Understanding the Many Faces of a Medical Mystery

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

Management of Long COVID

Management and treatment of long COVID should be patient-centered and cautiously implemented. The World Health Organization (WHO) and other forums have emphasized the importance of improving patients’ clinical characteristics.14 However, the lack of COVID-19 dedicated treatment facilities impedes access to appropriate care for patients with long COVID.

The NICE guidelines suggest using a holistic approach to identifying and diagnosing long COVID, but offer limited guidance on management.7 Many patients experience spontaneous improvement in symptoms between 4 and 12 weeks after COVID-19 infection and should be offered self-management support and monitoring; those who do not improve should be referred for further services. Treatment should focus on providing symptomatic relief as data is lacking on pharmacologic interventions to treat the condition itself.7

Because of the breadth of long COVID symptoms, this review will focus on the 3 most common systems affected: cardiovascular, neuropsychiatric, and pulmonary. Patients with signs or symptoms of acute or life‑threatening complications should be immediately referred for acute services. These symptoms include the following:7,11

  • Hypoxemia or oxygen desaturation during exercise
  • Signs of severe lung disease
  • Cardiac chest pain
  • Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)
  • Severe psychiatric symptoms or are displaying high risk for self‑harm or suicide
Cardiovascular Symptoms

After ruling out any life-threatening complications (such as a patient complaining of chest pain), the health care provider should also consider patients’ exercise tolerance and the presence of any type of orthostatic changes in pulse or blood pressure before starting physical reconditioning.14 Depending on the presenting clinical symptoms and physical examination findings, NICE also recommended the use of medications such as beta-blockers for symptoms of non-COVID-related angina, arrhythmias, and acute coronary syndrome (ACS).14

For patients with myocarditis, supportive measures and/or immunomodulating therapies may help, along with anticoagulation treatment for those with evidence of hypercoagulability risks.14 Myocarditis may also resolve spontaneously over time.14

For POTS, patient education, structured exercise programs, and increased water and salt intake (2 to 4 L of water and 10 to 12 g of sodium) may be considered along with avoidance of caffeine, alcohol, prolonged heat, and use of norepinephrine transport inhibitors.14,15 Patients who do not respond to these nonpharmacologic approaches may be treated with an acute intravenous infusion of up to 2 L of saline and medications including fludrocortisone, pyridostigmine, midodrine, or low-dose propranolol.14,15 For patients with prominent hyperadrenergic features, clonidine or methyldopa may be used.14,15

Neuropsychiatric Symptoms

Few evidence-based treatments have been studied for patients suffering from fatigue, dizziness, and cognitive problems from long COVID.7 Self-management and support appear to be the mainstay approach for long COVID treatment, according to NICE.14 Some conditions fit the diagnostic criteria of both long COVID and chronic fatigue syndrome (CFS); therefore, the treatment algorithms for CFS may benefit some patients with long COVID.14 Findings from randomized control studies suggest that cognitive behavioral therapy (CBT) and group therapy may be effective for CFS; in theory, these interventions may be beneficial for long COVID patients.14 Occupational and speech therapies may also be needed, based on symptoms assessment.

Consider referral for patients with anxiety, depression, and other mental health symptoms and/or follow evidence-based clinical guidelines for treating these conditions.7,14 Researchers are also investigating interleukin-6 (IL-6) as a potential mediator of neuropsychiatric symptoms of long COVID.16

Pulmonary Symptoms

The patient’s exercise tolerance can be used as a tool to measure the degree of breathlessness and need for intervention along with chest radiography and pulse oximetry, according to the NICE guidance.14 Self-management interventions include stopping smoking and avoiding environmental pollutants, extreme temperature changes, and exercise.14

Strategies for managing dyspnea include breathing exercises, pulmonary rehabilitation, and optimal body position placement for postural relief.14 Findings from a randomized controlled trial showed that home-based inspiratory muscle training was associated with clinically meaningful improvement in symptoms of breathlessness and chest symptoms.17 Consider using antifibrotic and/or antimicrobial therapies in cases with pulmonary fibrotic changes or infection.14

Clinical trials evaluating the use of montelukast, hyperbaric oxygen, breathing exercises, deupirfenidone, and other interventions in the management of pulmonary symptoms of long COVID are ongoing.14,18,19

Self-Management Support

Advice on self-management should be offered to all patients with long COVID symptoms and may include measures to reduce weight (eg, caloric restriction diet, tailored graded exercise, stress reduction, and good sleep hygiene) given the link between obesity and long COVID.7 Nonpharmacologic approaches to improve breathlessness have also been suggested such as pulmonary rehabilitation, breathing exercise, and alternative therapies (eg, acupuncture, body rotation, and stretching).


The variety of symptom presentations in long COVID is extensive, with fatigue being most common. Researchers are continuously working to better understand the pathophysiology of this condition and optimize long COVID treatment.

Louise Lee, EdD, MHA, PA-C, is an associate professor and director of PA studies at St. John’s University in Queens, New York; Corinne I. Alois, MS, PA-C, is an assistant professor at St. John’s University.


1. Sykes DL, Holdsworth L, Jawad N, Gunasekera P, Morice AH, Crooks MG. Post-COVID-19 symptom burden: what is long-COVID and how should we manage it? Lung. 2021;199(2):113-119. doi:10.1007/s00408-021-00423-z

2. Sisó-Almirall A, Brito-Zerón P, Conangla Ferrín L, et al. Long Covid-19: proposed primary care clinical guidelines for diagnosis and disease management. Int J Environ Res Public Health. 2021;18(8):4350. doi:10.3390/ijerph18084350

3. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open. 2021;4(2):e210830. doi:10.1001/jamanetworkopen.2021.0830

4. Hirschtick JL, Titus AR, Slocum E, et al. Population-based estimates of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) prevalence and characteristics. Clin Infect Dis. 2021;73(11):2055-2064. doi:10.1093/cid/ciab408

5. van Kessel SAM, Olde Hartman TC, Lucassen PLBJ, van Jaarsveld CHM. Post-acute and long-COVID-19 symptoms in patients with mild diseases: a systematic review. Fam Pract. 2022;39(1):159-167. doi:10.1093/fampra/cmab076

6. Centers for Disease Control and Prevention. Post-COVID conditions: information for healthcare providers. Updated July 9, 2021. Accessed April 28, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html

7. National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. NICE guideline [NG188]; 2020. Updated November 11, 2021. Accessed April 28, 2022. https://www.nice.org.uk/guidance/ng188 

8. World Health Organization. A clinical case definition of post COVID-19 condition by a Delphi consensus. https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1 (6 October 2021).

9. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022;43(11):1157-1172. doi:10.1093/eurheartj/ehac031

10. Centers for Disease Control and Prevention. Evaluating and caring for patients with post-covid conditions: interim guidance. Updated June 2021. Accessed April 28, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-workup.html

11. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-associated multisystem inflammatory syndrome in children – United States, March-July 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1074-1080. doi:10.15585/mmwr.mm6932e2

12. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis. 2022;22(1):43-55. doi:10.1016/S1473-3099(21)00460-6

13. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28(3):583-590. doi:10.1038/s41591-022-01689-3

14. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid-mechanisms, risk factors, and management. BMJ. 2021;374:n1648. doi: 10.1136/bmj.n1648

15. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12(6):e41-63. doi:10.1016/j.hrthm.2015.03.029

16. McNarry MA, Berg RMG, Shelley J, Hudson J, Saynor ZL, Duckers J, Lewis K, Davies GA, Mackintosh KA. Inspiratory muscle training enhances recovery post COVID-19: a randomised controlled trial. Eur Respir J. 2022:2103101. doi:10.1183/13993003.03101-2021

17. Mera-Cordero F, Bonet-Monne S, Almeda-Ortega J, García-Sangenís A, Cunillera-Puèrtolas O, et al. Double-blind placebo-controlled randomized clinical trial to assess the efficacy of montelukast in mild to moderate respiratory symptoms of patients with long COVID: E-SPERANZA COVID Project study protocol. Trials. 2022;23(1):19. doi:10.1186/s13063-021-05951-w

18. Robbins T, Gonevski M, Clark C, Baitule S, Sharma K, Magar A, Patel K, Sankar S, Kyrou I, Ali A, Randeva HS. Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention. Clin Med (Lond). 2021 Nov;21(6):e629-e632. doi:10.7861/clinmed.2021-0462

19. Kappelmann N, Dantzer R, Khandaker GM. Interleukin-6 as potential mediator of long-term neuropsychiatric symptoms of COVID-19. Psychoneuroendocrinology. 2021;131:105295. doi:10.1016/j.psyneuen.2021.105295

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