Postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID or post−COVID-19 condition, has affected millions of people worldwide and encompasses a variety of conditions and symptoms that can persist months to years with impact on quality of life and function.^1-6 Evolving definitions, growing mechanistic understanding, and clinical heterogeneity present challenges to the diagnosis and treatment of PASC.^7-9 There is an urgent need for evidence-based treatments for PASC but currently a paucity of published trials testing interventions that target underlying pathophysiology.^10-13

BACKGROUND: Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive. METHODS: Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit. RESULTS: Our cohort ( n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution. CONCLUSION: We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04373148. FUNDING: NIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

The global prevalence of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) stands at approximately 43 % among individuals who have previously had acute COVID-19. In contrast, in the United States, the National Center for Health Statistics (NCHS) estimates that around 11 % of individuals who have been infected with SARS-CoV-2 go on to experience long COVID. The underlying causes of PASC remains under investigation, and there are no currently established FDA-approved therapies. One of the leading hypotheses for the cause of PASC is the persistent activation of innate immune cells with increase systemic inflammation. Naltrexone is a medication with anti-inflammatory and immunomodulatory properties that has been used in other conditions that overlap with PASC. We performed a retrospective review of a clinical cohort of 59 patients at a single academic center who received low-dose naltrexone (LDN) off-label as a potential therapeutic intervention for PASC. The use of LDN was associated with a fewer number of symptoms, improved clinical symptoms (fatigue, post-exertional malaise, unrefreshing sleep, and abnormal sleep pattern), and a better functional status. This observation warrants testing in rigorous, randomized, placebo-controlled clinical trials.

Post-acute sequelae of SARS-CoV-2 (PASC) or long COVID is a major public health problem. The underlying mechanism(s) of this disease remains unclear, and there is a lack of effective therapies. We report a case of a 47-year-old patient who experienced breakthrough acute COVID-19 with PASC after two doses of COVID-19 vaccination, and its symptom resolution following a course of the novel combination of antiviral nirmatrelvir-ritonavir. One of several leading hypotheses on the pathogenesis of PASC is a persistent viral reservoir. This case report raises important questions on the potential role of antiviral therapies in long COVID, and the need for further research and clinical trials in this field of study.

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Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID, is a major public health problem. Encouraging data suggest that vaccination can reduce the risk of PASC. We report a cautionary case of breakthrough PASC and its resolution following a course of the novel combination antiviral nirmatrelvir-ritonavir.