Author(s): Brionn K. Tonkin, MD, Aldo Salgado-Hernandez, MD, Alyssa Axelrod, BS
Originally published: April 10, 2024 Last updated: April 10, 2024
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Disease/Disorder

Definition

With evolution of the pandemic and more study, the definition and criteria for this condition have evolved and there continue to be several definitions in use. We use the World Health Organization’s definition of post-acute sequela of the SARS-CoV2 infection (PASC): A constellation of symptoms following acute viral infection usually within three months. These symptoms will last for 2 months and cannot be explained by an alternative diagnosis.1

Etiology

Two proposed mechanisms following acute viral infection include (1) end-organ damage from the viral infection itself and (2) effects and subsequent damage from the prolonged immune response. Future work will continue to clearly elucidate the etiology which should better inform treatments.2

Epidemiology including risk factors and primary prevention

In 2022 the National Institutes of Health (NIH) used a population-representative survey that found a prevalence of PASC at 7.3% of the population. It also found that the prevalence of PASC was higher in women, patients that had comorbidities, and among those that were not boosted or vaccinated.3 Identified comorbidities that can increase the risk of someone developing PASC include obesity, diabetes, and chronic lung disease. Socioeconomic status is also likely to play a role in risk of developing PASC following acute infection.4

Estimates of the incidence of PASC range from 7.5 to 38%, oftentimes depending on the definition and diagnostic criteria used.5,6

Patho-anatomy/physiology

Similar to other aspects of this condition, there are evolving theories about the pathophysiology of PASC. Endothelial dysfunction seems to be the most supported theory followed by immune system dysregulation, but other evolving theories include auto-immunity, occult viral persistence, and coagulation activation.2 Pathophysiology of PASC may differ between organ systems based on specific immune modulators. For example, hematologic effects seem to implicate autoantibodies to IFN-I and certain antinuclear antibodies.7 Another example is that SARS-CoV2 specific T-cells have been found to be present for much longer duration than would be expected and are thought to contribute to the pulmonary manifestations of PASC.8

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

While some in the literature have considered it a phase of the acute viral illness, PASC is generally defined as a post-acute syndrome and the diagnosis is made after the acute infection. It consists of prolonged symptoms that can change with time. Phases of PASC itself have not been reliably described. It is classified as a chronic disease lasting beyond three months.

Essentials of Assessment

History

Any patient with new or persistent symptoms lasting more than 12 weeks after acute infection should have an assessment for PASC. It is crucial to rule out other causes for the clinical presentation, such as complications from COVID-19, preexisting underlying conditions, or other etiologies.9 The main goal of the history is to assess the timeframe and breadth of symptoms. As the distribution of symptoms is widespread, a full history of infection and course, as well as a review of systems should be done. Using a developed tool like the Yorkshire Rehabilitation screening tool or another one could be helpful.

Physical examination

Vital signs and anthropometric measurements are important parts of our exam. We should also evaluate the patient with ambulatory pulse oximetry and orthostatic vital signs, especially if the patient presents with fatigue, respiratory symptoms, and or postural symptoms.10 Further examination should be focused on the organ systems affected based on patient symptom report. This would include almost all systems but neurological, musculoskeletal, HEENT, and cardiopulmonary are likely to be included. An additional goal of the physical examination is to help with ruling out other causes for the existing symptoms.

Functional assessment

It is recommended to do a functional assessment initially and on subsequent visits to evaluate progress, although there are no strong recommendations as to which tests to use. There are several tests that could be used, among them the sit-to-stand test or the Short Physical Performance Battery.9 Serial testing could help us readjust our interventions by assessing the patient’s progress.

Laboratory studies

Tests should be done according to symptoms and to rule out other underlying conditions. C-reactive protein, erythrocyte sedimentation rate, complete blood count, kidney function tests, and liver function tests are good general initial tests. Cardiac enzymes and B-type natriuretic peptides are appropriate to evaluate when there are cardiac symptoms. We can evaluate thyroid function tests, A1c levels, and fasting glucose to evaluate thyroid disease and diabetes, respectively.9 Laboratory studies can aid us to exclude diseases or uncover underlying conditions that might explain the patient’s symptoms.

Imaging

If persisting respiratory symptoms, an initial chest X-ray can help rule out other underlying conditions, although a chest CT would be a better option to assess structural changes in the lungs. Persisting changes could be observed for months following an acute COVID infection, and this should be taken into consideration. TTE can be considered to evaluate if experiencing cardiac symptoms to rule out a myocardial injury. Currently, there is no strong evidence for brain imaging on PASC.9 Imaging, overall, will help to assess structural changes in affected systems and to exclude other etiologies.

Supplemental assessment tools

Supplemental tests can be ordered depending on predominant symptoms. If there is persistent dyspnea or if there is a history of severe COVID-19 infection, PFTs and diffusion capacity can be obtained.9 Different testing modalities are being studied and developed, such as methods for detecting microclots, tests to analyze QRS complex changes, and different biomarkers.12 Though in development, most of these are symptom specific tests and clinical utility, sensitivity, specificity, etc. remain to be evaluated.

Early predictions of outcomes

Disease severity, ICU stay, performance in functional tests, and laboratory tests such as altered cardiac enzymes, higher viral loads, or inflammatory markers such as CRP during active COVID-19 infection can be early predictors for cardiovascular sequela in PASC. Admission to ICU, medications used during admission, such as corticosteroids, encephalopathy during acute illness, and illness severity can be predictors for developing neuropsychiatric sequela.13

Environmental

Factors like location, work environment, ethnicity, and vulnerable groups such as older and or disabled people are at greater risk for developing PASC.11,14 Being unable to have adequate healthcare due to a lack of resources, accessibility, and cultural barriers seems to increase the risk of acquiring the disease and thus sequela.

Social role and social support system

Health inequities already increase the risk of acquiring COVID and also contribute to the risk of developing PASC. Developing PASC can incapacitate patients from returning to work, prevent them from returning to their daily activities, limit their social involvement, and impact their mental health.11,14 Social services should be involved when identifying these situations.

Professional issues

There are further studies needed to improve management, assess patient outcomes, and better understand disease progression over the long term. Unfortunately, PASC is a recent occurrence; moving forward, we should also target to identify ways to improve its social impact, as well as to recognize the ethical implications of health inequities.9,14

Rehabilitation Management and Treatments

At different disease stages

New onset/acute

The management of COVID depends both on the severity and acuity of the illness. Treatments for acute COVID include antivirals, assistive oxygenation devices for more severe respiratory symptoms, and antipyretics, over the counter pain relievers, and rest for more mild symptoms.15 Those with severe Covid and prolonged ICU stay and/or respiratory support are at risk for post-ICU syndrome with symptoms such as pain, weakness, and dyspnea.16 Thus, PT and OT are used for severe Covid patients to prevent deconditioning and hasten return to normal.

Subacute

Paxlovid administered within the first few days of acute COVID infection may be a preventative factor in developing PASC. Management of symptoms and rehabilitation strategies are individualized due to variability of symptoms but should incorporate an interprofessional approach targeting both clinical and psychological effects of this disorder.17

Chronic/stable

Unfortunately, PASC seems to be more and more common as further research is conducted and more is known about possible sequelae. The best strategies for preventing post-COVID syndrome are to take antivirals during the acute phase, and to get vaccinated in order to prevent re-infection, as re-infection has been shown to increase the risk of PASC.18 Those diagnosed with PASC need rehabilitation focused on neurological and psychological symptoms, cardiopulmonary sequelae, and fatigue as these are the most common symptoms associated with this disease.17 Overall, an interdisciplinary, holistic patient-centered approach is what is required to best optimize functional improvement and symptom relief.

Pre-terminal or end of life care

Although atypical for PASC, end of life care for those with terminal COVID should focus on pain relief and management of patient comfort. While functional improvement is no longer the goal, physiatry can still be incredibly useful in managing functional comfort and maximizing patient independence. It is also essential to involve palliative care, psychology, spiritual support, and social work to work with both the patient and their family.

Coordination of care

The coordination of a patient’s healthcare and social needs helps reduce costs and high healthcare utilization by addressing a patient’s biopsychosocial needs. Most commonly, care coordination is conducted through a team-based structure involving physicians, nurses, social workers, and specialists. For PASC patients this team will usually focus on rehabilitation and functional improvement, and often consist of physiatrists, physical therapists, and occupational therapists.

Patient & family education

When discussing PASC with patients and their families it is important to emphasize that each patient’s symptoms, timeline, and rehabilitation journey will be unique as COVID causes an extensive variety of symptoms. Therefore, predicting speed and extent of progress is difficult due not only to this variability, but also to the fact that not enough research has yet been conducted.

Measurement of treatment outcomes

One study involving countries around the world finalized a core outcome set for post-COVID syndrome focusing on outcomes that mattered most to patients. The outcomes considered most important as a measurement of improvement included post-exertion symptoms, fatigue or exhaustion, work or occupational changes, survival, and symptoms and functioning of the cardiovascular, nervous, respiratory, mental health, and cognitive systems.18 Another study found the following criteria to be most important in determining treatment outcomes: whether the person can live alone without assistance, if there are activities they are no longer able to perform, if they need to avoid or reduce activities, and if they have continuing symptoms.19

Cutting Edge/Emerging and Unique Concepts and Practice

N/A

Gaps in the Evidence-Based Knowledge

There still exist many gaps in knowledge in regard to COVID and rehabilitation. The risk factors for post-covid sequelae are not entirely understood or categorized. While some studies have shown that age and sex play a factor, the only truly conclusive risk factor documented is severity of acute Covid infection.20 With limited ability to prevent acute infection, and minimal knowledge on prevention of PASC, the management of post-Covid syndrome continues to be difficult. Additionally, because there is such a broad range of possible sequelae, and each person is affected differently regardless of initial severity, it is challenging to preemptively determine a rehabilitation plan for a patient and requires constant adjustments as new symptoms develop or existing symptoms change. Therefore, it is essential to continue to study post-Covid sequelae and efficacy of rehabilitation management.

References

  1. Soriano J, et al. A clinical case definition of post COVID-19 condition by a Delphi consensus. World Health Organization, Oct 2021.
  2. Castaneres-Zapatero D, et al. Pathophysiology and Mechanism of Long-COVID: A Comprehensive Review. Annals of Medicine. 2022 Dec;54(1):1473-1487
  3. Robertson MM, et al. The Epidemiology of Long Coronavirus Disease in US Adults, Clin Infect Dis. 2023 May 3;76(9):1636-1645
  4. Peluso MJ, Deeks SG. Early clues regarding the pathogenesis of long-covid. Trends in Immunology. 2022 Apr; 43(4): 268–270
  5. Melamed E, et al. Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of neurologic sequelae in patients with post-acute sequelae of SARS-CoV-2 infection (PASC). PM&R. 2023;15:640–662
  6. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220622.htm. Accessed 11/8/2023
  7. Ahamed J, et al. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches. J Clin Invest. 2022;132(15)
  8. Littlefield KM, Watson RO, Schneider JM, Neff CP, Yamada E, Zhang M, et al. (2022) SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2. PLoS Pathog 18(5): e1010359. https://doi.org/10.1371/journal.ppat.1010359
  9. Yelin D, Moschopoulos CD, Margalit I, Gkrania-Klotsas E, Landi F, Stahl JP, Yahav D. ESCMID rapid guidelines for assessment and management of long COVID. Clin Microbiol Infect. 2022 Jul;28(7):955-972. doi: 10.1016/j.cmi.2022.02.018. Epub 2022 Feb 17.
  10. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html#symptom-condition-assessment
  11. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
  12. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023 Mar;21(3):133-146. doi: 10.1038/s41579-022-00846-2. Epub 2023 Jan 13. Erratum in: Nat Rev Microbiol. 2023 Jun;21(6):408
  13. Joshee S, Vatti N, Chang C. Long-Term Effects of COVID-19. Mayo Clin Proc. 2022 Mar;97(3):579-599. doi: 10.1016/j.mayocp.2021.12.017. Epub 2022 Jan 12
  14. Aiyegbusi OL, Hughes SE, Turner G, Rivera SC, McMullan C, Chandan JS, Haroon S, Price G, Davies EH, Nirantharakumar K, Sapey E, Calvert MJ; TLC Study Group. Symptoms, complications and management of long COVID: a review. J R Soc Med. 2021 Sep;114(9):428-442
  15. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management-of-adults/nonhospitalized-adults–therapeutic-management/
  16. Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, wt al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation. .J Med Virol. 2020 Jul 30. doi: 10.1002/jmv.26368.
  17. Chippa V, Aleem A, Anjum F. Post-Acute Coronavirus (COVID-19) Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570608/
  18. Al-Aly Z. Prevention of long COVID: progress and challenges. Lancet Infect Dis. 2023 Jul;23(7):776-777. doi: 10.1016/S1473-3099(23)00287-6. Epub 2023 May 5.
  19. Klok FA, et al. The Post-COVID-19 Functional Status scale: a tool to measure functional status over time after COVID-19. European Respiratory Journal 2020 56: 2001494
  20. Najafi MB, Javanmard SH. Post-COVID-19 Syndrome Mechanisms, Prevention and Management. Int J Prev Med. 2023 May 24;14:59.

Author Disclosure

Brionn K. Tonkin, MD
Nothing to Disclose

Aldo Salgado-Hernandez, MD
Nothing to Disclose

Alyssa Axelrod, BS
Nothing to Disclose