Understanding immune dysregulation in post-acute sequelae of COVID-19 (PASC)—The hunt for effective treatments
Authors: Norman B. Gaylis, Otto O. Yang
Journal: Journal of Infection (2024)

Dear Editor, Fernandez-de-las-Peñas and colleagues reported the alarmingly high persistence of post-COVID symptoms two years after acute infection with SARS-CoV-2.1Fernandez-de-Las-Peñas C. Notarte K.I. Macasaet R. Velasco J.V. Catahay J.A. Ver A.T. et al.Persistence of post-COVID symptoms in the general population two years after SARS-CoV-2 infection: A systematic review and meta-analysis.J Infect. 2024; 88: 77-88Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The SARS-CoV-2 pandemic triggered an unprecedented mobilization of the global scientific community leading to the rapid availability of direct acting antivirals and vaccines. The introduction of these antivirals and vaccines successfully limited the spread of new cases of SARS-CoV-2 and provided options for treating the infection. However, despite these advances there is still a worryingly high number of individuals with post-acute sequelae of COVID-19 (PASC), also commonly known as long COVID. This chronic condition is characterised by heterogenous, multisystemic, signs and symptoms that continue after the initial acute phase of the SARS-CoV-2 infection has resolved. PASC may worsen over time, fluctuate in severity, and in some individuals can be highly debilitating and even life-threatening. It is estimated that in 2022, 6.9% of adults living in the USA had ever suffered PASC and 3.4% were experiencing PASC at the time of the interview with more women (8.5%) than men (5.2%) reported ever suffering PASC.2Adjaye-Gbewonyo D. Vahratian A. Perrine C.G. Bertolli J. Long COVID in Adults: United States, 2022.NCHS Data Brief. 2023; : 1-8Google Scholar Compared to a control group receiving supportive treatment alone, the occurrence of PASC is reduced by 27.5% among individuals receiving antiviral treatments during the early stages of SARS-CoV-2 infection (OR = 0.725; 95%CI = 0.409−0.747) with a 29.7% reduction in the risk of PASC-associated hospitalization and mortality (OR = 0.721; 95%CI = 0.697−0.794).3Choi Y.J. Seo Y.B. Seo J.W. Lee J. Nham E. Seong H. et al.Effectiveness of Antiviral Therapy on Long COVID: A Systematic Review and Meta-Analysis.J Clin Med. 2023; 12Crossref Scopus (1) Google Scholar In a different study among double-vaccinated versus unvaccinated participants PASC was reported by 9.5% of vaccinated individuals and 14.6% unvaccinated individuals (aOR = 0.59; 95%CI = 0.50−0.69).4Ayoubkhani D. Bosworth M.L. King S. Pouwels K.B. Glickman M. Nafilyan V. et al.Risk of Long COVID in People Infected With Severe Acute Respiratory Syndrome Coronavirus 2 After 2 Doses of a Coronavirus Disease 2019 Vaccine: Community-Based, Matched Cohort Study.Open Forum Infect Dis. 2022; 9ofac464Crossref PubMed Scopus (45) Google Scholar Despite the positive impact of antiviral treatments and vaccinations on the occurrence of PASC it remains a significant burden for many people. In the study reported by Fernandez-de-las-Peñas and colleagues they describe the results from a meta-analysis across 12 studies including 7912 COVID-19 survivors.1Fernandez-de-Las-Peñas C. Notarte K.I. Macasaet R. Velasco J.V. Catahay J.A. Ver A.T. et al.Persistence of post-COVID symptoms in the general population two years after SARS-CoV-2 infection: A systematic review and meta-analysis.J Infect. 2024; 88: 77-88Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar They summarised post-COVID symptoms approximately 2 years after infection and reported that the most prevalent post-COVID symptoms were fatigue (28.0%; 95%CI = 12.0−47.0), cognitive impairment (27.6%; 95%CI = 12.6−45.8), and pain (8.4%; 95%CI = 4.9−12.8). Thus not only is PASC a debilitating and potentially life-threatening condition it can persist for at least two years in some individuals. Considering the huge numbers of people suffering PASC globally, and its persistence over time, there is a considerable burden of disease associated with PASC, and an urgent need to better understand and ultimately treat PASC. A significant barrier to developing effective treatments for PASC is that currently the exact pathophysiology of PASC is poorly understood. However, most theories suggest that PASC is driven, at least in part, by immune dysregulation. We performed an exploratory study in 55 individuals with PASC who were randomly assigned to receive either leronlimab or placebo.5Gaylis N.B. Ritter A. Kelly S.A. Pourhassan N.Z. Tiwary M. Sacha J.B. et al.Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome.Clin Infect Dis. 2022; 75: 1232-1234Crossref PubMed Scopus (10) Google Scholar Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody. CCR5 plays a role in a number of diseases including acute severe COVID-19 where leronlimab is believed to resolve inappropriate inflammation through its interaction with CCR5.6Patterson B.K. Seethamraju H. Dhody K. Corley M.J. Kazempour K. Lalezari J. et al.CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14.Int J Infect Dis. 2021; 103: 25-32Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar We postulated a priori that PASC is mediated by persisting inflammation after acute COVID-19. We explored changes in symptom severity scores through day 56 for 24 common symptoms reported in individuals with PASC. Overall the mean symptom score changes from baseline to the latest available time point from day 30−56 was −16.0 and −12.0 for leronlimab and placebo, respectively. Of importance a greater numerical decrease in symptom severity score was seen for 19 of the 24 symptoms for leronlimab treated individuals compared to placebo treated individuals (Fig. 1). However, it is important to note that the trial was not powered for statistical comparisons between treatments. The trial also observed significantly increased blood cell surface CCR5 from baseline to day 56 in leronlimab treated symptomatic responders but not in leronlimab treated non-responders or those participants who received placebo. To our surprise, rather that showing that PASC is mediated by persisting inflammation after acute COVID-19 we had to conclude that at least in some individuals with PASC there is an unexpected immune downmodulation prior to leronlimab treatment which was normalized after leronlimab treatment.5Gaylis N.B. Ritter A. Kelly S.A. Pourhassan N.Z. Tiwary M. Sacha J.B. et al.Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome.Clin Infect Dis. 2022; 75: 1232-1234Crossref PubMed Scopus (10) Google Scholar Interestingly, this could be an explanation for the widely reported proposed link between Epstein-Barr Virus (EBV) reactivation among individuals with PASC. A further signal that immune dysregulation is a central feature of PASC is that emerging data suggests that autonomic dysfunction, which is commonly associated with other autoimmune and chronic inflammatory diseases, is commonly seen in individuals with PASC. Clearly the results of our trial are intriguing and suggest that immune dysregulation is a consistent factor in PASC. Our results, and those of others, strongly suggest that more efforts are needed to understand the role of the immune system in PASC and to explore the potential role of immunomodulators in the treatment of PASC. While the results of our trial are certainly encouraging what is less encouraging is the apparent lack of mobilization of the wider scientific community to find an effective treatment for PASC. Although we must acknowledge that some studies have proposed potentially effective treatments including, but not limited to, nutraceuticals,7Gaylis N.B. Kreychman I. Sagliani J. Mograbi J. Gabet Y. The results of a unique dietary supplement (nutraceutical formulation) used to treat the symptoms of long-haul COVID.Front Nutr. 2022; 91034169Crossref PubMed Scopus (1) Google Scholar hyperbaric oxygen,8Hadanny A. Zilberman-Itskovich S. Catalogna M. Elman-Shina K. Lang E. Finci S. et al.Long term outcomes of hyperbaric oxygen therapy in post covid condition: longitudinal follow-up of a randomized controlled trial.Sci Rep. 2024; 14: 3604Crossref PubMed Scopus (0) Google Scholar and home-based, supervised, group physical and mental health rehabilitation.9McGregor G. Sandhu H. Bruce J. Sheehan B. McWilliams D. Yeung J. et al.Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial.Bmj. 2024; 384e076506PubMed Google Scholar Worryingly a recent study by Bonuck and colleagues explored burden-commensurate funding for the top YLD (years of health life lost due to disability) conditions and for female versus male dominant conditions and found that PASC research funding is lagging behind its disability burden.10Bonuck K. Gao Q. Congdon S. Kim R. Long COVID Disability Burden in US Adults: YLDs and NIH Funding Relative to Other Conditions.medRxiv. 2024; (2024.01.09.24301057)Google Scholar The authors also pointed out that females are disproportionately affected by PASC and that there is evidence to suggest that other female dominated conditions also suffer from less research funding.10Bonuck K. Gao Q. Congdon S. Kim R. Long COVID Disability Burden in US Adults: YLDs and NIH Funding Relative to Other Conditions.medRxiv. 2024; (2024.01.09.24301057)Google Scholar Taken together we can be encouraged by the tremendous advances made in the last 3-4 years which has led to the availability of antiviral treatments and vaccines for SARS-CoV-2 but research into PASC needs to be dramatically increased and prioritized in line with the significant burden of disease. Immunomodulators remain potentially effective treatments for PASC but without a concerted effort from funding agencies and researchers alike progress will lag behind and PASC will remain a huge burden for millions of people around the world. The authors received no specific funding for this work.