Absolute counts of major lymphocyte subsets, particularly CD4+ and CD8+ T-cell counts, are significantly decreased in patients with severe disease.[483]

Late-phase thrombocytopenia (i.e., occurring 3 weeks or more after symptom onset) has been reported but is uncommon.[484]

Result

lymphopenia; leukocytosis; leukopenia; thrombocytopenia; decreased eosinophils; decreased hemoglobin

Test
Result
Test

Order in patients with severe illness.

Elevated liver enzymes, total bilirubin, creatinine, and blood urea nitrogen, and hypoalbuminemia are significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Hypokalemia has been reported in 54% of patients.[485] Hypocalcemia has been reported in 63% of patients.[486] Other electrolyte derangements may be present.

Result

elevated liver enzymes; elevated total bilirubin; renal impairment; hypoalbuminemia; electrolyte derangements

Test
Result
Test

Order in patients with severe illness.

Uncontrolled hyperglycemia has been shown to worsen prognosis in all patients, not only patients with diabetes.[487][488][489]

Result

variable

Test
Result
Test

Order in patients with severe illness.

Elevated D-dimer, elevated fibrinogen (and fibrin degradation product), and prolonged prothrombin time are significantly associated with severe disease, and may be useful for predicting disease progression.[481][490]

The risk of severe disease and mortality is 2-fold and 4-fold higher, respectively, in patients with elevated D-dimer levels.[491] Patients with very high D-dimer levels have an increased risk of thrombosis.[492][493]

Result

elevated D-dimer; prolonged prothrombin time; elevated fibrinogen

Test
Result
Test

Order in patients with severe illness.

Elevated serum troponin I and creatine kinase-myocardial band (CK-MB) are significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Other cardiac biomarkers (e.g., brain natriuretic peptide, cardiac troponin T) may also be elevated and are associated with severe disease and worse outcomes.[494][495]

CK-MB has been found to be elevated in mild disease in children. The significance of this is unknown.[406]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated C-reactive protein is significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Commonly elevated in patients with COVID-19.[404]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated serum lactate dehydrogenase is significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated interleukin-6 level is significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Less likely to be elevated in children.[496]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated serum procalcitonin is significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Elevated serum procalcitonin may be more common in children.[398]

May be elevated in patients with secondary bacterial infection.[35][36] 

There is insufficient evidence to recommend routine procalcitonin testing to guide decisions about the use of antibiotics.[497]

However, it may be helpful in limiting overuse of antibiotics in patients with COVID-19-related pneumonia.[498]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated ferritin is significantly associated with severe disease, and may be useful for predicting disease progression.[499]

May indicate development of cytokine release syndrome.[500]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Levels increase in severe disease; therefore, it may be useful as a biomarker for predicting disease progression.[501]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated serum creatine kinase and myoglobin are significantly associated with severe disease, and may be useful for predicting disease progression.[481]

Result

may be elevated

Test
Result
Test

Collect blood and sputum specimens for culture in patients with severe or critical disease to rule out other causes of lower respiratory tract infection and sepsis, especially patients with an atypical epidemiologic history.[2]

Testing is most useful when there is concern for multidrug-resistant pathogens.[498]

Specimens should be collected prior to starting empiric antimicrobials if possible.

Result

negative for bacterial infection

Test
Result
Test

Order in all patients with suspected pneumonia.

Unilateral lung infiltrates are found in 25% of patients, and bilateral lung infiltrates are found in 75% of patients.[35][36][440]

Although chest x-ray appears to have a lower sensitivity compared with chest CT, it has the advantages of being less resource-intensive, associated with lower radiation doses, easier to repeat sequentially, and portable.[441]

Result

unilateral or bilateral lung infiltrates

Investigations to consider

Test
Result
Test

Consider a CT scan of the chest. Consult local guidance on whether to perform a CT scan. The British Society of Thoracic Imaging (BSTI) recommends CT imaging in patients with clinically suspected COVID-19 who are seriously ill if chest x-ray is uncertain or normal. BSTI: radiology decision tool for suspected COVID-19 external link opens in a new window Some institutions in the UK recommend a more pragmatic approach for patients with high clinical suspicion of COVID-19, with chest CT recommended only after two indeterminate or normal chest x-rays in combination with a negative RT-PCR test.[442] The American College of Radiology recommends reserving CT for hospitalized, symptomatic patients with specific clinical indications for CT, and emphasizes that a normal chest CT does not mean that a patient does not have COVID-19 and that an abnormal chest CT is not specific for COVID-19 diagnosis.[443]

Abnormal chest CT findings have been reported in up to 97% of hospitalized patients.[444] Evidence of pneumonia on CT may precede a positive RT-PCR result for SARS-CoV-2 in some patients.[445] CT imaging abnormalities may be present in asymptomatic patients. The pooled estimate of the rate of positive chest CT findings in asymptomatic cases was 62%, while it was 90% in those who developed symptoms.[446] Some patients may present with a normal chest finding despite a positive RT-PCR.[447] Also, results of RT-PCR testing may be false-negative, so patients with typical CT findings should have repeat RT-PCR testing to confirm the diagnosis.[448]

The most common findings are ground-glass opacity, either in isolation or coexisting with other findings such as consolidation, interlobular septal thickening, or crazy-paving pattern. The most common distribution pattern is bilateral, peripheral/subpleural, posterior distribution of the opacities, with a lower lobe predominance. Extensive/multilobar involvement with consolidations is more common in older patients and those with severe disease. Pulmonary vascular enlargement, interlobular or intralobular septal thickening, adjacent pleural thickening, air bronchograms, subpleural lines, crazy-paving pattern, bronchus distortion, bronchiectasis, vacuolar retraction sign, and halo sign are atypical features. Pleural effusion, pericardial effusion, cavitation, pneumothorax, and mediastinal lymphadenopathy have also been reported rarely.[449]

Children frequently have normal or mild CT chest findings. The most common signs in children are patchy ground-glass opacity and, less frequently, nonspecific patchy shadows, areas of consolidation, and a halo sign. Abnormalities are more common in the lower lobes and are predominantly unilateral. Pleural effusion is rare.[452]

CT scan generally shows an increase in the size, number, and density of ground-glass opacities in the early follow-up period, with a progression to mixed areas of ground-glass opacities, consolidations, and crazy paving peaking at day 10 to 11, before gradually resolving or persisting as patchy fibrosis.[449]

The positive predictive value was low (1.5% to 30.7%) in low-prevalence regions, and the negative predictive value ranged from 95.4% to 99.8% in one meta-analysis. Pooled sensitivity and specificity were 94% to 96% and 37%, respectively.[502][503] The simultaneous presence of ground-glass opacity and other features of viral pneumonia had optimum performance in the detection of COVID-19 (sensitivity 90% and specificity 89%).[450]

In a cohort of over 1000 patients in a hyperendemic area in China, chest CT had a higher sensitivity for diagnosis of COVID-19 compared with initial RT-PCR from swab samples (88% versus 59%). Improvement of abnormal CT findings also preceded change from RT-PCR positivity to negativity in this cohort during recovery. The sensitivity of chest CT was 97% in patients who ultimately had positive RT-PCR results. However, in this setting, 75% of patients with negative RT-PCR results also had positive chest CT findings. Of these patients, 48% were considered highly likely cases, while 33% were considered probable cases.[504]com.bmj.content.model.Caption@26f868ff[Figure caption and citation for the preceding image starts]: Transverse CT scans from a 32-year-old man, showing ground-glass opacity and consolidation of lower lobe of right lung near the pleura on day 1 after symptom onset (top panel), and bilateral ground-glass opacity and consolidation on day 7 after symptom onsetXu XW et al. BMJ. 2020;368:m606 [Citation ends].

Result

ground-glass opacity in isolation or coexisting with other findings (e.g., consolidation, interlobular septal thickening, crazy-paving pattern); bilateral, peripheral/subpleural, posterior distribution with a lower lobe predominance

Test
Result
Test

Cannot be used as a standalone diagnostic for acute infections; however, may be useful in various settings (e.g, negative molecular testing, diagnosing patients with late presentation or prolonged symptoms, serosurveillance studies).[369][430]

BMJ practice pointer: testing for SARS-CoV-2 antibodies external link opens in a new window

The World Health Organization (WHO) recommends collecting a paired serum sample, one specimen in the acute phase and one in the convalescent phase 2 to 4 weeks later, in patients where infection is strongly suspected and the RT-PCR result is negative. Seroconversion or a rise in antibody titers in paired sera help to confirm whether the infection is recent and/or acute. If the initial sample tests positive, this could be due to a past infection that is not related to the current illness. Seroconversion may be faster and more robust in patients with severe disease compared with those with mild disease or asymptomatic infection.[369]

The Centers for Disease Control and Prevention recommends serologic testing as a method to support the diagnosis of acute infection in patients who present late (i.e., 9 to 14 days after symptom onset) in addition to other viral detection methods (e.g., RT-PCR, antigen detection tests), or patients who present with late complications (e.g., pediatric inflammatory multisystem syndrome in children).[431]

The Infectious Diseases Society of America recommends serologic testing in the following circumstances: evaluation of patients with a high clinical suspicion for infection when molecular diagnostic testing is negative and at least 2 weeks have passed since symptom onset; evaluation of pediatric inflammatory multisystem syndrome in children; and serosurveillance studies.[432]

Antibody responses to SARS-CoV-2 typically occur during the first 1 to 3 weeks of illness, with the seroconversion time of IgG antibodies often being earlier than that of IgM antibodies.[433][434]

The estimated sensitivity of antibody tests ranged from 18.4% to 96.1% (the lowest reported sensitivity was from a point-of-care test, although a sensitivity <50% was reported for one laboratory test), and specificity ranged from 88.9% to 100%. Estimates of diagnostic accuracy need to be interpreted with caution in the absence of a definitive reference standard to diagnose or rule out COVID-19.[419]

Limitations of testing: serologic testing cannot be used to determine acute infection; results do not indicate the presence or absence of current or previous infection with certainty; reliable diagnosis is often only possible in the recovery phase when opportunities for management or interruption of transmission have passed; cross-reactivity with other coronaviruses, which can result in false-positive results.[369][431]

While rapid antibody detection kits have been approved for the qualitative detection of SARS-CoV-2 IgG/IgM antibodies in serum, plasma, or whole blood, the WHO does not recommend the use of these tests outside of research settings as they have not been validated as yet.[436]

Result

positive for SARS-CoV-2 virus antibodies; seroconversion or a rise in antibody titers in paired sera

Test
Result
Test

Rapid diagnostic test. Relies on direct detection of SARS-CoV-2 viral proteins in nasal swabs and other respiratory specimens using a lateral flow immunoassay. Results are usually available in less than 30 minutes. While antigen tests are substantially less sensitive than RT-PCR, they offer the possibility of rapid, inexpensive, and early detection of the most infectious cases in appropriate settings. If used, testing should occur within the first 5 to 7 days following the onset of symptoms. The World Health Organization recommends antigen testing only in certain scenarios where RT-PCR is unavailable or where prolonged turnaround times preclude clinical utility, provided that the test meets the minimum performance requirements of ≥80% sensitivity and ≥97% specificity compared with a RT-PCR reference assay.[438]

Result

positive for SARS-CoV-2 virus antigen

Emerging tests

Test
Result
Test

A similar process to RT-PCR, but uses constant temperatures and produces more viral DNA compared with RT-PCR. While simple and quick, it is a newer technology and there is less evidence for its use. Assays for SARS-CoV-2 have been developed and are being evaluated.[453][454][455]

Result

positive for SARS-CoV-2 viral RNA

Test
Result
Test

Lung ultrasound is used as a diagnostic tool in some centers as an alternative to chest x-ray and chest CT. Although there is only very low-certainty evidence supporting its diagnostic accuracy, it might be helpful as a supplemental or alternate imaging modality.[441]

Has the advantages of portability, bedside evaluation, reduced healthcare worker exposure, easier sterilization process, absence of ionizing radiation exposure, and repeatability during follow-up. It may also be more readily available in resource-limited settings. However, it also has some limitations (e.g., it is unable to discern chronicity of a lesion) and other imaging modalities may be required.

B-lines are the prominent pattern in patients with COVID-19, occurring with a pooled frequency of 97%. Pleural line abnormalities are also common with a pooled frequency of 70%. While these findings are not specific for COVID-19, they increase the likelihood of disease in the context of a characteristic clinical presentation. Other findings include consolidations, pleural thickening, and pleural effusion.[456]

May be used in pregnant women and children.[457][458]

BSTI: lung ultrasound (LUS) for COVID-19 patients in critical care areas external link opens in a new window

Result

B-lines; pleural line abnormalities

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