Although most people infected with SARS-CoV-2 typically experience resolution of symptoms within weeks of infection, many will experience new, returning, or persistent symptoms 4 or more weeks after infection, a condition known as long COVID.1 Ongoing complaints of brain fog, fatigue, joint pain, shortness of breath, cough, and palpitations are familiar among clinicians treating patients who have had COVID-19 infection. The symptomatology of long COVID encompasses a multitude of body systems from physical to neuropsychiatric, and it is unclear which patients are at risk of developing this syndrome.1 Research on long-COVID treatment is rapidly emerging.

The prevalence of long COVID varies widely by study and country, with rates in the United States ranging from 10% to 53%.2-5 The definition of and terminology for long COVID also differ by source and are evolving as more data become available (Box).6-9 The rapidly emerging research on the various clinical presentations of long COVID can help guide diagnosis and management decisions.

Clinical Presentation of Long COVID

The symptoms of long COVID are numerous with fatigue being the most common along with anxiety, brain fog, chest discomfort/heart palpitations, depression, dyspnea, headaches, and myalgias (Table).1,10 Joint pain, nausea and vomiting, hair loss, and skin rash are also commonly reported.

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Virtually all body systems may be involved in the clinical presentation of long COVID including the cardiovascular, gastrointestinal, hematologic, immune, musculoskeletal, neurologic, pulmonary, and renal systems along with new-onset mental health conditions.3 Additionally, general pain syndromes are common in these patients and require a multimodal approach to diagnosis and treatment, which may include pharmacological therapeutics, physical therapy, and psychological intervention.4

Children may present with lack of concentration, short-term memory loss, and/or difficulty performing everyday tasks 4 weeks or longer after acute COVID-19 illness, although evidence on long COVID in children and young people is limited, according to National Institute for Health and Care Excellence (NICE) guidance.7 Cardiac and respiratory symptoms appear to be less common in children than in adults. Development of multisystem inflammatory syndrome in children (MIS-C) is associated with COVID-19.11

Risk Factors for Long COVID

Research has shown an association between long COVID and the following risk factors: older age, female sex, non-White ethnicity, obesity, asthma, poor general health, poor prepandemic mental health, and poor sociodemographic factors.1,9  The risk for developing long COVID does not appear to be linked to the severity of acute COVID-19 infection including the need for hospitalization.1,7

Some evidence suggests that COVID-19 vaccination may be associated with a lower risk for long COVID. One study found that people receiving 2 vaccine doses were less likely to have symptoms for 28 days or more (odds ratio, 0.51) compared with unvaccinated individuals (P =0.0060).12 However, more research on this topic is needed to draw firm conclusions.

Diagnosis and Workup of Long COVID

Because the clinical presentation of long COVID can include numerous organ systems and symptoms, health care providers need to start the diagnostic process by obtaining a thorough medical history and performing a complete physical examination to elicit the frequency, severity, and changes of any reported symptoms and examine for clinical signs of disease. The clinician should assess for physical, cognitive, psychological, and psychiatric symptoms.7 System-based conditions have also been reported by some patients following the acute COVID-19 infection and should be included in the workup (Figure).10 Moreover, the health care provider must assess the overall impact of patients’ reported symptoms on quality of life and daily functioning.7

The diagnostic workup of long COVID can prove to be an arduous one and may involve a significant financial burden for many patients, creating potential barriers to care (time, cost, and availability of specialists and long-COVID clinics). The medical history and clinical findings should help guide the provider in ordering appropriate laboratory tests. Basic diagnostic laboratory testing may be considered based on the patient’s symptoms to assess for conditions that may respond to treatment such as complete blood cell count, basic metabolic panel, kidney and liver function testing, inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, ferritin), thyroid function, hemoglobin A1C, and vitamin D and B12 levels.2,7,10

For those patients with more advanced symptomatology such as arthralgias, possible coagulation concerns, and chest discomfort, it is vital to rule out more serious conditions. In these patients, the diagnostic workup may include laboratory tests for troponin, D-dimer, and fibrinogen levels and studies checking for rheumatologic conditions such as an antinuclear antibody, rheumatoid factor, anticyclic citrullinated peptide, anticardiolipin, and creatine phosphokinase.2,10

A study has shown a higher risk for cardiovascular disease for a 12-month span during the post-acute COVID phase.13 It is, therefore, vital to pay close attention to cardiovascular health and disease in patients with reported thoracic long COVID symptoms.13 Testing for B-type natriuretic peptide may help differentiate symptoms of cardiac vs pulmonary origin.10

Other diagnostic tests may include echocardiography (ECG), chest radiography, computed tomography (CT), or magnetic resonance imaging (MRI) for concerning thoracic complaints; abdominal ultrasonography, CT, or MRI for gastrointestinal concerns; and possibly a brain CT or MRI for more severe neurologic symptoms such as severe, intractable headaches.2

For patients reporting new or worsening mental health concerns, it is imperative to properly refer them to a mental health care provider. These recommendations are general, require more evidence to support their use, and must be guided by the patient’s medical history and clinical findings.6 Patients reporting new cognitive symptoms (eg, brain fog, confusion, memory loss) should be evaluated using validated screening tools that assess for functional impairment, effect on daily activities, and quality of life.7

For patients with postural symptoms (eg, palpations or dizziness on standing), assessing blood pressure when supine and standing and heart rate recordings (3‑minute active stand test for orthostatic hypotension, or 10 minutes for postural orthostatic tachycardia syndrome [POTS] or other forms of orthostatic intolerance) are recommended.7