Investigations

1st investigations to order

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 recognising further deterioration (e.g., National Early Warning Score 2 [NEWS2] scores) may not help predict those patients who go on to develop respiratory failure.[340]

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, and thrombocytopenia are associated with severe disease; therefore, they may be useful as biomarkers for predicting disease progression.[418]

High neutrophil-to-lymphocyte ratio is a useful marker for indicating risk for severe illness and poor prognosis.[419][420]

Absolute counts of major lymphocyte subsets, particularly CD4+ and CD8+ T-cell counts, are significantly decreased in patients with severe disease.[421]

Late-phase thrombocytopenia (i.e., occurring 3 weeks or more after symptom onset) has been reported but is uncommon.[422]

Result

lymphopenia; leukocytosis; leukopenia; thrombocytopenia; decreased haemoglobin; decreased eosinophils 

Test
Result
Test

Order in patients with severe illness.

The most common laboratory abnormalities in patients hospitalised with pneumonia include elevated liver transaminases. Other abnormalities include decreased albumin and renal impairment.[30][31]

Elevated liver transaminases increase in severe disease; therefore, they may be useful as biomarkers for predicting disease progression.[423]

Serum urea and creatinine levels increase in severe disease; therefore, they may be useful as biomarkers for predicting disease progression.[418]

Hypoalbuminaemia is associated with severe disease and may be useful as a biomarker for predicting disease progression.[424]

Hypokalaemia has been reported in 54% of patients.[425] Hypocalcaemia has been reported in 63% of patients.[426] Other electrolyte derangements may be present. 

Result

elevated liver transaminases; decreased albumin; renal impairment; electrolyte derangements

Test
Result
Test

Order in patients with severe illness.

Uncontrolled hyperglycaemia has been shown to worsen prognosis in all patients, not only patients with diabetes.[427][428][429]

Result

variable

Test
Result
Test

Order in patients with severe illness.

The most common abnormalities are elevated D-dimer and fibrinogen, and prolonged prothrombin time.[30][31][385][430]

D-dimer levels increase in severe disease; therefore, it may be useful as a biomarker for predicting disease progression.[418]

Patients with very high D-dimer levels have an increased risk of thrombosis.[431][432]

Result

elevated D-dimer; prolonged prothrombin time; elevated fibrinogen

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.[418][433]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Commonly elevated in patients with COVID-19.[344]

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.[418]

May be more common in patients with COVID-19 compared with other types of pneumonia.[373]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Interleukin-6 is the most common cytokine released by activated macrophages. Levels increase in severe disease; therefore, it may be useful as a biomarker for predicting disease progression.[418][434] It is less likely to be elevated in children.[435]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Serum troponin I level may be elevated in patients with cardiac injury. Levels increase in severe disease; therefore, it may be useful as a biomarker for predicting disease progression.[418]

Other cardiac biomarkers (e.g., creatine kinase-myocardial band, brain natriuretic peptide, cardiac troponin T) may also be elevated and are associated with severe disease and worse outcomes.[436][437]

Creatine kinase-myocardial band has been found to be elevated in mild disease in children.[346]

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.[438]

May be elevated in patients with secondary bacterial infection.[30][31] May be more common in children.[338]

There is insufficient evidence to recommend routine procalcitonin testing to guide decisions about the use of antibiotics.[439]

However, it may be helpful in limiting overuse of antibiotics in patients with COVID-19-related pneumonia.[440]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

May indicate development of cytokine release syndrome.[441]

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.[418]

Result

may be elevated

Test
Result
Test

Order in patients with severe illness.

Elevated creatine kinase has been reported in 13% to 33% of patients.[30][31]

Indicates muscle or myocardium injury.

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 epidemiological history.[2]

Testing is most useful when there is concern for multidrug-resistant pathogens.[440]

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

Result

negative for bacterial infection

Test
Result
Test

Molecular testing is required to confirm the diagnosis. Nucleic acid sequencing may be required to confirm the diagnosis.[350] Priorities for testing depend on local guidelines and available resources.

The positive predictive value ranged from 47.3% to 96.4%, and the negative predictive value ranged from 96.8% to 99.9% in one meta-analysis. Pooled sensitivity was 89%.[442]

Collect upper respiratory specimens (nasopharyngeal and oropharyngeal swab or wash) in ambulatory patients and/or lower respiratory specimens (sputum and/or endotracheal aspirate or bronchoalveolar lavage) in patients with more severe respiratory disease. Also consider collecting additional clinical specimens (e.g., blood, stool, urine). Specimens should be collected under appropriate infection prevention and control procedures. Consider the high risk of aerolisation when collecting lower respiratory specimens.[350]

There are little data available on the rates of false-positive and false-negative results for the various RT-PCR tests available; however, both have been reported. If a negative result is obtained from a patient with a high index of suspicion for COVID-19, additional specimens should be collected and tested, especially if only upper respiratory tract specimens were collected initially.[350]

Many tests are available under the US Food and Drug Administration’s emergency-use authorisation scheme. 

A point-of-care test that provides results within hours is available in some countries.[443] While rapid point-of-care tests are available, the World Health Organization does not recommend the use of these tests outside of research settings as they have not been validated as yet.[355] A pooled sensitivity of 64.8% and specificity of 98% has been reported with point-of-care tests.[444]

Tests are available in many laboratories worldwide and testing should be done according to instructions from local health authorities and adhere to appropriate biosafety practices. If testing is not available nationally, specimens should be shipped to an appropriate reference laboratory.

Sensitivity and specificity of RT-PCR for diagnostic testing are unknown.[445]

Collect nasopharyngeal swabs to rule out influenza and other respiratory infections according to local guidance. It is important to note that co-infections can occur, and a positive test for a non-COVID-19 pathogen does not rule out COVID-19.[2][354]

There is emerging evidence that saliva may be a reliable specimen for detecting SARS-CoV-2 by RT-PCR.[446][447] A test that uses saliva has just been approved.[448]

The Food and Drug Administration has approved the first diagnostic test in the US with a home collection option, which allows for testing of a sample taken from the nose using a self-collection kit. After the sample is taken, it is sent in an insulated package to a designated laboratory for testing.[449]

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 all patients with suspected pneumonia.

Unilateral lung infiltrates are found in 25% of patients, and bilateral lung infiltrates are found in 75% of patients.[30][31][362]

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.[363]

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.[365] The American College of Radiology recommends reserving CT for hospitalised, symptomatic patients with specific clinical indications for CT, and emphasises 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.[366]

Abnormal chest CT findings have been reported in up to 97% of hospitalised patients.[367] Evidence of pneumonia on CT may precede a positive RT-PCR result for SARS-CoV-2 in some patients.[368] CT imaging abnormalities may be present in minimally symptomatic or asymptomatic patients.[83][369] Some patients may present with a normal chest finding despite a positive RT-PCR.[370] 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.[371]

The most common findings are ground-glass opacity, either in isolation or co-existing 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.[372]

Children frequently have normal or mild CT chest findings. The most common signs in children are patchy ground-glass opacity and, less frequently, areas of consolidation. Abnormalities are more common in the lower lobes and are predominantly unilateral. Pleural effusion is rare.[374]

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.[372]

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% and 37%, respectively.[442] A sensitivity of 96% has been reported in another meta-analysis.[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.[451]com.bmj.content.model.Caption@25a99f37[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 co-existing 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

Serological testing is becoming increasingly available for use; however, 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 World Health Organization does not recommend the use of these tests outside of research settings as they have not been validated as yet.[355]

Evidence is particularly weak for point-of-care serological tests. A meta-analysis found that the overall sensitivity of chemiluminescent immunoassays (CLIAs) for IgG or IgM was approximately 98%, and the sensitivity of enzyme-linked immunosorbent assays (ELISAs) was 84%; however, lateral flow immunoassays (LFIAs), which have been developed as point-of-care tests, had the lowest sensitivity at 66%. Test sensitivity was highest 3 or more weeks after onset of symptoms. Available evidence does not support the use of existing point-of-care serological tests.[356]

The US Centers for Disease Control and Prevention recommends that serological assays that have received emergency-use authorisation from the Food and Drug Administration are preferred. There is no advantage of assays whether they test for IgG, IgM, IgM and IgG, or total antibody. The test’s positive predictive value should be high (99.5% or greater), and results should be interpreted in the context of the expected predictive values (positive and negative). Testing can be used to aid the diagnosis of patients who present 9 to 14 days after symptom onset. Serological tests should not be used to make decisions about people returning to their workplace.[357]

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.[358][359] 

A Cochrane review found that antibody tests for IgG/IgM only detected 30% of people with COVID-19 when the test was performed 1 week after the onset of symptoms, but accuracy increased in week 2 with 70% detected and week 3 with over 90% detected. Data beyond 3 weeks were limited. Tests gave false positive results in 2% of patients without COVID-19. The review found that the sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role in the diagnosis of COVID-19, but tests are likely to have a useful role in detecting previous infection if used 15 or more days after symptom onset (although there were very little data beyond 35 days).[360]

Serum samples can be stored to retrospectively define cases when validated serology tests become available. 

Result

positive for SARS-CoV-2 virus antibodies

Emerging tests

Test
Result
Test

In the US, the Food and Drug Administration has issued an emergency-use authorisation for the first COVID-19 antigen test. These tests detect fragments of proteins found on or within the virus by testing samples collected from nasal cavity swabs. The test works faster than RT-PCR; however, while it is very specific for the virus, it is not as sensitive, so a negative result should be followed up with a RT-PCR test.[378]

Result

positive for SARS-CoV-2 virus antigen

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.[375][376][377]

Result

positive for SARS-CoV-2 viral RNA

Test
Result
Test

Lung ultrasound is used as a diagnostic tool in some centres 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.[363]

Has the advantages of portability, bedside evaluation, reduced healthcare worker exposure, easier sterilisation process, absence of ionising 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.[379]

May be used in pregnant women and children.[380][381]

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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