Long COVID: Understanding the Lingering Shadow of SARS‑CoV‑2

Long COVID, also referred to as Post-Acute Sequelae of SARS‑CoV‑2 (PASC), has emerged as a significant public health concern, affecting a substantial proportion of COVID-19 survivors. While most individuals recover within a few weeks of acute infection, an estimated 10 to 30 percent continue to experience symptoms that persist for months, regardless of whether the initial infection was mild or severe. These lingering effects can severely impact daily functioning, quality of life, and the broader healthcare system.

Symptoms and Clinical Presentation

Patients with long COVID often report a constellation of symptoms that span multiple organ systems. Fatigue is among the most commonly reported complaints, frequently accompanied by post-exertional malaise. Cognitive impairment, often described as “brain fog,” and respiratory difficulties such as persistent shortness of breath and cough are also prevalent. Cardiovascular symptoms, including palpitations and chest discomfort, are reported alongside neurological and psychological manifestations like anxiety, depression, headaches, and sleep disturbances. Gastrointestinal issues, including abdominal pain and diarrhea, have been documented in some patients, further illustrating the multi-systemic nature of this condition.

Underlying Mechanisms

Research into the mechanisms underlying long COVID is ongoing, but several hypotheses have emerged. Viral persistence may allow fragments of SARS‑CoV‑2 to remain in tissues, potentially triggering ongoing immune responses. Immune dysregulation, including chronic inflammation or the development of autoimmunity, has been observed in some patients. Endothelial dysfunction and microvascular injury may contribute to cardiovascular and neurological sequelae, while direct or immune-mediated effects on the nervous system may underlie cognitive symptoms.

Diagnosis and Assessment

Diagnosing long COVID remains a challenge, as no definitive laboratory or imaging test currently exists. Clinicians rely on a combination of patient history, symptom patterns, and the exclusion of alternative diagnoses. Comprehensive assessment may include laboratory tests for inflammation or autoantibodies, imaging studies such as CT or MRI to evaluate organ function, and functional testing, including lung function assessment or exercise tolerance evaluations.

Management Strategies

Management of long COVID is largely supportive and multidisciplinary. Symptom-directed care addresses specific complaints such as fatigue, pain, and respiratory difficulties, while rehabilitation programs may include physical therapy, occupational therapy, and cognitive rehabilitation. Mental health support is increasingly recognized as a crucial component, with counseling, cognitive behavioral therapy, and mindfulness-based interventions playing a key role. Lifestyle strategies, including pacing activities, optimizing sleep, and carefully monitored exercise, are recommended to improve overall well-being. While pharmacologic interventions remain largely supportive, ongoing research seeks to identify targeted therapies that address the underlying pathophysiology.

Research and Future Directions

Looking forward, research efforts are focusing on immunological profiling, biomarker discovery, and potential antiviral or anti-inflammatory treatments. Global initiatives such as the NIH RECOVER project and the WHO Long COVID clinical network aim to create registries and foster collaboration, which may pave the way for precision medicine approaches that tailor rehabilitation and therapy to an individual’s immune or genetic profile.

Conclusion

Long COVID represents a complex, multi-system condition with significant implications for patients and healthcare systems worldwide. Early recognition, patient-centered care, and multidisciplinary management are essential to improve outcomes and quality of life. Continued research, public education, and healthcare support are critical to addressing this emerging challenge.

References

1. Davis, H. E., Assaf, G. S., McCorkell, L., Wei, H., Low, R. J., Re’em, Y., Redfield, S., Austin, J. P., & Akrami, A. (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine, 38, Article 101019. https://doi.org/10.1016/j.eclinm.2021.101019

2. Iqbal, N. T., Khan, H., Khalid, A., Mahmood, S. F., Nasir, N., Khanum, I., de Siqueira, I., & Van Voorhis, W. (2025). Chronic inflammation in post‑acute sequelae of COVID‑19 modulates gut microbiome: A review of literature on COVID-19 sequelae and gut dysbiosis. Molecular Medicine, 31(1), 22. https://doi.org/10.1186/s10020-024-00986-6

3. Kelly, J. D., Curteis, T., Rawal, A., Murton, M., Clark, L. J., Jafry, Z., Shah‑Gupta, R., Berry, M., Espinueva, A., Chen, L., Abdelghany, M., Sweeney, D. A., & Quint, J. K. (2023). SARS‑CoV‑2 post‑acute sequelae in previously hospitalised patients: systematic literature review and meta‑analysis. European Respiratory Review, 32(169), 220254. https://doi.org/10.1183/16000617.0254‑2022 

4. Marshall, G. D., Jr. (2023). The pathophysiology of post‑acute sequelae of COVID‑19 (PASC): Possible role for persistent inflammation. Asia Pacific Allergy, 13(2), 77–84. https://doi.org/10.5415/apallergy.0000000000000106

5. Mayo Clinic. (2023). Management of patients with post‑acute sequelae of SARS‑CoV‑2 (PASC). Mayo Clinic. https://www.mayoclinic.org/medical-professionals/physical-medicine-rehabilitation/news/management-of-patients-with-post-acute-sequelae-of-sars-cov-2-pasc/mac-20538518

6. Proal, A. D., & VanElzakker, M. B. (2021). Long COVID or post‑acute sequelae of COVID‑19 (PASC): An overview of biological factors that may contribute to persistent symptoms. Frontiers in Microbiology, 12, 698169. https://doi.org/10.3389/fmicb.2021.698169

7. Soriano, J. B., Murthy, S., Marshall, J. C., Relan, P., & Diaz, J. V.; WHO Clinical Case Definition Working Group on Post‑COVID-19 Condition. (2022). A clinical case definition of post‑COVID‑19 condition by a Delphi consensus. The Lancet Infectious Diseases, 22(4), e102–e107. https://doi.org/10.1016/S1473-3099(21)00703‑9 

8. Su, Q., Lau, R. I., Liu, Q., Li, M. K. T., Mak, J. W. Y., Lu, W., Lau, I. S. F., Lau, L. H. S., Yeung, G. T. Y., Cheung, C. P., Tang, W., Liu, C., Ching, J. Y. L., Cheong, P. K., Chan, F. K. L., & Ng, S. C. (2024). The gut microbiome associates with phenotypic manifestations of post‑acute COVID‑19 syndrome. Cell Host & Microbe, 32(5), 651–660.e4. https://doi.org/10.1016/j.chom.2024.04.005 

9. Zhang, C., Hung, C.-Y., & Hsu, C. G. (2024). Epidemiology, symptoms and pathophysiology of Long COVID complications. Journal of Cellular Immunology, 6(5), 219–230. https://doi.org/10.33696/immunology.6.209 

Assessed and Endorsed by the MedReport Medical Review Board