Differentials
Community-acquired pneumonia
SIGNS / SYMPTOMS
Differentiating COVID-19 from community-acquired bacterial pneumonia is not usually possible from signs and symptoms. However, patients with bacterial pneumonia are more likely to have rapid development of symptoms and purulent sputum. They are less likely to have myalgia, anosmia, or pleuritic pain.[632]
INVESTIGATIONS
Blood or sputum culture or molecular testing: positive for causative organism.
RT-PCR: negative for SARS-CoV-2 viral RNA (coinfections are possible).
CT chest: centrilobular nodules, mucoid impactions.[633]
Influenza infection
SIGNS / SYMPTOMS
Differentiating COVID-19 from community-acquired respiratory tract infections is not possible from signs and symptoms. However, fever is less common with influenza. Rhinorrhea, sore throat, myalgia, headache, and dyspnea are more common.[634][635] New-onset smell and/or taste disorders were less common in a case-control study.[636]
More common in children.[637] Children with COVID-19 tend to be older, and are more likely to have comorbidities, fever, gastrointestinal symptoms, headache, and chest pain compared with those with influenza.[638]
Coinfection is possible, but is not significantly associated with mortality.[639] Coinfection is higher in children and critically ill patients.[640]
INVESTIGATIONS
Only testing can distinguish between influenza infection and COVID-19 and identify coinfection.
RT-PCR: positive for influenza A or B viral RNA; negative for SARS-CoV-2 viral RNA (coinfections are possible).
Chest x-ray: less likely to be abnormal.[634]
CT chest: there is emerging evidence that CT can be used for differentiating between influenza and COVID-19. COVID-19 patients are more likely to have rounded or linear opacities, crazy-paving sign, vascular enlargement, and interlobular septal thickening, but less likely to have nodules, tree-in-bud sign, bronchiectasis, and pleural effusion.[641][642]
Inflammatory markers and coagulation screen: there is emerging evidence that inflammatory markers (lactate dehydrogenase, erythrocyte sedimentation rate, C-reactive protein) and coagulation parameters are not as high in patients with influenza compared with COVID-19.[643]
Common cold
SIGNS / SYMPTOMS
Differentiating COVID-19 from community-acquired respiratory tract infections is not possible from signs and symptoms. However, fever is less common with the common cold, and headache, rhinorrhea, myalgia, and sore throat are more common. Patients may have a greater number of general symptoms.[635]
INVESTIGATIONS
RT-PCR: positive for causative organism; negative for SARS-CoV-2 viral RNA (coinfections are possible).
Respiratory syncytial virus (RSV) infection
SIGNS / SYMPTOMS
Primarily affects children <5 years of age.[454]
History of exposure to RSV.
Seasonal outbreaks during winter (may vary between regions).
Increased work of breathing, wheeze, apnea, or poor feeding may be noted in infants.
INVESTIGATIONS
RT-PCR: positive for respiratory syncytial virus RNA; negative for SARS-CoV-2 viral RNA (coinfections are possible).
Other viral or bacterial respiratory infections
SIGNS / SYMPTOMS
Differentiating COVID-19 from community-acquired respiratory tract infections is not possible from signs and symptoms.
Adenovirus and Mycoplasma should be considered in clusters of pneumonia patients, especially in closed settings such as military camps and schools.
INVESTIGATIONS
Blood or sputum culture of molecular testing: positive for causative organism.
RT-PCR: negative for SARS-CoV-2 viral RNA (coinfections are possible).
Aspiration pneumonia
SIGNS / SYMPTOMS
Differentiating COVID-19 from aspiration pneumonia is not usually possible from signs and symptoms.
INVESTIGATIONS
RT-PCR: negative for SARS-CoV-2 viral RNA (coinfections are possible).
CT chest: difficult to distinguish on CT; however, anterior lung involvement may be more suggestive of COVID-19 pneumonia.[644]
Pneumocystis jirovecii pneumonia
SIGNS / SYMPTOMS
Differentiating COVID-19 from pneumocystis jirovecii pneumonia is not usually possible from signs and symptoms. However, patients with pneumocystis jirovecii pneumonia are usually immunocompromised (e.g., HIV positive) and duration of symptoms may be longer.
INVESTIGATIONS
Sputum culture: positive for Pneumocystis.
RT-PCR: negative for SARS-CoV-2 viral RNA (coinfections are possible).
CT chest: ground-glass opacity is usually more diffusely distributed with a tendency to spare the subpleural regions.[633]
Avian influenza A (H5N1) virus infection
SIGNS / SYMPTOMS
Close contact with infected birds (e.g., farmer or visitor to a live market in endemic areas), or living in/travel to an area when avian influenza is endemic.
INVESTIGATIONS
RT-PCR: positive for H5N1 viral RNA.
Middle East respiratory syndrome (MERS)
SIGNS / SYMPTOMS
Travel history to the Middle East or contact with a confirmed case of MERS.
Differentiating COVID-19 from MERS is not possible from signs and symptoms. However, the clinical course of MERS is usually more severe and the case fatality rate is higher.
INVESTIGATIONS
Reverse-transcriptase polymerase chain reaction (RT-PCR): positive for MERS-CoV viral RNA.
Avian influenza A (H7N9) virus infection
SIGNS / SYMPTOMS
Close contact with infected birds (e.g., farmer or visitor to a live market in endemic areas), or living in/travel to an area when avian influenza is endemic.
INVESTIGATIONS
RT-PCR: positive for H7-specific viral RNA.
Pulmonary tuberculosis
SIGNS / SYMPTOMS
Consider diagnosis in endemic areas, especially in patients who are immunocompromised.
History of symptoms is usually longer.
Presence of night sweats and weight loss may help to differentiate.
INVESTIGATIONS
Chest x-ray: fibronodular opacities in upper lobes with or without cavitation; atypical pattern includes opacities in middle or lower lobes, or hilar or paratracheal lymphadenopathy, and/or pleural effusion.
Sputum acid-fast bacilli smear and sputum culture: positive.
Molecular testing: positive for Mycobacterium tuberculosis.
Febrile neutropenia
SIGNS / SYMPTOMS
Symptoms of COVID-19 and neutropenic sepsis may be difficult to differentiate at initial presentation. Suspect neutropenic sepsis in patients with a history of recent systemic anticancer treatment who present with fever (with or without respiratory symptoms) as this can be rapid and life-threatening.
Patients with febrile neutropenia are at increased risk of COVID-19.[645]
INVESTIGATIONS
CBC: neutropenia.
RT-PCR: negative for SARS-CoV-2 viral RNA.
Other
SIGNS / SYMPTOMS
COVID-19 should be considered a differential diagnosis for many conditions. The differential is very broad and includes many common respiratory, infectious, cardiovascular, oncologic, and gastrointestinal diseases.[646]
INVESTIGATIONS
RT-PCR: negative for SARS-CoV-2 viral RNA.
Other differentiating tests depend on the suspected diagnosis.
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