Approach

COVID-19 is a notifiable disease. Report all suspected or confirmed cases to your local health authorities.

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.

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.[139] 

Best Practice has published a separate topic on the management of coexisting conditions in the context of COVID-19. BMJ Best Practice: Management of coexisting conditions in the context of COVID-19 external link opens in a new window

Key recommendations

  • 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.[139]

  • 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.[195]

  • Suspect the diagnosis in patients with a new continuous cough, fever, or altered sense of taste or smell.[504] Patients may also present with symptoms including dyspnea, fatigue, myalgia/arthralgia, sore throat, headache, nasal congestion or rhinorrhea, sputum production, chest tightness, or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).[505] 

  • 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.[506] 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.[507] 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.[508] 

  • 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.[509] Consult local guidelines. 

  • For full details and guidance see information below.

History

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:[195]

  • 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 during the 2 days before and the 14 days after the onset of symptoms of a probable or confirmed case:

    • 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.

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).[196]

Ask anyone seeking routine or emergency care, regardless of whether they have symptoms, about recent travel to countries where there is transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (consult local guidance for current list of countries), or whether they are a contact of a returning traveler from these countries.[197]

Clinical presentation in adults

Approximately 15% of patients present with the symptom triad of fever, cough, and dyspnea, and 90% present with more than one symptom.[52] 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. According to a UK study, approximately 25% of people who had evidence of past infection were asymptomatic, and 40% did not have one of the three classic symptoms (i.e., fever, persistent dry cough, altered sense of taste/smell).[510]

The most common symptoms are:

  • Fever

  • Cough

  • Dyspnea

  • Altered sense of taste/smell.

Less common symptoms include:

  • Myalgia or arthralgia

  • Fatigue

  • Sputum production

  • Chest tightness

  • Gastrointestinal symptoms

  • Sore throat

  • Headache

  • Dizziness

  • Neurologic symptoms

  • Ocular symptoms

  • Audio-vestibular symptoms

  • Cutaneous symptoms

  • Rhinorrhea/nasal congestion

  • Chest pain

  • Hemoptysis.

Signs and symptoms of febrile respiratory illness may not possess the necessary sensitivity for early diagnostic suspicion.[511] 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. No single symptom or sign included in the review could accurately diagnose COVID-19 and the authors concluded that neither the absence or presence of signs or symptoms are accurate enough to rule in or rule out disease. However, 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.[505] Nonrespiratory symptoms may appear before the onset of fever and lower respiratory tract symptoms.[512] Lower urinary tract symptoms have also been reported rarely.

The clinical presentation has varied slightly across geographic locations. Initial impressions from the US note that the clinical presentation may be broader than that observed in China and Italy, with chest pain, headaches, altered mental status, and gastrointestinal symptoms all observed on initial presentation. Severe hepatic and renal dysfunction that spares the lungs has also been observed.[513] Data from the first hospitalized patients in New York found that while the most common presenting symptoms were fever, cough, dyspnea, and myalgia, gastrointestinal symptoms appeared to be more common than in China.[514]

Severity

  • 80% of adults present with mild to moderate illness

  • 14% of adults present with severe illness

  • 5% of adults present with critical illness

  • 1% of adults present with asymptomatic illness.[4]

The most prevalent symptoms in patients with mild to moderate illness, according to one European study, are headache, loss of smell, nasal congestion, cough, asthenia, myalgia, rhinorrhea, gustatory dysfunction, and sore throat. Fever was reported less commonly. The mean duration of symptoms was 11.5 days. The presentation varied according to age, with younger patients generally having ear, nose, and throat complaints, and older patients generally having fever, fatigue, and loss of appetite.[515] More common symptoms in patients with severe disease include fever, dyspnea, and anorexia.[142]

Pregnant women

  • The clinical characteristics in pregnant women are similar to those reported for nonpregnant adults.[516] 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.[22][23]

  • 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.[139]

Atypical presentations

  • Atypical presentations may occur, especially in older patients and patients who are immunocompromised (e.g., falls, delirium/confusion, functional decline, reduced mobility, syncope, persistent hiccups, absence of fever). Older patients and those with comorbidities may present with mild symptoms, but have a high risk of deterioration.[139]

  • There have been case reports of parotitis (possibly related to intraparotid lymphadenitis), oral vesiculobullous lesions, retinal lesions, and androgenetic alopecia in patients with COVID-19; however, it is unknown whether these findings are associated with SARS-CoV-2 infection as yet.[517][518][519][520]

Coinfections

  • The pooled prevalence of coinfection with viruses and atypical bacteria in SARS-CoV-2-positive patients was 11.6% (16.8% in studies that tested 100% of patients for copathogens).[521]

  • Bacterial coinfections have been reported in 7% of hospitalized patients, and 14% of patients in intensive care units. The most common bacteria were Mycoplasma pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, and Klebsiella pneumoniae. Coinfections with fungal pathogens and viruses (e.g., respiratory syncytial virus, influenza A) were less commonly reported.[522]

  • Fungal infections have been reported in 12% of patients admitted to the intensive care unit.[523]

  • Coinfections are more common in critically ill patients.[524]

  • Coinfections may be associated with protracted respiratory symptoms, prolonged intensive care stay, morbidity, and mortality if not detected and treated early.[525] 

  • Patients with influenza coinfection showed similar clinical characteristics to patients with COVID-19 only.[526][527]

  • Patients with tuberculosis or influenza and SARS-CoV-2 coinfection have an increased risk of mortality, while the clinical outcomes in patients with HIV or chronic hepatitis and SARS-CoV-2 coinfection are comparable to patients without coinfection.[528]

Clinical presentation in children

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.

Evidence suggests a milder, or asymptomatic, disease course in the majority of children, with low rates of severe disease and mortality. Infants under 1 year of age and adolescents 10 to 14 years of age have a higher risk for developing severe disease. Risk factors for severe disease include the presence of comorbidities and higher viral load. The clinical presentation in children is heterogeneous and includes a wide spectrum of clinical features. The most common presenting symptoms in children are fever and cough. Gastrointestinal symptoms (nausea, vomiting, diarrhea) are also common in children. Other less common symptoms include dyspnea, nasal congestion, rhinorrhea, rash, conjunctivitis, fatigue, abdominal pain, and neurologic symptoms. A higher prevalence of gastrointestinal symptoms has been reported in children >5 years of age compared with children ≤5 years of age.[507] Fever, cough, appetite loss, and dyspnea are less common in children compared with adults.[529]

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.[507][530][531][532]

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.[533] See the Complications section for more information.

Coinfections may be more common in children.[534] Coinfection was documented in 6% of children in US and Italian studies, with the most common pathogens being respiratory syncytial virus, rhinoviruses, Epstein-Barr virus, enteroviruses, influenza A, non-SARS coronaviruses, and Streptococcus pneumoniae.[11][535]

Physical exam

Perform a physical exam. Avoid use of a stethoscope if possible due to risk of viral contamination. 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. 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.[536]

Pulse oximetry

Pulse oximetry may reveal low oxygen saturation (SpO₂ <90%). 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.[537]

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.[538]

Pulse oximeters may exhibit suboptimal accuracy in certain populations. Limited data from studies with small numbers of participants suggest that skin pigmentation can affect pulse oximeter accuracy. In one study, occult hypoxemia (defined in the study as arterial oxygen saturation <88% by arterial blood gas despite oxygen saturation of 92% to 96% on pulse oximetry) was not detected by pulse oximetry nearly three times more frequently in Black patients compared with White patients.[539] 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.[540]

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.[537]

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.[541]

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).

BMJ Practice Pointer: remote management of covid-19 using home pulse oximetry and virtual ward support external link opens in a new window

Initial laboratory investigations

Order the following laboratory investigations in all patients with severe illness:

  • ABG

  • CBC

  • Comprehensive metabolic panel

  • Blood glucose level

  • Coagulation screen

  • Inflammatory markers (e.g., serum C-reactive protein, erythrocyte sedimentation rate, interleukin-6, lactate dehydrogenase, procalcitonin, amyloid A, and ferritin)

  • Cardiac biomarkers

  • Serum creatine kinase and myoglobin.

The most common laboratory abnormalities are lymphopenia, leukocytosis, leukopenia, thrombocytopenia, hypoalbuminemia, elevated cardiac biomarkers, elevated inflammatory markers, elevated D-dimer, and abnormal liver and renal function.[514][542][543][544] Laboratory abnormalities – in particular, lymphopenia, leukocyte abnormalities, and other markers of systemic inflammation – are less common in children.[545][546] 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.[547]

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. Specimens should be collected prior to starting empiric antimicrobials if possible.[139]


Radial artery puncture animated demonstrationRadial artery puncture animated demonstration

Molecular testing

Testing strategies vary widely between countries.[548]

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).[549]

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 (see the Criteria section).[506] 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 of concern.[197]

Who to test

  • Base decisions about who to test on clinical and epidemiologic factors.[506] 

  • In the UK, testing is recommended in:[550]

    • People with symptoms of new continuous cough, high temperature, or altered sense of smell/taste

    • People with acute respiratory infection, influenza-like illness, clinical or radiologic evidence of pneumonia, or acute worsening of underlying respiratory illness, or fever without another cause (whether presenting in primary or secondary care).

  • In the US, testing is recommended in:[551]

    • People with signs or symptoms consistent with COVID-19

    • 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

    • Asymptomatic people without recent known or suspected exposure to SARS-CoV-2 for early identification, isolation, and disease prevention (when screening testing if recommended by public health officials).

  • 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 who require screening based on recommendations from public health authorities or other situations (e.g., prior to a medical procedure such as elective surgery or as a school or workplace requirement). 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 are symptomatic or other criteria are met.[552]

  • Consult local health authorities for guidance as testing priorities depend on local recommendations and available resources.

Specimens

  • The optimal specimen for testing depends on the clinical presentation and the time since symptom onset. The WHO recommends the following.[506]

    • 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.[553]

    • Saliva: 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.[554][555][556][557] The WHO does not currently recommend the use of saliva as the sole specimen type for routine clinical diagnostics. In contrast, the Infectious Diseases Society of America recommends saliva as a suitable option for molecular testing in symptomatic people.[558]

    • 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; or nasopharyngeal/nasal wash/aspirate. Recommended lower respiratory tract specimens include: sputum, bronchoalveolar lavage, tracheal aspirate, pleural fluid, and lung biopsy.[559] Nasal mid-turbinate swab is an acceptable specimen for home or onsite self-collection.[559]

  • Collect specimens under appropriate infection prevention and control procedures.

Test result

  • 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).[506] 

  • 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.[506]

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.[560][561]

  • A case of iatrogenic cerebrospinal fluid leak has been reported after nasal testing for COVID-19 in a woman with an undiagnosed skull base defect at the fovea ethmoidalis.[562]

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.[139][563]

  • 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.[501]

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.[549]

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.[564]

  • 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.[565] 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.[566] 

  • 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.[567] 

It is not clear whether a positive result always indicates the presence of infectious virus.

  • 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.[568] 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.[565]

  • 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.[569] Another study found that patients with a cycle threshold of 34 or above do not excrete infectious virus.[570] 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.[568]

  • Centre for Evidence-Based Medicine: are you infectious if you have a positive PCR test result for COVID-19? external link opens in a new window

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.[567]

  • 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%.[564]

  • 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.[567] When the pretest probability is low, positive results should be interpreted with caution, and ideally a second specimen tested for confirmation.[571]

  • Post-test probability: the lower the prevalence of disease in a given population, the lower the post-test probability.[572] 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.[573]

  • BMJ Practice Pointer: interpreting a covid-19 test result external link opens in a new window

False-positive results

  • 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).[574] False-positive results are more likely when the prevalence of SARS-COV-2 is moderate to low.[575] 

  • There is 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%.[576] 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.[571] 

  • Examples of the potential consequences of false-positive test results include:[571]

    • 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 results

  • False-negative rates of between 2% and 29% have been reported.[567] 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.[577]

  • 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.[578] 

  • Examples of the potential consequences of false-negative test results include:[567] 

    • 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.

Serologic testing

Serology cannot be used as a standalone diagnostic test for acute SARS-CoV-2 infections. However, it may be useful in various settings (e.g, negative molecular testing, diagnosing patients with late presentation or prolonged symptoms, serosurveillance studies).[506][579]

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

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.[506]

  • 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:[580]

  • 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:[581]

  • 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

  • Serosurveillance studies.

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.[582][583]

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).[584]

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%.[564]

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.[506]

  • 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.[580] A reliable diagnosis is often only possible in the recovery phase when opportunities for management or interruption of transmission have passed.[506]

  • 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.[506]

  • 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.[580]

  • 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.[580]

Rapid diagnostic tests

Antibody detection

  • 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.[585]

  • 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.[586]

Antigen detection

  • Antigen testing 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.[587]

  • The WHO 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 an RT-PCR reference assay.[587]

  • 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.[588]

  • 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.[589]

  • Antigen testing has demonstrated a higher positive predictive value (90%) than RT-PCR (70%) compared with viral culture results. The positive percentage agreement for detection of infectious virus for the antigen test was similar to RT-PCR when compared with culture results.[590]

  • Laboratory-based (nonrapid) antigen tests are also available in some countries.

Molecular testing

  • 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).[589]

Chest imaging

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.[591]

Order a chest x-ray 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.[51][52][592]

  • 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.[593]

  • 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.[594]

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.[595] 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.[509] 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.[596]

    • 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.[597]

  • 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.[593] Accuracy appears to be lower among children; however, there are limited data in this population.[598]

  • Evidence of pneumonia on CT may precede a positive RT-PCR result for SARS-CoV-2 in some patients.[599] Some patients may present with a normal chest finding despite a positive RT-PCR.[600] 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.[601]

  • 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).[602]

  • 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.[603]

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.[604] 

  • 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.[605]

  • Ground-glass opacity has the highest diagnostic performance for COVID-19 pneumonia, followed by ground-glass opacity plus consolidation, and consolidation only.[606] 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%).[607]

  • 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.[605]

  • 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.[608]

  • 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. Children may have signs of pneumonia on chest imaging despite having minimal or no symptoms.[609] 

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.[605]

The WHO recommends chest imaging in the following scenarios:[594]

  • 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).

Emerging tests

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.[610][611][612]

Lung ultrasound

  • 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.[594]

  • 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.[593]

  • 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.[613]

  • 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.[614][615]

  • 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).[616]

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

Viral isolation

  • 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.[506]

Calprotectin

  • 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.[617]

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