Early recognition and rapid diagnosis are essential to prevent transmission and provide supportive care in a timely manner. Have a high index of clinical suspicion for COVID-19 in all patients who present with fever and/or acute respiratory illness; however, be aware that some patients may not present with signs or symptoms of a febrile respiratory illness.
Best Practice has published a separate topic on the Management of coexisting conditions in the context of COVID-19.
COVID-19 is a notifiable disease. Report all suspected or confirmed cases to your local health authorities.
Isolate all suspected or confirmed cases immediately. Triage patients with a standardized triage tool and evaluate the severity of disease. Follow local infection prevention and control guidelines.
Have a high index of clinical suspicion in all patients who present with fever and/or acute respiratory illness. People with a history of residence/work/travel in a location with a high risk of transmission or community transmission and contacts of probable and confirmed cases are at higher risk of infection.
Suspect the diagnosis in patients with a new continuous cough, fever, or altered sense of taste or smell. Other common symptoms, particularly in the context of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and highly vaccinated populations, include headache, sore throat, rhinorrhea, sneezing, and fatigue. Patients may also present with dyspnea, myalgia/arthralgia, sputum production, chest tightness, or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Order a real-time reverse transcription polymerase chain reaction (RT-PCR) to confirm the diagnosis. Upper and lower respiratory specimens are preferred. Serologic testing may be useful in some settings. Results should be interpreted in the context of the pretest probability of disease.
Be on high alert for children and adolescents with acute gastrointestinal symptoms and signs of cardiac inflammation. Evidence so far suggests a milder or asymptomatic course of disease in children and adolescents. However, a rare multisystem inflammatory condition with some features similar to those of Kawasaki disease and toxic shock syndrome has been temporally associated with COVID-19 in children and adolescents.
Order the following laboratory investigations in hospitalized patients: complete blood count, comprehensive metabolic panel, arterial blood gas, blood glucose level, coagulation screen, inflammatory markers, cardiac biomarkers, serum creatine kinase, and blood and sputum cultures for other pathogens. Pulse oximetry may reveal low oxygen saturation.
Prioritize a chest x-ray in patients who are seriously ill with suspected pneumonia. Consider a computed tomography (CT) scan of the chest if chest x-ray is uncertain or normal. Consult local guidelines.
For full details and guidance see information below.
COVID-19 care pathways should be established at local, regional, and national levels for people with suspected or confirmed COVID-19.
Screen patients at the first point of contact within the health system based on case definitions and an assessment of symptoms, and enter suspected or confirmed cases into the pathway. Suspected cases should remain in the pathway until proven negative.
Immediately isolate all suspected and confirmed cases and implement local infection prevention and control procedures.
Triage patients with a standardized triage tool and evaluate the patient to assess the severity of disease.
Use clinical judgment, including consideration of the patient’s values and preferences and local and national policy if available, to guide management decisions including admission to hospital and to the intensive care unit, rather than currently available prediction models for prognosis.
Take a detailed history to ascertain the level of risk for COVID-19 and assess the possibility of other causes, including a travel history and an assessment of risk factors.
Suspect the diagnosis in:
People residing or working in an area with a high risk of transmission (e.g., closed residential settings, humanitarian setting), people residing in or traveling to an area with community transmission, and people working in a health setting (including within health facilities and households) at any time within the 14 days prior to symptom onset
People who have had contact with a probable or confirmed case. A contact is a person who has experienced any one of the following exposures:
Face-to-face contact with a probable or confirmed case within 3 feet (1 meter) and for at least 15 minutes
Direct physical contact with a probable or confirmed case
Direct care for a patient with probable or confirmed COVID-19 without using recommended personal protective equipment
Other situations as indicated by local risk assessments.
Exposure must have occurred during the infectious period of the case. For symptomatic cases, this means 2 days before and 10 days after symptom onset of the case, plus at least 3 additional days without symptoms, for a minimum of 13 days total after symptom onset. For asymptomatic cases, this means 2 days before and 10 days after the date on which the sample that led to confirmation was taken.
The Centers for Disease Control and Prevention defines a close contact as someone who has been within 6 feet (2 meters) of an infected person for at least 15 minutes over a 24-hour period, beginning 2 days before symptom onset (or 2 days before testing in asymptomatic patients).
Clinical presentation in adults
Some patients may be minimally symptomatic or asymptomatic, while others may present with severe pneumonia or complications such as acute respiratory syndrome, septic shock, acute myocardial infarction, venous thromboembolism, or multi-organ failure. Approximately 80% of patients have mild illness that does not warrant medical intervention or hospitalization.
The classic key symptoms are:
Altered sense of taste/smell.
Other common symptoms, particularly in the context of circulating SARS-CoV-2 variants and highly vaccinated populations, include:
Less common or uncommon symptoms include:
Myalgia or arthralgia
Lower urinary tract symptoms
The UK's official list of COVID-19 symptoms was updated in April 2022 to include sore throat, fatigue, headache, dyspnea, aching body, blocked or runny nose, loss of appetite, diarrhea, and feeling sick or being sick. Previously, the UK’s official list of symptoms only included fever, persistent cough, and loss or change in taste or smell.
No single sign or symptom can accurately diagnose COVID-19, and neither the absence or presence of specific signs or symptoms are accurate enough to rule in or rule out disease.
A Cochrane review found that at least half of patients had a cough, sore throat, fever, myalgia/arthralgia, fatigue, or headache. Anosmia and/or ageusia was also common. The presence of fever, myalgia/arthralgia, fatigue, and headache substantially increased the likelihood of COVID-19 when present. Cough and sore throat were common in people without COVID-19, so these symptoms alone were less helpful for diagnosis. The presence of anosmia and/or ageusia may be useful as a red flag for diagnosis. The presence of fever or cough may also be useful to identify people for further testing.
Signs and symptoms may differ in the context of circulating SARS-CoV-2 variants or highly vaccinated populations.
Data from the UK COVID Symptom Study in the context of the Delta variant report that the most common symptoms after full vaccination are headache, rhinorrhea, sneezing, and sore throat. The previous traditional symptoms such as anosmia, shortness of breath, fever, and cough rank further down the list and are no longer top indicators of having COVID-19 in vaccinated people, according to this data. In patients who are unvaccinated, headache, sore throat, rhinorrhea, fever, and persistent cough are the most common symptoms, which differs from when the disease initially appeared.
Data from the UK COVID Symptom Study in the context of the Omicron variant report that the most common symptoms are headache, runny nose, sneezing, sore throat, and mild to severe fatigue. The initial analysis found no clear differences in early symptoms between Delta and Omicron.
Symptoms that characterize infection with the Omicron variant differ moderately from those that characterize infection with the Delta variant. Sore throat and hoarse voice were consistently more prevalent among people with Omicron infection compared with those with Delta infection. Loss of/altered smell, eye soreness/burning, sneezing, headache, fever, dizziness, and brain fog were significantly less prevalent among people with Omicron infection compared with those with Delta infection. Loss of smell, a pathognomonic feature of previous SARS-CoV-2 variants, was present in only <20% of cases of people infected with the Omicron variant.
Pregnant women generally present in a similar way to nonpregnant people.
The clinical characteristics in pregnant women are similar to those reported for nonpregnant adults.
The most common symptoms in pregnant women are fever and cough. However, pregnant women are less likely to report fever, dyspnea, and myalgia compared with nonpregnant women of reproductive age. Pregnant and recently pregnant women were more likely to be asymptomatic than nonpregnant women of reproductive age.
It is important to note that symptoms such as fever, dyspnea, gastrointestinal symptoms, and fatigue may overlap with symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events.
Atypical presentations have been reported.
Atypical presentations may occur, especially in older patients and patients who are immunocompromised (e.g., falls, delirium/confusion, functional decline, reduced mobility, syncope, absence of fever). Older patients and those with comorbidities may present with mild symptoms, but have a high risk of deterioration.
There have been case reports of parotitis (possibly related to intraparotid lymphadenitis), oral vesiculobullous lesions, retinal lesions, persistent hiccups, and androgenetic alopecia in patients with COVID-19; however, it is unknown whether these findings are associated with SARS-CoV-2 infection as yet.
Coinfections are possible.
The pooled prevalence of coinfection in SARS-CoV-2-positive patients was 19%, with viral coinfections being more common than bacterial and fungal coinfections. The most frequently identified bacteria were Klebsiella pneumonia, Streptococcus pneumoniae, and Staphylococcus aureus. The most frequently identified viruses were influenza type A, influenza type B, and respiratory syncytial virus. The most frequently identified fungi was Aspergillus. Coinfection with tuberculosis, HIV, and malaria have been reported.
Clinical presentation in children and adolescents
Signs and symptoms may be similar to other common viral respiratory infections and other childhood illnesses, so a high index of suspicion for COVID-19 is required in children and adolescents.
Children and adolescents usually have fewer and milder symptoms, and they are less likely to progress to severe disease compared with adults. The reasons for this are still under investigation. Early studies suggested a higher risk of severe or critical disease in infants <1 year of age compared with children of other age groups; however, the studies had limitations and there is no conclusive evidence that younger age is a risk factor for severe disease in children and adolescents. The severity of disease caused by new variants of SARS-CoV-2, in comparison with previous lineages, remains under investigation.
Fever, cough, and dyspnea are less common in children compared with adults. Gastrointestinal symptoms are common in children. A higher prevalence of gastrointestinal symptoms has been reported in children >5 years of age compared with children ≤5 years of age. The presence of diarrhea has been associated with a severe clinical course in children.
The most common symptoms in neonates include fever, inability to feed, lethargy, irritability, feeding difficulties, dyspnea, silent hypoxia, and neurologic symptoms. Cases of late-onset neonatal sepsis and encephalitis have been reported rarely.
Be alert for signs and symptoms of pediatric inflammatory multisystem syndrome (PIMS), also known as multisystem inflammatory syndrome in children (MIS-C).
Consider PIMS/MIS-C in children presenting with fever and abdominal symptoms, particularly if they develop conjunctivitis or a rash. Refer to a pediatric emergency department for evaluation. See the Complications section for more information.
Coinfections are possible in children.
Perform a physical exam.
Patients may be febrile (with or without chills/rigors) and have obvious cough and/or difficulty breathing.
Auscultation of the chest may reveal inspiratory crackles, rales, and/or bronchial breathing in patients with pneumonia or respiratory distress. Use caution when auscultating patients given the risk for cross-contamination. Clean the stethoscope properly between uses.
Patients with respiratory distress may have tachycardia, tachypnea, or cyanosis accompanying hypoxia. Bradycardia has been noted in a small cohort of patients with mild to moderate disease.
Pulse oximetry may reveal low oxygen saturation.
The UK National Institute for Health and Care Excellence recommends using oxygen saturation levels below 94% for adults (or below 88% for adults with known type 2 respiratory failure) and below 91% for children in room air at rest to identify people who are seriously ill.
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.
Pulse oximeters may exhibit suboptimal accuracy in certain populations, especially in those who have darker skin.
The US Food and Drug Administration (FDA) has warned that multiple factors can affect the accuracy of a pulse oximeter reading (e.g., poor circulation, skin pigmentation, skin thickness, skin temperature, current tobacco use, use of fingernail polish). The FDA recommends considering accuracy limitations when using a pulse oximeter to assist in diagnosis and treatment decisions, and to use trends in readings over time rather than absolute cut-offs if possible.
Traditional methods of recognizing further deterioration may not help predict those patients who go on to develop respiratory failure.
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. While NEWS2 is still recommended for use in patients with COVID-19, the UK Royal College of Physicians now advises that any increase in oxygen requirements in these patients should trigger an escalation call to a competent clinical decision maker, and prompt an initial increase in observations to at least hourly until a clinical review happens.
A systematic review and meta-analysis found that the NEWS2 score had moderate sensitivity and specificity in predicting the deterioration of patients with COVID-19. The score showed good discrimination in predicting the combined outcome of the need for intensive respiratory support, admission to the intensive care unit, or in-hospital mortality.
Pulse oximeters can be used at home to detect hypoxia.
Home pulse oximetry requires clinical support (e.g., regular phone contact from a health professional in a virtual ward setting).
Initial laboratory investigations
Order the following laboratory investigations in all patients with severe disease:
Comprehensive metabolic panel
Thyroid function tests
Blood glucose level
Inflammatory markers (e.g., serum C-reactive protein, erythrocyte sedimentation rate, interleukins, lactate dehydrogenase, procalcitonin, amyloid A, and ferritin)
Serum creatine kinase and myoglobin.
Elevated cardiac biomarkers
Elevated inflammatory markers
Abnormal liver and renal function.
Laboratory abnormalities – in particular, lymphopenia, leukocyte abnormalities, and other markers of systemic inflammation – are less common in children. Most patients (62%) with asymptomatic disease present with normal laboratory parameters. Of those with laboratory abnormalities, leukopenia, lymphopenia, elevated lactate dehydrogenase, and elevated C-reactive protein were the most common findings.
Collect blood and sputum specimens for culture in patients with severe or critical disease.
Cultures are required to rule out other causes of lower respiratory tract infection and sepsis, especially patients with an atypical epidemiologic history. Specimens should be collected prior to starting empiric antimicrobials if possible.
Regularly monitor the following in hospitalized patients to facilitate early recognition of deterioration and monitor for complications:
Vital signs (temperature, respiratory rate, heart rate, blood pressure, oxygen saturation)
Hematologic and biochemistry parameters
Coagulation parameters (D-dimer, fibrinogen, platelet count, prothrombin time)
Signs and symptoms of venous or arterial thromboembolism.
Patients may develop bacterial or fungal coinfections; therefore, it is important to ensure appropriate imaging is ordered and microbiologic specimens are taken when this is suspected.
Radial artery puncture animated demonstration
SARS-CoV-2 diagnostic testing
There are three main methods for detecting SARS-CoV-2 infection:
Rapid antigen tests.
Molecular tests are highly specific and sensitive at detecting viral RNA, and are the preferred test for confirming diagnosis in symptomatic people. However, these tests are expensive and require specialized skills and instruments, and results can take up to 24 to 48 hours. Rapid antigen tests that detect viral protein are less sensitive than molecular tests, but are faster, easier, and cheaper, and are able to detect infection in those who are most likely to be at risk of transmitting the virus. Serologic tests may be used to establish a late or retrospective diagnosis if molecular and antigen rapid tests are both negative, or may be useful surveillance tools to inform public policy. The role of these tests has evolved over the course of the pandemic. The choice of which test to use in which setting requires careful consideration of the purpose of testing and the resources available, while also balancing test characteristics of accuracy, accessibility, affordability, and the rapidity with which results are needed.
Testing strategies vary widely between countries, and you should consult your local guidance.
Molecular testing is required to confirm the diagnosis.
Molecular testing is an aid to diagnosis only. The World Health Organization (WHO) recommends that healthcare providers consider a positive or negative result in combination with specimen type, clinical observations, patient history, and epidemiologic information. Where a test result does not correspond with the clinical presentation, a new specimen should be taken and retested using the same or a different molecular test (see Limitations of molecular testing below).
Order a nucleic acid amplification test, such as real-time reverse-transcription polymerase chain reaction (RT-PCR), for SARS-CoV-2 in patients with suspected infection whenever possible.
Tests should be performed according to guidance issued by local health authorities and adhere to appropriate biosafety practices.
Commonly used assays are expected to be able to detect SARS-CoV-2 variants. However, some tests may be impacted by variants.
Who to test
Base decisions about who to test on clinical and epidemiologic factors. The World Health Organization recommends testing all people who meet the suspected case definition of COVID-19, regardless of vaccination status or disease history. When resources are constrained, people who are at risk of developing severe disease, healthcare workers, inpatients, and the first symptomatic individuals in the setting of a suspected outbreak should be prioritized. Testing of asymptomatic individuals is currently recommended only for specific groups including contacts of confirmed or probable cases and frequently exposed groups such as healthcare workers and long-term care facility workers.
In England, testing symptomatic people is no longer required. Guidance and eligibility for testing varies between the nations of the UK, and you should check your local guidelines. In England, testing is still recommended in the following groups:
Patients in a hospital setting with symptoms or suspicion of COVID-19 to support a diagnostic pathway; for asymptomatic screening; testing on discharge to certain settings; and in patients with severe immunocompromise
Patients on admission in unplanned care settings or preadmission in elective care settings
Patients in the community at high risk of complications who are eligible for COVID-19 antivirals and other treatments, or where a clinician requires a test to support clinical decisions in their care
Staff in health and social care settings for asymptomatic screening or if they develop symptoms.
In the US, testing is recommended in:
Anyone with signs or symptoms consistent with COVID-19 (regardless of vaccination status)
Asymptomatic people with recent known or suspected exposure to SARS-CoV-2, including those who 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. Fully vaccinated people should be tested 5 to 7 days after the exposure, and people who are not fully vaccinated should be tested immediately
Asymptomatic people without recent known or suspected exposure to SARS-CoV-2 for early identification, isolation, and disease prevention (only when screening testing is recommended by public health officials). This may include unvaccinated people who have taken part in activities that put them at higher risk because they cannot physically distance as needed to avoid exposure (e.g., travel, attending large social or mass gatherings, being in crowded or poorly ventilated indoor settings).
Consult local health authorities for guidance as testing priorities depend on local recommendations and available resources.
The optimal specimen for testing depends on the clinical presentation and the time since symptom onset. The WHO recommends the following.
Upper respiratory specimens: recommended for early-stage infections, especially asymptomatic or mild cases. Nasopharyngeal swabs yield a more reliable result than oropharyngeal swabs; combined nasopharyngeal and oropharyngeal swabs further improve reliability.
Lower respiratory specimens: recommended for later-stage infections, or patients in whom there is a strong suspicion for infection and their upper respiratory tract specimen test was negative. Suitable specimens are sputum and/or endotracheal aspirate or bronchoalveolar lavage in patients with more severe respiratory disease. However, consider the high risk of aerosol transmission when collecting lower respiratory specimens – an induced sputum specimen is not recommended as it may increase the risk of aerosol transmission.
Other respiratory specimens: studies on combined oropharyngeal and nares/nasal swabs, mid-turbinate or lower nasal or nares swabs, or tongue swabs have been conducted; however, further assessment and validation is required. Oral fluid collection may be suitable in some circumstances (e.g., young children, older patients with dementia). A systematic review and meta-analysis found that pooled nasal and throat swabs offered the best diagnostic performance of alternative sampling approaches compared with nasopharyngeal swabs for diagnosis in an ambulatory care setting. The sensitivity was 97%, the specificity was 99%, the positive predictive value was 97%, and the negative predictive value was 99%. Throat swabs gave a much lower sensitivity and positive predictive value. Self-collection was not associated with any impairment of diagnostic accuracy.
Saliva specimens: meta-analyses of paired saliva samples and nasopharyngeal swabs found no statistically significant difference in sensitivity or specificity between these specimens for SARS-CoV-2 detection, especially in the ambulatory setting. Sensitivity was not significantly different among asymptomatic people and outpatients. Methods of saliva collection may affect sensitivity. Meta-analyses demonstrate that saliva is as valid as nasopharyngeal sampling for the detection of SARS-CoV-2 infections in symptomatic and asymptomatic patients. Saliva sampling is simple, fast, noninvasive, inexpensive, and painless. The WHO does not currently recommend the use of saliva as the sole specimen type for routine clinical diagnostics.
Fecal specimens: consider when upper or lower respiratory specimens are negative and the clinical suspicion for infection remains (may be used from the second week after symptom onset).
Recommended specimen types may differ between countries. For example, in the US, the Centers for Disease Control and Prevention (CDC) recommends the following upper respiratory specimens: nasopharyngeal or oropharyngeal swab; nasal mid-turbinate swab; anterior nares swab; nasopharyngeal/nasal wash/aspirate; or saliva (self collection). Recommended lower respiratory tract specimens include: sputum, bronchoalveolar lavage, tracheal aspirate, pleural fluid, and lung biopsy.
Anterior nasal swabs appear to be less sensitive (82% to 88%) compared with nasopharyngeal swabs (98%). Mid-turbinate and anterior nares swabs perform similarly.
Collect specimens under appropriate infection prevention and control procedures.
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).
Genomic sequencing is not routinely recommended, but may be useful to investigate the dynamics of an outbreak, including changes in the size of an epidemic over time, its spatiotemporal spread, and testing hypotheses about transmission routes. It is also useful in the context of circulating SARS-CoV-2 variants to differentiate between variants.
Complications of nasal swab testing
Complications associated with nasal swab testing are not well characterized and data is scarce. Complications were extremely low in one study (1.24 complications per 100,000 tests). Adverse effects may include epistaxis, nasal discomfort, headache, ear discomfort, rhinorrhea, and broken swabs being stuck (and requiring removal via nasal endoscopy). Bleeding may be life-threatening. Correct sampling techniques are crucial.
Testing for other infections
Collect nasopharyngeal swabs for testing to rule out infection with other respiratory pathogens (e.g., influenza, atypical pathogens) when clinically indicated according to local guidance. Depending on local epidemiology and clinical symptoms, test for other potential causes including malaria, dengue fever, and typhoid fever as appropriate. 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.
Limitations of molecular testing
Molecular testing is an aid to diagnosis only.
The WHO recommends that healthcare providers consider a positive or negative result in combination with specimen type, clinical observations, patient history, and epidemiologic information. It also recommends that laboratories ensure that specimens with high cycle threshold values are not incorrectly assigned a positive result due to background noise, and that they provide the cycle threshold value in the report to the healthcare provider. Disease prevalence alters the predictive value of test results. As disease prevalence decreases, the risk of a false positive increases. This means that the probability that a person who has a positive result is truly infected decreases as prevalence decreases, irrespective of the claimed specificity of the test. Careful interpretation of weak positive results is needed.
Interpret RT-PCR test results with caution.
The evidence for the use of RT-PCR in the diagnosis of COVID-19 is still emerging, and uncertainties about its efficacy and accuracy remain. 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. Also, more evidence is needed about the efficacy of testing outside of hospital settings and in asymptomatic or mild cases.
Few studies have attempted to culture live SARS-CoV-2 virus from human samples. This is an issue because viral culture is regarded as a gold standard test against which any diagnostic index test for viruses must be measured and calibrated, to understand the predictive properties of that test. Prospective routine testing of reference and viral culture specimens is necessary to establish the usefulness and reliability of RT-PCR to diagnose COVID-19, and its relation to patients factors such as date of onset of symptoms and copy threshold, in order to help predict infectivity.
As there is no clear-cut "gold standard" for COVID-19 testing, evaluating test results can be challenging. Clinical adjudication may be the best available ‘gold standard’ based on repeat swabs, history, clinical presentation, and chest imaging.
Results can fluctuate from positive to negative at all stages of infection, can become positive again after two consecutive negative tests, can be detected for longer in those with severe infection, and may fluctuate at the level of detection for several weeks. Results may also vary according to the sample site.
It is not clear whether a positive result always indicates the presence of infectious virus.
RT-PCR may overestimate the duration of infectiousness. RT-PCR detects viral RNA, but it is not fully understood how that represents infectious virus. Complete live viruses are necessary for transmission, not the fragments identified by PCR. This could ultimately lead to restrictions for people who do not present an infection risk. Because inactivated RNA degrades slowly over time, it may still be detected many weeks after the patient is no longer infectious.
One study found that only 28.9% of positive RT-PCR SARS-CoV-2 samples demonstrated viral growth when incubated on Vero cells. There was no growth in samples with an RT-PCR cycle threshold >24, or when the symptom onset to test time was >8 days. Therefore, infectivity of patients with a cycle threshold >24 and duration of symptoms >8 days may be low. Another study found that patients with a cycle threshold of 34 or above do not excrete infectious virus. A systematic review found that cycle threshold values were significantly lower and log copies higher in specimens that produce live virus culture. Those with high cycle threshold are unlikely to have infectious potential.
Interpreting test results depends on the accuracy of the test itself, and the pre- and post-test probabilities of disease. The accuracy of the result depends on various factors including the site and quality of sampling, stage of disease, degree of viral multiplication or clearance, and disease prevalence.
Sensitivity and specificity: the pooled sensitivity has been estimated to be 87.8%, with the specificity estimated to be in the range of 87.7% to 100%.
Pretest probability: the pretest probability estimate should be made using knowledge of local rates of infection from national and regional data, as well as the patient’s symptoms, potential exposure to cases, a previous medical history of COVID-19 or the presence of antibodies, and the likelihood of an alternative diagnosis. When the pretest probability is low, positive results should be interpreted with caution, and ideally a second specimen tested for confirmation.
Post-test probability: the lower the prevalence of disease in a given population, the lower the post-test probability. For example, if a test with a specificity of 99% is used to test a high-risk symptomatic population where the likelihood of infection is 50%, the positive predictive value is 99%. This means that for every 100 people with a positive test result, 99 people will have SARS-CoV-2 infection but 1 person without infection will have a false-positive result. Conversely, in a low-risk asymptomatic population where the likelihood of infection is low (e.g., 0.05%), the positive predictive value is around 4.3%. This means that for every 100 people with a positive test result, 4 to 5 people will have SARS-CoV-2 infection, but 95 to 96 people without infection will have a false-positive result.
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). False-positive results are more likely when the prevalence of SARS-COV-2 is moderate to low.
There are a lack of data on the rate of false-positive tests. However, preliminary estimates in the UK are in the range of 0.8% to 4%. This rate could translate into a significant proportion of daily false-positive results due to the current low prevalence of the virus in the UK population, adversely affecting the positive predictive value of the test.
Examples of the potential consequences of false-positive test results include:
Unnecessarily postponing or canceling elective procedures or treatments
Potential exposure to infection following a wrong pathway in hospital settings during urgent hospital admissions
Financial losses due to self-isolation, income losses, and canceled travel
Psychological damage due to misdiagnosis including fear of infecting others or stigmatization
Increased depression or domestic violence due to lockdown and isolation
Overestimating the incidence and extent of asymptomatic infection in the population.
False-negative rates of between 2% and 29% have been reported. A systematic review found that the false-negative rate varied across studies from 1.8% to 58% (median 11%); however, there was substantial and largely unexplained heterogeneity across studies.
The probability of a false-negative result in an infected person decreases from 100% on day 1 of infection to 67% on day 4. The median false-negative rate drops to 38% on the day of symptom onset, decreases to 20% on day 8, and then starts to increase again from day 9.
Examples of the potential consequences of false-negative test results include:
Patients may be moved into non-COVID-19 wards leading to spread of hospital-acquired infection
Caregivers could spread infection to vulnerable dependents
Healthcare workers risk spreading the infection to multiple vulnerable individuals.
Serology cannot be used as a standalone diagnostic test for acute SARS-CoV-2 infections.
The 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.
The CDC recommends serologic testing as a method to support the diagnosis of illness or complications in the following situations:
A positive antibody test at least 7 days following acute illness onset in people with a previous negative antibody test (i.e., seroconversion) and who did not receive a positive viral test may indicate SARS-CoV-2 infection between the dates of the negative and positive antibody tests
A positive antibody test can help support a diagnosis when patients present with complications of COVID-19 illness, such as multisystem inflammatory syndrome and other post-acute sequelae of COVID-19.
Assays with FDA emergency-use authorization are recommended. Serologic tests with very high sensitivity and specificity are preferred because they are more likely to exhibit high expected predictive values when administered at least 3 weeks following onset of illness.
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
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).
Limitations of serologic testing
The evidence for the use of antibody tests in the diagnosis of COVID-19 is still emerging, and uncertainties about their efficacy and accuracy remain.
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. More evidence is needed about the efficacy of testing outside of hospital settings and in asymptomatic or mild cases. 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%.
Understanding of the antibody response to SARS-CoV-2 is still emerging; therefore, antibody detection tests must be used with caution, and not used to determine acute infections.
Results do not indicate the presence or absence of current or previous infection with certainty as IgM and IgG antibodies may take 1 to 3 weeks to develop after infection. A reliable diagnosis is often only possible in the recovery phase when opportunities for management or interruption of transmission have passed.
The duration of the persistence of antibodies produced in response to SARS-CoV-2 is still under investigation. The presence of antibodies that bind to SARS-CoV-2 does not guarantee that they are neutralizing antibodies, or that they offer protective immunity.
Although an antibody test may employ a specific antigen(s), antibodies developed in response to different proteins may cross-react (i.e., the antigen may detect antibodies it is not intended to detect). Therefore, it may not provide sufficient information on the presence of antigen-specific antibodies.
Vaccination may cause false-positive results for tests that utilize the S antigen or subunits like receptor-binding domains, but not for tests that use the N antigen.
Rapid diagnostic tests
Antigen testing relies on direct detection of SARS-CoV-2 viral proteins in upper respiratory specimens or saliva using a lateral flow immunoassay.
Results are usually available in less than 30 minutes.
While antigen tests are substantially less sensitive than RT-PCR, particularly in asymptomatic people, they offer the possibility of rapid, inexpensive, and early detection of the most infectious cases in appropriate settings.
Antigen testing is recommended in settings likely to have the most impact on early detection of cases for care and contact tracing, and where test results are most likely to be correct.
International guidelines on the use of rapid antigen tests vary. Consult your local guidance.
The WHO recommends antigen testing for primary case detection, for contact tracing, during outbreak investigations, and to monitor trends of disease incidence in communities. Tests should meet the minimum performance requirements of ≥80% sensitivity and ≥97% specificity compared with an RT-PCR reference assay. Antigen testing should be prioritized for use in symptomatic people who meet the case definition in the first 5 to 7 days of symptom onset, and to test asymptomatic people at high risk of infection, including contacts and health workers, particularly in settings where molecular testing capacity is limited. Results are most reliable in areas where there is ongoing community transmission. Self-testing should be offered in addition to professionally administered testing services. It should always be voluntary and never mandatory or coercive.
In the UK, rapid antigen tests are recommended in certain situations, including: before visiting people who are at higher risk of severe disease; for contacts of a confirmed case who do not have to self-isolate; and for people who will be in high-risk situations on a particular day (e.g., in crowded and enclosed spaces, or if there is limited fresh air).
In the US, the Infectious Diseases Society of America recommends antigen testing in some individuals only when molecular testing is not readily available or is logistically infeasible, noting that the overall quality of available evidence supporting its use was graded as very low to moderate. The CDC recommends that antigen tests may be used in congregate and community settings; however, confirmatory molecular testing may be needed. The FDA has warned that false-positive results can occur with antigen tests, including when users do not follow the instructions for use, and that the number of false-positive tests increases as disease prevalence decreases.
Evidence for the use of rapid antigen tests is emerging.
A Cochrane review found that rapid antigen tests vary in sensitivity. Sensitivity was higher in the first week after symptom onset in symptomatic people (78.3%), compared with the second week of symptoms (51%). Sensitivity was higher in those with RT-PCR cycle threshold values ≤25 (94.5%), compared with those with cycle threshold values >25 (40.7%). Sensitivity was higher in symptomatic people (72%), compared with asymptomatic people (58.1%). Sensitivity also varied between brands of tests. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Evidence for testing in asymptomatic cohorts was limited, and no studies assessed the accuracy of repeated lateral flow testing or self‐testing.
A systematic review found that the performance of lateral flow tests is heterogenous and depends on the manufacturer. Sensitivity ranged between 37.7% to 99.2%, with specificity ranging between 92.4% to 100% across studies.
A systematic review and meta-analysis found that the pooled overall diagnostic sensitivity and specificity of rapid antigen tests in pediatric populations was 64.2% and 99.1%, respectively. Sensitivity was higher in symptomatic children compared with asymptomatic children.
An observational cohort study that assessed the performance of rapid antigen lateral flow testing against RT-PCR in an asymptomatic general population in the UK found that the lateral flow test can be useful for detecting infections among asymptomatic adults, particularly those with a high viral load who are likely to be infectious. Lateral flow tests showed a sensitivity of 40%, specificity of 99.9%, positive predictive value of 90.3%, and negative predictive value of 99.2% in this population. Approximately 10% of people with a higher viral load detected by RT-PCR were missed by lateral flow tests.
Rapid antigen testing appears to be a reliable diagnostic tool to quickly detect people with a high viral load and in the first week of symptom onset, and can help to detect and isolate potential superspreaders before RT-PCR results are available. However, testing is unsuccessful in detecting people with lower viral load and asymptomatic patients.
Laboratory-based (nonrapid) antigen tests are also available in some countries.
Rapid molecular tests are available. Some rapid molecular tests show accuracy levels similar to laboratory-based RT-PCR tests with high sensitivity and specificity. However, there is limited evidence available to support their use in symptomatic people, and there is no evidence for their use in asymptomatic populations. Resource implications of their use at scale are potentially high. Rapid molecular tests may be suitable for some testing scenarios (e.g., where obtaining test results within 2 hours will enable appropriate decision-making).
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.
Evidence is particularly weak for point-of-care serologic 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 serologic tests.
All imaging procedures should be performed according to local infection prevention and control procedures to prevent transmission. Chest imaging is considered safe in pregnant women.
Order a chest x-ray in all patients with suspected pneumonia.
Approximately 74% of patients have an abnormal chest x-ray at the time of diagnosis. The most common abnormalities are ground-glass opacity (29%) and consolidation (28%). Distribution is generally bilateral, peripheral, and basal zone predominant. Pneumothorax and pleural effusions are rare. There is no single feature on chest x-ray that is diagnostic.
Chest x‐ray is moderately sensitive and moderately specific for the diagnosis of COVID‐19. Pooled results found that chest x‐ray correctly diagnosed COVID‐19 in 80.6% of people who had the disease. However, it incorrectly identified COVID‐19 in 28.5% of people who did not have the disease.
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.
Consider ordering a CT scan of the chest.
Chest CT may play a role in diagnosis in a limited number of hospitalized patients, particularly when initial molecular testing has been inconclusive, or when an alternative diagnosis is being considered. However, it is not diagnostic for COVID-19 and local guidance should be consulted 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. Without the suspicion of COVID-19, the radiology is nonspecific and could represent many other disease processes. The BSTI in collaboration with NHS England have produced a radiology decision support tool to help clinicians decide whether or not chest imaging should be ordered. BSTI: radiology decision tool for suspected COVID-19 Opens in 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.
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.
Chest CT is sensitive and moderately specific for the diagnosis of COVID‐19. Pooled results found that chest CT correctly diagnosed COVID‐19 in 87.9% of people who had the disease. However, it incorrectly identified COVID‐19 in 20% of people who did not have the disease. Therefore, chest CT may have more utility for excluding COVID‐19 than for differentiating it from other causes of respiratory illness. Accuracy appears to be lower among children; however, there are limited data in this population.
Evidence of pneumonia on CT may precede a positive RT-PCR result for SARS-CoV-2 in some patients. Some patients may present with a normal chest finding despite a positive RT-PCR. 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.
CT imaging abnormalities may be present in asymptomatic patients. The pooled estimate of the rate of positive chest CT findings in asymptomatic cases was 47.6% (mainly ground-glass opacity).
Pregnant women appear to present more commonly with more advanced CT findings compared with the general adult population; however, results are similar to those in the general adult population.
Typical features of chest CT
Abnormal chest CT findings have been reported in up to 97% of COVID-19 patients in one meta-analysis of 50,466 hospitalized patients.
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.
Ground-glass opacity has the highest diagnostic performance for COVID-19 pneumonia, followed by ground-glass opacity plus consolidation, and consolidation only. 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%).
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.
A small comparative study found that patients with COVID-19 are more likely to have bilateral involvement with multiple mottling and ground-glass opacity compared with other types of pneumonia.
Children frequently have normal or mild CT chest findings. The most common signs in children are patchy ground-glass opacity, nonspecific patchy shadows, areas of consolidation, infected nodules, and a halo sign. Abnormalities are more common in multiple lobes and are predominantly bilateral. Pleural effusion is rare. Children may have signs of pneumonia on chest imaging despite having minimal or no symptoms. Ground-glass opacity and peribronchial thickening were the most prevalent findings in infants younger than 1 year of age.
Atypical features of chest CT
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.
The WHO recommends chest imaging in the following scenarios:
Symptomatic patients with suspected COVID-19 when RT-PCR is not available, RT-PCR test results are delayed, or initial RT-PCR testing is negative but there is a high clinical suspicion for COVID-19 (for diagnosis)
Patients with suspected or confirmed COVID-19 who are not currently hospitalized and have mild symptoms (to decide on hospital admission versus home discharge)
Patients with suspected or confirmed COVID-19 who are not currently hospitalized and have moderate to severe symptoms (to help decide on regular ward admission versus intensive care unit admission)
Patients with suspected or confirmed COVID-19 who are currently hospitalized and have moderate to severe symptoms (to inform therapeutic management).
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.
Ultrasound is sensitive but not specific for the diagnosis of COVID‐19. Pooled results found that lung ultrasound correctly diagnosed COVID‐19 in 86.4% of people with the disease. However, it incorrectly diagnosed COVID‐19 in 45% of people who did not have the disease. Therefore, ultrasound may have more utility for excluding COVID‐19 than for differentiating it from other causes of respiratory illness.
B-lines (confluent or separated and usually at least 3) and pleural abnormalities, with a bilateral distribution, are the most frequent findings in COVID-19. Other findings include consolidations, pleural effusion, air bronchogram, and pneumothorax. While these findings are not specific for COVID-19, they may increase the likelihood of disease in the context of a characteristic clinical presentation.
It 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. Ultrasound may be used in pregnant women and children.
Possible roles for ultrasound include: reducing nosocomial transmission; monitoring progress of patients; and a possible role in subpopulations who are vulnerable but are not suitable for CT (e.g., pregnant women). Lung ultrasound score may play a role in prognosis.
Reverse transcription loop-mediated isothermal amplification
Reverse transcription loop-mediated isothermal amplification (RT-LAMP) assays are an emerging test to detect SARS-CoV-2 viral RNA. While assays are simple and quick, there is less evidence for their use. Assays for SARS-CoV-2 have been developed and are being evaluated.
RT-LAMP appears to be a reliable assay, comparable to RT-PCR, particularly with medium to high viral loads (i.e., cycle threshold <35), especially in resource-limited settings. A sensitivity of 95.5% and specificity of 99.5% has been reported.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostic methods have been developed for detecting SARS-CoV-2 viral RNA. These simple, high-throughput molecular tests have the advantage of providing results in less than 1 hour, can be used with various specimens, and have high specificity/sensitivity (similar to RT-PCR).
Various CRISPR-based tests have been granted emergency-use authorization by the US Food and Drug Administration.
Breath analysis has been shown to have potential in diagnosing COVID-19 by analyzing volatile organic compounds in exhaled breath.
The US Food and Drug Administration has issued an emergency-use authorization for the first COVID-19 diagnostic test that detects chemical compounds in breath samples associated with SARS-CoV-2 infection. The test has been shown to have 91.2% sensitivity and 99.3% specificity in one company-sponsored study of 2409 participants, including those with and without symptoms. However, the test currently has many limitations (e.g., size of the device, number of samples that can be processed, lack of evidence for this method of diagnosis, other diseases or food/drinks that can affect result, test result is presumptive and still requires confirmation), and more research is required.
Viral isolation is not recommended as a routine diagnostic procedure. All procedures involving viral isolation in cell culture require trained staff and biosafety level 3 (BSL-3) facilities.
Calprotectin is an emerging biomarker of interest. Calprotectin levels often increase following infection or trauma, and in inflammatory disease. Serum/fecal calprotectin levels have been demonstrated to be significantly elevated in COVID-19 patients with severe disease, and it may have prognostic significance.
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