Post-Acute Sequelae of COVID-19 Infection (PASC), or "Long-COVID"

Please Note: The information below is intended for healthcare professionals, specifically primary care providers. These are not meant to be guidelines or supplant individual provider discretion in the management of PASC, as evidence-based consensus guidelines for the diagnosis of management of this new disease do not exist currently. The following represents the expert opinions of an interprofessional group that is appraising emerging evidence and should be interpreted as recommendations and clinical guidance rather than the standard of care.

Post-Acute Sequelae of COVID-19 Infection (PASC), or “Long-COVID”

Written May 14, 2021 by: W. Michael Brode, MD

PASC, more commonly known as “long-COVID” or “post-COVID,” is a multisystem disease that persists after acute COVID-19 infection (initial illness can last up to 4 weeks). Over 205 symptoms have been reported lasting more than 6 months,1 although no consensus criteria for diagnosing this syndrome have been established, let alone randomized trial evidence for specific therapies. Research into this emerging disease is an international priority.2

There is no diagnostic test or consensus criteria for PASC, therefore workup should focus on evaluating for end-organ damage or other causes of the symptoms based on the chief complaint (i.e. PASC is a rule out diagnosis). Relapsing and remitting symptoms have been widely reported in the absence of objective findings though, so for patients who were healthy prior to their COVID-19 infection it is likely that most symptoms can be attributed to PASC.

Pulmonary fibrosis, diastolic heart failure, and chronic kidney disease are examples of end-organ damage from severe COVID-19 infection3 and should be treated according to existing evidence-based guidelines. Most constitutional symptoms of PASC improve gradually with time (especially when the initial illness was mild or asymptomatic),4–6 yet so far treatment consists of symptomatic management, supervised rehabilitation with a graduated exercise plan, and addressing stress and mental health comorbidities.

This website and clinical guidance is intended for healthcare professionals, with the goal of supporting frontline primary care providers encountering this emerging disease. The guidance and recommendations here are meant to be brief and practical, focused on what can be managed in the primary care setting, or the baseline workups prior to specialist referral. This is not an exhaustive review of each complication or manifestation of the disease, and represents expert opinion from an interprofessional group.

Guidance will certainly change as more information and evidence emerges around PASC. This website will grow and be updated regularly over time.

Healthcare providers are welcome to join the Austin PASC Collaborative, a monthly case conference discussing PASC cases with an interprofessional expert panel that is developing this guidance.

The emergence of patients with “long-COVID” or “post-COVID” symptoms was recognized early in the pandemic, but the clinical syndrome was not given a name until February 2021 when the NIH announced it would be called Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). Experts have proposed the following definitions for the timing of persistent symptoms7:

  • Acute COVID-19 infection: up to 4 weeks from symptom onset
  • Subacute or ongoing symptomatic COVID-19: 4 to 12 weeks from symptom onset
  • Chronic or post-COVID-19 syndrome (PASC): > 12 weeks from acute onset and not attributable to alternative diagnoses

Without consensus criteria or definitions of what constitutes PASC, the estimated prevalence of the disease varies widely. Persistent symptoms have been reported in 33-87% of patients whose initial illness was severe or critical requiring hospitalization,3,8,9 compared to 19-33% of patients of who had asymptomatic to moderate disease who recovered as outpatients.4,6,10

  • The severity of the initial COVID-19 infection is closely associated with persistent end-organ damage. For example, 59% of patients who required mechanical ventilation had decreased DLCO on PFTs at 6 months compared to 29% who just required oxygen3. Similarly, patients who had acute kidney injury from severe disease had greater persistent eGFR decrease compared to non-COVID patients, independent of pre-existing comorbidities.11
  • In patients who never required hospitalization, their healthcare utilization and risk of death is much higher than those who were not infected12. The rates of persistent symptoms in this population is also very high, but chronic end-organ damage is rare.4,13 Initial reports suggest that persistent symptoms after mild disease are more common in younger adults and women.6
  • This suggests there may be different phenotypes of PASC, one comprising of hospitalized patients (who are more likely to be elderly and male) with end-organ damage, and another in patients recovering from mild disease (who are more likely to be young women) who present with more autoimmune or chronic fatigue features.

205 symptoms in 10 organ symptoms have been reported in PASC. The most common symptoms are fatigue/malaise, cough, cognitive dysfunction, altered taste/smell, and psychological disorders (anxiety, depression, PTSD). Other symptoms include dysautonomia (e.g. postural orthostatic tachycardia syndrome, or POTS), chronic GI symptoms, skin changes, and tinnitus, with the majority of patients reporting that these symptoms are relapsing and remitting.1

The underlying pathophysiology of PASC is not fully understood, but proposed mechanisms include autoimmunity/immune dysregulation, post-infectious chronic inflammation, and organ damage from direct viral toxicity or microvascular injury.7,14,15

Please review the recommended workup and treatment of common PASC symptoms organized by presenting symptom. Please check back regularly as this will be updated and expanded upon over time.

No current diagnostic test or criteria exists for PASC, so although in many cases a patient’s symptoms can be attributed to this emerging disease (especially if the patient was healthy prior to their COVID-19 illness), for now workup is focused on ruling out other causes of the symptoms or evaluating for end-organ damage that would require specific intervention.

For the majority of patients, constitutional symptoms of PASC improve gradually with time (especially when the initial illness was mild or asymptomatic).4–6 Currently no FDA approved medications or evidence-based interventions for PASC exist. Therefore, treatment consists of symptomatic management, supervised rehabilitation with a graduated exercise plan, and addressing stress and mental health comorbidities.

1. Davis, H. E. et al. Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact. http://medrxiv.org/lookup/doi/… (2020) doi:10.1101/2020.12.24.20248802.

2. Subbaraman, N. US health agency will invest $1 billion to investigate ‘long COVID’. Nature 591, 356–356 (2021).

3. Huang, C. et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. The Lancet 0, (2021).

4. Logue, J. K. et al. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw. Open 4, e210830 (2021).

5. Tenforde, M. W. et al. Characteristics of Adult Outpatients and Inpatients with COVID-19 — 11 Academic Medical Centers, United States, March–May 2020. MMWR Morb. Mortal. Wkly. Rep. 69, 841–846 (2020).

6. Huang, Y. et al. COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic. medRxiv 2021.03.03.21252086 (2021) doi:10.1101/2021.03.03.21252086.

7. Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021).

8. Chopra, V., Flanders, S. A., O’Malley, M., Malani, A. N. & Prescott, H. C. Sixty-Day Outcomes Among Patients Hospitalized With COVID-19. Ann. Intern. Med. M20-5661 (2020) doi:10.7326/M20-5661.

9. Carfì, A., Bernabei, R., Landi, F., & for the Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA 324, 603 (2020).

10. Sonnweber, T. et al. Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial. Eur. Respir. J. 57, (2021).

11. Nugent, J. et al. Assessment of Acute Kidney Injury and Longitudinal Kidney Function After Hospital Discharge Among Patients With and Without COVID-19. JAMA Netw. Open 4, e211095 (2021).

12. High-dimensional characterization of post-acute sequalae of COVID-19 | Nature. https://www.nature.com/articles/s41586-021-03553-9.

13. Joy George et al. Prospective Case-Control Study of Cardiovascular Abnormalities 6 Months Following Mild COVID-19 in Healthcare Workers. JACC Cardiovasc. Imaging 0,.

14. Vlachoyiannopoulos, P. G. et al. Autoantibodies related to systemic autoimmune rheumatic diseases in severely ill patients with COVID-19. Ann. Rheum. Dis. 79, 1661–1663 (2020).

15. Ellul, M. A. et al. Neurological associations of COVID-19. Lancet Neurol. 19, 767–783 (2020).