fatigue and brain fog. Ivabradine has become an important alternative for patients whose tachycardia persists or whose cognitive symptoms worsen with beta-blockers. Ongoing studies may better clarify its role in long COVID dysautonomia. Systemic inflammation also appears to play a major role in long COVID symptoms. Low-dose naltrexone (LDN) has generated interest because, at low doses, it may reduce neuroinflammation through immune-modulating effects rather than traditional opioid receptor blockade. Because LDN requires compounding, pharmacy quality and consistency matter. Microvascular dysfunction and micro-thrombotic disease may also contribute to chronic inflammation and tissue injury in PASC. One of the most compelling emerging theories involves viral persistence. Multiple studies have identified SARS-CoV-2 RNA or protein in tissues months to years after acute infection, even after mild illness. Proposed downstream effects include: • Chronic immune activation and T-cell exhaustion • Autoimmunity through molecular mimicry • Endothelial inflammation and microthrombosis • Gut microbiome disruption • Neuroimmune dysfunction involving the brainstem and spinal cord • Reactivation of latent herpesviruses such as Epstein-Barr virus These findings have pushed researchers toward antiviral-based treatment strategies. Although there is still no FDA-approved treatment for long COVID, several investigational combination therapies are being explored. One of the most discussed is IMC-2 combined with nirmatrelvir-ritonavir (Paxlovid), targeting both SARS-CoV-2 persistence and herpesvirus reactivation. Other proposed therapies include maraviroc with pravastatin, colchicine, and additional antiviral or immunomodulatory combinations, though evidence quality remains limited. Long COVID has had a major impact on healthcare workers, with estimates of 7-18% feeling unable to return to full-time work. Under the Americans with Disabilities Act (ADA), long COVID may qualify as a disability, especially when associated with post-exertional malaise (PEM). Cardiopulmonary exercise testing (CPET) can objectively demonstrate exertional impairment, but in some patients, it may also provoke severe and prolonged symptom flares and should be undertaken with caution. Supportive multidisciplinary care remains essential. Occupational, physical and speech therapy can help patients develop pacing strategies, cognitive adaptations and practical workarounds for daily activities. Figure 1 shows a useful pacing method for scanning your mental and physical energy when you first wake up in the morning. Importantly, graded exercise therapy is generally discouraged in patients with post-exertional malaise (PEM), as it has been repeatedly proven to worsen symptoms rather than improve them. We understand far more about long COVID than we did in 2020, but there is still a great deal left to learn. For many clinicians and patients, it remains a frustrating, evolving and deeply human illness — one that continues to challenge many of the assumptions we once had about recovery after viral disease. REFERENCES A complete list of references for this article appears in the online version, which you can access by scanning the QR code. https://uafp-journal.thenewslinkgroup.org/long-covid-management/ Figure 1: Daily Traffic Light Pacing Strategy. Courtesy of Dallin Sudbury, OT, modified for clarity by author. 23
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