Approach

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.[2] Immediately isolate all suspected and confirmed cases and implement local infection prevention and control procedures. Triage patients with a standardised triage tool and evaluate the patient to assess the severity of disease. COVID-19 is a notifiable disease. Suspected cases should remain in the pathway until proven negative. 

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. 

Diagnosis should be suspected in:[147]

  • Patients with acute respiratory illness (i.e., fever and at least one sign/symptom of respiratory disease such as cough or shortness of breath) and a history of travel to or residence in a location reporting community transmission of COVID-19 disease during the 14 days prior to symptom onset.

  • Patients with any acute respiratory illness if they have been in contact with a confirmed or probable COVID-19 case in the last 14 days prior to symptom onset.

See Diagnostic criteria section for case definitions. 

Clinical presentation in adults

Approximately 15% of patients present with the symptom triad of fever, cough, and dyspnoea, and 90% present with more than one symptom.[31] 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. 

The most common symptoms are:

  • Fever

  • Cough

  • Dyspnoea

  • Altered sense of taste/smell.

Less common symptoms include:

  • Myalgia or arthralgia

  • Fatigue

  • Anorexia

  • Sputum production

  • Chest tightness

  • Gastrointestinal symptoms

  • Sore throat

  • Dizziness

  • Headache

  • Neurological symptoms

  • Cutaneous symptoms

  • Rhinorrhoea/nasal congestion 

  • Chest pain

  • Conjunctivitis

  • Haemoptysis. 

Signs and symptoms of febrile respiratory illness may not possess the necessary sensitivity for early diagnostic suspicion.[316] A Cochrane review found that at least half of patients had a cough, sore throat, fever, myalgia/arthralgia, fatigue, or headache. 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.[317]

The clinical presentation has varied slightly across geographical 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.[318] Data from the first hospitalised patients in New York found that while the most common presenting symptoms were fever, cough, dyspnoea, and myalgia, gastrointestinal symptoms appeared to be more common than in China.[155]

In terms of severity:[4]

  • 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. 

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, rhinorrhoea, 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.[319]

There is anecdotal evidence suggesting that the course of the disease may be protracted, with ever-changing symptoms and periods of feeling better interspersed with periods of relapse in some patients (similar to a post-viral fatigue syndrome), even in those with mild disease.[320]

Pregnant women

  • The clinical characteristics in pregnant women are similar to those reported for non-pregnant adults.[321] It is important to note that symptoms such as fever, dyspnoea, gastrointestinal symptoms, and fatigue may overlap with symptoms due to physiological adaptations of pregnancy or adverse pregnancy events.[2]

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.[2]

  • 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as yet.[322][323][324][325]

Co-infections

  • Bacterial co-infections have been reported in 7% of hospitalised patients, and 14% of patients in intensive care units. The most common bacteria were Mycoplasma pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, and Klebsiella pneumoniae. Co-infections with fungal pathogens and viruses (e.g., respiratory syncytial virus, influenza A) were less commonly reported.[326]

  • Co-infections may be associated with protracted respiratory symptoms, prolonged intensive care stay, morbidity, and mortality if not detected and treated early.[327] 

  • Patients with influenza co-infection showed similar clinical characteristics to patients with COVID-19 only.[328][329]

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.

In terms of severity:[330]

  • 37% of children present with mild illness 

  • 45% of children present with moderate illness 

  • 3% of children present with severe illness

  • 0.6% of children present with critical illness

  • 16% of children present with asymptomatic illness.

Evidence so far suggests a milder, or asymptomatic, course of disease in about 95% of children, but with possible evidence of radiological lung changes in both categories. Symptoms commonly reported include fever, cough, sore throat, nasal congestion, and rhinorrhoea. Fever, cough, and dyspnoea are less common in children compared with adults. Children may present with gastrointestinal symptoms more commonly than adults, particularly newborns and infants, and they may be the only symptom.[331] Febrile seizures have been reported rarely.[12] The clinical manifestations in children under 5 years of age appear to be milder compared with those of influenza A infection.[332]  

Severe disease has been reported rarely in children.[331][333] In a cross-sectional study of 48 critically ill infants and children in the US, the clinical course and hospital outcomes were better compared with adults. Similar to adults, 80% of critically ill children had pre-existing comorbidities, most commonly immune suppression/cancer, obesity, and diabetes.[334] There is increasing concern that a related inflammatory syndrome is emerging in children with severe disease. See the Complications section for more information.

Cases of COVID-19 have been reported in neonates. Dyspnoea is the most common sign in neonates. Although illness is usually mild, severe illness, including cases of late-onset neonatal sepsis and encephalitis, has been reported. Severe illness is slightly more common in neonates compared with older children. Infants may present with irritability, crying, feeding difficulties, silent hypoxia, and neurological symptoms.[331][335][336][337]

Co-infections may be more common in children.[338] Co-infection 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][12]

Physical examination

Perform a physical examination. 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, tachypnoea, or cyanosis accompanying hypoxia. Bradycardia has been noted in a small cohort of patients with mild to moderate disease.[339]

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. Only a small proportion of patients have other organ dysfunction, meaning that after the initial phase of acute deterioration, traditional methods of recognising further deterioration (e.g., National Early Warning Score 2 [NEWS2] scores) may not help predict those patients who go on to develop respiratory failure.[340]

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.[341]

Initial laboratory investigations

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

  • ABG

  • FBC

  • 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.

The most common laboratory abnormalities are lymphopenia, leukocytosis, leukopenia, thrombocytopenia, decreased albumin, elevated cardiac biomarkers, elevated inflammatory markers, elevated D-dimer, and abnormal liver and renal function.[155][342][343][344] Laboratory abnormalities – in particular, lymphopenia, leukocyte abnormalities, and other markers of systemic inflammation – are less common in children.[331][345][346] 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.[347]

Collect blood and sputum specimens for culture in patients with severe or critical disease to rule out other causes of lower respiratory tract infection and sepsis, especially patients with an atypical epidemiological history. Specimens should be collected prior to starting empirical antimicrobials if possible.[2]


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Molecular testing

Molecular testing is required to confirm the diagnosis. Diagnostic tests should be performed according to guidance issued by local health authorities and should adhere to appropriate biosafety practices. If testing is not available nationally, specimens should be shipped to an appropriate reference laboratory. Specimens for testing should be collected under appropriate infection prevention and control procedures.

Decisions about who to test should be based on clinical and epidemiological factors. Consult local health authorities for guidance as testing priorities will depend on local guidelines and available resources. When resources are limited, certain groups of people may need to be prioritised for testing. In the UK, testing is recommended in all people with symptoms of new continuous cough, high temperature, or altered sense of smell/taste.[348] In the US, the Centers for Disease Control and Prevention has published detailed testing recommendations, including testing guidance for nursing homes and long-term care facilities, and essential workers who have been exposed.[349]

Perform a nucleic acid amplification test, such as real-time reverse-transcription polymerase chain reaction (RT-PCR), for SARS-CoV-2 in appropriate patients with suspected infection, with confirmation by nucleic acid sequencing when necessary.[350]

  • Collect upper respiratory specimens (nasopharyngeal and oropharyngeal swab or wash) in ambulatory patients and/or lower respiratory specimens (sputum and/or endotracheal aspirate or bronchoalveolar lavage) in patients with more severe respiratory disease. Consider the high risk of aerolisation when collecting lower respiratory specimens. 

  • Also consider collecting additional clinical specimens (e.g., blood, stool, urine).

Interpreting the test result depends on the accuracy of the test, and the pretest probability (or estimated risk of disease) before testing. A positive result holds more weight than a negative test due to the test’s high specificity (around 95%) but moderate sensitivity (around 70%).[351]

False-negative rates of between 2% and 29% have been reported.[351] 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.[352]

One or more negative results do not rule out the possibility of infection. If a negative result is obtained from a patient with a high index of suspicion for COVID-19 (or a high pretest probability), additional specimens should be collected and tested, especially if only upper respiratory tract specimens were collected initially.[350] Guidelines recommend that two consecutive negative tests (at least one day apart) are required to exclude COVID-19; however, there is a case report of a patient who returned two consecutive negative results and didn’t test positive until 11 days after symptom onset and confirmation of typical chest computed tomography (CT) findings.[353]

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 co-infections can occur, and a positive test for a non-COVID-19 pathogen does not rule out COVID-19.[2][354]

Serological testing

Serological testing is becoming increasingly available for use; however, while rapid antibody detection kits have been approved for the qualitative detection of SARS-CoV-2 immunoglobulin G (IgG)/IgM antibodies in serum, plasma, or whole blood, the World Health Organization (WHO) does not recommend the use of these tests outside of research settings as they have not been validated as yet.[355]

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

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

Antibody responses to SARS-CoV-2 typically occur during the first 1 to 3 weeks of illness, with the seroconversion time of IgG antibodies often being earlier than that of IgM antibodies.[358][359] A Cochrane review found that antibody tests for IgG/IgM only detected 30% of people with COVID-19 when the test was performed 1 week after the onset of symptoms, but accuracy increased in week 2 with 70% detected and week 3 with over 90% detected. Data beyond 3 weeks were limited. Tests gave false positive results in 2% of patients without COVID-19. The review found that the sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role in the diagnosis of COVID-19, but tests are likely to have a useful role in detecting previous infection if used 15 or more days after symptom onset (although there were very little data beyond 35 days).[360]

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

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.[361]

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.[30][31][362] Although chest x-ray appears to have a lower sensitivity compared with chest CT, it has the advantages of being less resource-intensive, associated with lower radiation doses, easier to repeat sequentially, and portable.[363]

Consider ordering a CT scan of the chest. CT imaging is the primary imaging modality in some countries, such as China. It may be helpful in making the diagnosis, guiding individual patient management decisions, aiding the diagnosis of complications, or giving clues to an alternative diagnosis. 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 non-specific 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.[364]

BSTI: radiology decision tool for suspected COVID-19 external link opens in a new window

Some institutions in the UK recommend a more pragmatic approach for patients with high clinical suspicion of COVID-19, with chest CT recommended only after two indeterminate or normal chest x-rays in combination with a negative RT-PCR test.[365]

The American College of Radiology recommends reserving CT for hospitalised, symptomatic patients with specific clinical indications for CT, and emphasises that a normal chest CT does not mean that a patient does not have COVID-19 and that an abnormal chest CT is not specific for COVID-19 diagnosis.[366]

Abnormal chest CT findings have been reported in up to 97% of COVID-19 patients in one meta-analysis of 50,466 hospitalised patients.[367] Evidence of pneumonia on CT may precede a positive RT-PCR result for SARS-CoV-2 in some patients.[368] CT imaging abnormalities may be present in minimally symptomatic or asymptomatic patients.[83][369] More than half of patients with asymptomatic disease present with CT abnormalities.[347] Some patients may present with a normal chest finding despite a positive RT-PCR.[370] Also, results of RT-PCR testing may be false-negative, so patients with typical CT findings should have repeat RT-PCR testing to confirm the diagnosis.[371]

Typical features

  • The most common findings are ground-glass opacity, either in isolation or co-existing with other findings such as consolidation, interlobular septal thickening, or crazy-paving pattern. The most common distribution pattern is bilateral, peripheral/subpleural, posterior distribution of the opacities, with a lower lobe predominance. Extensive/multilobar involvement with consolidations is more common in older patients and those with severe disease.[372]

  • CT scan generally shows an increase in the size, number, and density of ground-glass opacities in the early follow-up period, with a progression to mixed areas of ground-glass opacities, consolidations, and crazy paving peaking at day 10 to 11, before gradually resolving or persisting as patchy fibrosis.[372]

  • 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.[373]

  • Children frequently have normal or mild CT chest findings. The most common signs in children are patchy ground-glass opacity and, less frequently, areas of consolidation. Abnormalities are more common in the lower lobes and are predominantly unilateral. Pleural effusion is rare.[374] Children may have signs of pneumonia on chest imaging despite having minimal or no symptoms.[338] 

Atypical features

  • Pulmonary vascular enlargement, interlobular or intralobular septal thickening, adjacent pleural thickening, air bronchograms, subpleural lines, crazy-paving pattern, bronchus distortion, bronchiectasis, vacuolar retraction sign, and halo sign are atypical features. Pleural effusion, pericardial effusion, cavitation, pneumothorax, and mediastinal lymphadenopathy have also been reported rarely.[372]

The WHO recommends chest imaging in the following scenarios:[363]

  • 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 hospitalised and have mild symptoms (to decide on hospital admission versus home discharge) 

  • Patients with suspected or confirmed COVID-19 who are not currently hospitalised 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 hospitalised 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.[375][376][377]

Antigen testing

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

Lung ultrasound

  • Lung ultrasound is used as a diagnostic tool in some centres as an alternative to chest x-ray and chest CT. Although there is only very low-certainty evidence supporting its diagnostic accuracy, it might be helpful as a supplemental or alternate imaging modality.[363] It has the advantages of portability, bedside evaluation, reduced healthcare worker exposure, easier sterilisation process, absence of ionising radiation exposure, and repeatability during follow-up. It may also be more readily available in resource-limited settings. However, it also has some limitations (e.g., it is unable to discern chronicity of a lesion) and other imaging modalities may be required. B-lines are the prominent pattern in patients with COVID-19, occurring with a pooled frequency of 97%. Pleural line abnormalities are also common, with a pooled frequency of 70%. While these findings are not specific for COVID-19, they increase the likelihood of disease in the context of a characteristic clinical presentation. Other findings include consolidations, pleural thickening, and pleural effusion.[379] May be used in pregnant women and children.[380][381]

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

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