Unraveling Links Between Chronic Inflammation and Long COVID: Current State, Challenges, and Opportunities (Abstracts)

Dysregulated immune responses in autoimmune diseases (ADs) “prime” the immune cells for an increase in production of proinflammatory cytokines (e.g., the type I interferons) upon an infection. Of interest, the development of certain common ADs (e.g., Sjogren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis) exhibits a female gender bias. Further, these ADs exhibit a female gender bias in activation of the type I interferon (IFN) response and an “IFN-signature” (an increase in the levels of type I IFN-inducible mRNAs) in immune cells due to activation of the cGAS-STING pathway by the IFN-stimulatory DNA (ISD). A constitutive activation of the pathway in aged (senescent) cells is associated with paracrine senescence and inflammaging. Notably, senescent cells accumulate in tissues and organs with human aging and in chronic inflammatory conditions. In the SARS-CoV-2 (COVID-19) virus infected patients, the lung pathology in the late phase of the infection is associated with activation of the ISD pathway, accumulation of senescent cells and senescence-associated secretory phenotype (SASP). The SASP promotes paracrine senescence. Interestingly, COVID-19 virus infection in human cells activated a DNA damage response and the LINE-1 (L1) retrotransposon element (TE). These responses activate the ISD pathway. Consequently, the viral infection leads to activation of the type I IFN response, accumulation of senescent cells, SASP, and chronic inflammation. Therefore, chronic activation of proinflammatory pathways by the COVID-19 virus in individuals with an AD has implications for gender and age-dependent increases in the risk to develop “long COVID”. Although, the mRNA vaccine against the SARS-CoV-2 virus is safe in AD patients, an improved understanding of the molecular interactions between the virus and proinflammatory pathways has potential to identify new therapeutic approaches to treat “long COVID” patients.

David Bann, PhD; George Ploubidis , PhD; Alissa Goodman, PhD; Richard J Silverwood, PhD

Background: Longer exposure to obesity, and thus a longer period in an inflamed state, may increase susceptibility to infectious diseases and worsen severity. Previous cross-sectional work finds higher BMI is related to worse COVID-19 outcomes, but less is known about associations with BMI across adulthood.
Methods: To examine this, we used body mass index (BMI) collected through adulthood in the 1958 National Child Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Participants were grouped by the age they first became overweight (>25kg/m2) and first became obese (>30kg/m2). Logistic regression was used to assess associations with COVID-19 (self-reported and serology-confirmed), severity (hospital admission and contact with health services) and long-COVID reported at ages 62 (NCDS , n= 7,769) and 50 (BCS70, n= 7,168).
Results: An earlier age at which participants first experienced obesity was associated with increased odds of adverse COVID-19 outcomes, but results were mixed and often underpowered. Those with an earlier exposure to obesity were over twice as likely in NCDS (odds ratio (OR) 2.15, 95% confidence interval (CI): 1.17 to 4.00) and three times as likely in BCS70 (OR 3.01, 95% CI: 1.74 to 5.22) to have long COVID. In NCDS they were also over four times as likely to be admitted to hospital (OR 4.69, 95% CI: 1.64 to 13.39). Most associations were somewhat explained by contemporaneous BMI or self-reported health, diabetes or hypertension; however, the association with hospital admission in NCDS remained.
Conclusion: An earlier age in which cohort members first experience obesity onset is related to COVID-19 outcomes in later life, providing evidence on the long-term impact of raised BMI on infectious disease outcomes in midlife.

The heart is suspected to play an important role in long COVID due to its proximity to the lungs and the myriad of pathologic changes identified in this organ during the acute phase of SARS-CoV-2 infection including myocarditis, myocardial macrophage infiltration, pericarditis, microthrombi, acute myocardial strain injury, acute myocardial ischemic injury, and SARS-CoV-2 viral infiltration and infection. Also, some of the symptoms of long COVID could be explained by cardiac dysfunction. While there have been numerous studies examining the cardiac pathology in the early acute phase and extended acute phase of COVID-19, up to 60 days from infection, there have been very few studies examining the cardiac pathology in the post-acute phase of the disease, beyond 60 days from infection. In the post-acute phase, viral persistence in the myocardium has been shown to be present in some patients. Likewise, cardiac pathological changes seen in the acute phases along with fibrous scarring can be seen in the hearts of patients in the post-acute phase. However, these changes are not entirely specific, and large studies correlating these cardiac pathologic changes and viral persistence with symptoms of long COVID are needed. In addition, the very low levels of virus being detected in the heart in the post-acute phase will require careful consideration of the methodologies to be best utilized for determining viral persistence and avoiding potential molecular confounders, such as the presence of SARS-CoV-2 vaccines. Finally, transcriptomic analyses should help elucidate the molecular changes of the cardiac tissue response in patients with long COVID.

Arman Fesharaki-Zadeh, M.D.

Long-COVID is frequently associated with debilitating cognitive deficits, colloquially referred to as “brain fog”. Characterization of these symptoms has revealed a consistent impairment in the functions of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves higher cognition. The dlPFC is needed for abstract reasoning, working memory and memory recall, the executive functions (e.g. planning and organization) and the top-down control of thought, action and emotion, including the ability to concentrate and focus, and protection against depression. Research in macaques has shown that the dlPFC has unusual molecular requirements that makes it especially vulnerable to inflammatory insults. These include a reliance on NMDA and nicotinic alpha-7 receptor neurotransmission, disrupted by kynurenic acid (KYNA) inflammatory signaling, and mGluR3 regulation of potassium channels, which is weakened by GCPII inflammatory signaling. Studies of animals have shown that N-acetyl cysteine (NAC) and the alpha-2A-adrenoceptor agonist, guanfacine, can restore dlPFC function in aged macaques with naturally-occurring KYNA and GCPII inflammation, likely through anti-inflammatory actions, including inhibition of KYNA production, and restoring cAMP regulation in dlPFC, respectively. Our recent, open label data from patients with cognitive deficits from long-COVID suggest that the combination of NAC and guanfacine (1-2mg) can markedly improve cognitive functioning (Fesharaki et al, Neuroimmunology Reports 3: 100154, 2023; https://www.sciencedirect.com/science/article/pii/S2667257X22001000), suggesting a path forward for those suffering from these symptoms.
If interested, see:
Fesharaki Zadeh A, Arnsten AFT, Wang M. Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID. Neurol Int. 2023 May 31;15(2):725-742. doi: 10.3390/neurolint15020045. PMID: 37368329; PMCID: PMC10303664.
Arnsten AFT, Ishizawa Y, Xie Z. Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders. Mol Psychiatry. 2023 Apr 7:1–13. doi: 10.1038/s41380-023-02057-4. Epub ahead of print. PMID: 37029295; PMCID: PMC10080530.

COVID-19- associated coagulopathy (CAC) is an acute, life-threatening complication of infection with SARS-CoV-2 that can result in thrombosis in multiple organs and tissues. Research on the underlying cellular and molecular mechanisms driving this condition has provided some answers but has also raised many more questions. Current thinking is that CAC derives from interactions between the immune response—particularly, the innate immune system—and coagulation, fibrinolytic and complement pathways, together with contributions from cells such as platelets and the vascular endothelium. A better understanding of the pathogenesis of CAC is required to mitigate the acute thrombotic risk in COVID-19, and this is even more urgent for understanding the contributions of CAC to long-COVID.

The gastrointestinal tract (GI) is targeted by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to its high physiological expression of ACE-2. During Acute COVID-19 infection, the GI tract shows evidence of attenuated inflammation. Additionally, in patients who have recovered from COVID-19, protracted presence of SARS-CoV-2 proteins and mRNA is noted. This leads to the speculation that lack of sterilizing immunity in the GI tract during acute COVID results in viral persistence, that may fuel manifestations of Long COVID. That said, to date, we and others have not been able to culture replication competent SARS-CoV-2 from the GI tract. This presentation examines GI involvement in patients with COVID and discusses the underlying pathophysiological mechanisms that include viral persistence and mucosal and systemic immune dysregulation. Due to the complex and potentially multifactorial nature of this syndrome, rigorous clinical definitions and pathophysiology-based therapeutic approaches are warranted.

Nikolaos Kotsiou, Bsc; Styliani Kokkori, MD PhD

Given the worldwide impact of COVID-19 and the uncertain long-term sequelae, better understanding of long COVID-19 predictors is of utmost importance. Similar to severe COVID-19, endothelial dysfunction might be commonly associated with COVID-19 sequelae. Our group has shown that complement-related variants along with gender differences predict COVID-19 morbidity and mortality. These findings were replicated not only in adults, of Caucasian and other origin, but also in children with severe infections. In an effort to utilize routine diagnostic markers, we created an artificial intelligence model that predicted COVID-19 outcomes with high accuracy. Regarding traditional risk factors, increased BMI, dyslipidaemia, and decreased physical endurance 6 months after COVID-19 have also predicted a higher risk of
metabolic disorders and cardiovascular complications, supporting the hypothesis of endothelial dysfunction as a primary driver of COVID-19 sequelae.
In conclusion, although no accurate prediction models exist for who will develop severe COVID-19 or sequelae, risk factors of vascular damage have emerged
as important predictors. Large and high-quality studies are needed utilising multidisciplinary teams not only from different medical specialties but also from
computational scientists that could suggest novel predictive models for the development of COVID-19 sequelae.

Covid-19: challenges for Neurology
Since the outbreak of the pandemic in 2020, all medical sub-specialities have been challenged in organizational, scientific, socioeconomic and educational activities. Prof. Helbok will provide some insight into initiatives taken by the European Academy of Neurology, the World Federation of Neurology and the WHO (Global COVID-19 Neuro Research Coalition) among others to guide clinicians and support science during the acute outbreak and throughout the pandemic. Furthermore, he will elude on the role of neurology in understanding neurological manifestations of COVID-19 during the pandemic and ongoing involvement in the care of patients suffering from post COVID-19 condition. Finally, the effect of COVID-19 on neurology training programs, telemedicine and research activities will be discussed.

Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a major public health crisis with estimates of over 25 million PASC cases in the United States alone. PASC encompasses various conditions and symptoms, such as fatigue, brain fog, and dyspnea, that develop in about 10% of individuals after an acute COVID-19 infection and can last for months or years with significant impact on quality of life and function. Several hypotheses have been proposed to explain the multiple symptoms present in the Post COVID-19 conditions, including viral persistence, dysregulated immune system, clotting abnormalities and dysbiosis. NIH launched the Researching COVID to Enhance Recovery (RECOVER), as a trans-NIH platform to characterize PASC prevalence, including the symptoms, natural history, and distinct phenotypes of PASC. Additionally, the goal is to define the biological mechanisms underlying PASC pathogenesis. This presentation will outline the study design implemented for RECOVER and share results on symptoms associated most strongly with a PASC phenotype as well as symptoms that appear to be co-associated.

Jin-Gyu Z Cheong, ; Arjun Ravishankar, MD; Christopher N. Parkhurst, MD, PhD; Simon Grassmann, PhD; Paoline Laurent, PhD; Robert E. Schwartz, MD, PhD; Jason Buenrostro, PhD; Rachel E. Niec, MD, PhD; Franck J. Barrat, PhD; Lindsay Lief, MD; Joseph Sun, PhD; Duygu Ucar, PhD

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether systemic inflammation, such as that caused by severe coronavirus disease 2019 (COVID-19), triggers innate immune memory in hematopoietic cells is unknown. We found that circulating hematopoietic stem and progenitor cells (HSPC), enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of HSPC epigenomic changes following COVID-19. Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to one year following severe COVID-19 and were associated with distinct transcription factor activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underly altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Emily Pfaff, PhD; Andrew Girvin, PhD; Richard Moffitt, PhD; Christopher Chute, MD, MPH

Post-acute sequelae of SARS-CoV-2 infection, or long-COVID, have severely impacted recovery from the pandemic for patients and society alike. This new disease is characterized by evolving, heterogeneous symptoms, which not only makes it a challenge to derive an unambiguous long-COVID definition, but hampers clinicians' ability to offer effective and timely treatment. Clinicians and patients report distinct albeit overlapping spectra of symptoms making long-COVID classification difficult for diagnosis and care management, and a gold standard definition of long-COVID remains elusive and even controversial. Electronic Health Records (EHRs) could aid in rapidly identifying patients with long-COVID. However, the aforementioned overlapping and incomplete spectra of symptoms make harvesting the correct data from heterogeneous EHR databases a significant challenge. The National COVID Cohort Collaborative (N3C) is a partnership across US academic medical centers (>232) to harmonize and link EHR data from >20M unique patients across research networks. The N3C has implemented an open team science approach to navigate the societal, technical, regulatory, and clinical obstacles to sharing, linking, and analyzing EHR data. Using the N3C, we developed XGBoost machine learning models to identify potential long-COVID patients. We examined demographics, healthcare utilization, diagnoses, and medications for adult COVID-19 patients. Our models identified potential long-COVID patients with high accuracy, with important features including rate of healthcare utilization, patient age, dyspnea, and other diagnoses and medications. Combinatorial approaches such as these are especially useful in the face of a new disease with different patient trajectories and few treatment options, and can provide the basis for research studies, public health surveillance, and treatment selection. The impact of the N3C data and community has been tremendous, with >200 manuscripts/preprints; changed Covid patient care guidelines (in multiple countries); White House & State requests for data; and the NIH & FASEB Dataworks! Grand Prize.

Rafi Ahmed,

In an ongoing longitudinal COVID-19 cohort established early in the pandemic, we evaluated the durability of immune memory and changes associated with Long COVID. Among ~600 participants enrolled, ~25% experienced continued or new symptoms post-infection associated with Long COVID. Among these, ~59% still have Long COVID after one year post-infection.

We examined features of immune memory associated with Long COVID vs COVID recovery. RBD IgM and IgA serum antibody responses to natural infection developed faster in Long COVID participants than in those who recovered. No significant differences in the frequencies and decay of IgG, IgM and IgA spike-specific memory B cells were observed. Moreover, no significant differences in frequencies of spike-specific CD4+ and CD8+ T cell frequencies and half-lives over ~300 days post symptom onset. Using an unbiased proteomic approach, we identified inflammatory and non-inflammatory subsets of Long COVID at day 60 or soon thereafter. Key inflammatory signatures (IFNg, TNF and NFkB) persisted over time in those with Long COVID. Validation was observed in a separate COVID cohort.

Studies underway and planned include a deeper dive in immune memory and immune signatures of Long-COVID, understanding effects of variants and response to potential treatments and eventual recovery in our 3-5 years longitudinal cohort study.

Bavithra Vijayakumar, MBBS Ph.D. ; Karim Boustani, Ph.D.; Patricia Ogger, Ph.D.; Artermis Papadaki, Ph.D.; Sara Fontenella, Ph.D.; James Peters, M.D. Ph.D. ; Pallav Shah, M.D. Ph.D.; Clare Lloyd, Ph.D.

As the primary site of SARS-CoV-2 infection the respiratory tract has the complex task of resolving initial infection, establishing long lasting protective immune and repairing tissue damage incurred. In many people this is achieved successfully, however in some signs of ongoing damage to the lungs and impaired respiratory function can be seen months or years after initial infection. Indeed respiratory symptoms are amongst the most common experienced in individuals suffering from post-acute sequelae of COVID19 (PASC). By characterising the immune and protein landscape of the post-COVID19 lung we can link distinct immunological or inflammatory events to different respiratory symptoms. Highlight how local sampling, but not systemic sampling, reveals these associations. Finally we identify the factors that might be involved in determining if respiratory disease post-COVID19 resolves rapidly, or is sustained for a longer period.

Hector Bonilla, MD; Karen Jacobson, MD; Haley Hedlin, PhD; PJ Utz, MD; Prasanna Jagannathan, MD; Aruna Subramanian, MD; Lu Tian, PhD; Upinder Singh, MD

Post-acute sequelae of SARS-CoV-2 (PASC) or Long COVID continues to impact millions of people worldwide. Long COVID encompasses a wide spectrum of symptoms and conditions, and, while models of pathogenesis are crystallizing, there is an urgency to find effective and safe therapeutics to treat patients with Long COVID. SARS-CoV-2 viral persistence has gained traction as a potential mechanism of disease and direct antivirals against SARS-CoV-2 present a promising therapeutic avenue for investigation. In our Selective Trial Of Paxlovid for PASC (STOP-PASC), a randomized, double-blind, placebo-controlled signal-seeking study, the primary objective is to assess the efficacy and safety of nirmatrelvir-ritonavir in the treatment of Long COVID symptoms and, in parallel, explore potential biological biomarkers and digital wearable biomarkers of Long COVID. This and other studies will add to the rapidly evolving and growing landscape of clinical trials to address the great unmet need for effective Long COVID therapeutics.

Joseph A Bellanti,

Following SARS-CoV-2 infection, several clinical outcomes have been identified ranging from asymptomatic infection, minor symptoms or to a devastating form of the disease requiring intensive care and often associated with death. Shortly after the beginning of the COVID-19 pandemic in 2020, another form of the disease appeared with reports suggesting that previously healthy individuals were now experiencing lingering symptoms and were not fully recovering from an initial infection with SARS-CoV-2 with a condition termed the Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC). Some of the common symptoms include fatigue, shortness of breath, chest pain, joint pain, brain fog, and difficulty concentrating. Although the precise etiology of long COVID is uncertain, various mechanisms have been proposed to explain its pathogenesis that include immune system dysregulation, hyperinflammatory states, oxidative stress, autoimmunity, and autonomic nervous system dysfunction. This presentation puts forth a hypothesis-driven model of viral persistence for the pathogenesis of the condition and proposes that Long COVID originates from a state of increased proinflammatory cytokine production resulting from persistence of the SARS-CoV-2 or one of its molecular components. Several publications demonstrating the persistence of SARS-CoV-2 S1 protein in COVID-19 infection after infection support the hypothesis. Long COVID presents a significant challenge for patients and healthcare providers, as it can profoundly have an impact on a person's quality of life and ability to work or carry out daily activities. Although no practical diagnostic tests or specific treatments currently exist for the condition, health care providers can play a crucial role in managing patients with Long COVID by providing the necessary support and care modalities for their management. These include early recognition and diagnosis, symptom management, and shared disease management with specialists and other health professionals who can provide supportive measures to help patients regain their quality of life and functionality.

Mohammad Sajadi, MD

We have devised a novel metric for assessing symptoms through the application of probability theory. This metric allows us to investigate the interconnectedness between individual diseases, specific bodily systems, and the overarching concept of a body clock measured through a probability-theory-based symptom metric.

Our hypothesis centers on the idea that the overall health of the body, as indicated by the body clock metric, correlates with an elevated symptom metric, serving as a proxy for accelerated aging. We anticipate observing a positive association between the two.

Furthermore, the symptom metric itself holds potential utility as a predictive tool for long-COVID and can find application in critical care settings and prognostic models.

A wide variety of neurological manifestations have been reported with SARS-CoV-2 infection. In the acute setting loss of smell and taste are due to direct infection. Metabolic encephalopathy is often in sick patients due to end organ damage and vascular complications are related to coagulopathies and endothelial cell damage. In the subacute phase a number of inflammatory syndromes may occur. This includes acute disseminated encephalomyelitis, transverse myelitis, acute necrotizing hemorrhagic encephalomyelitis and acute inflammatory demyelinating peripheral neuropathy. In children a multisystem inflammatory syndrome may. Each of these syndromes have distinct immunopathophysiological mechanisms. A subset of individuals with mild acute infection develop a variety of new neurological symptoms after recovery termed Long-COVID/PASC. These involve cognitive or psychiatric manifestations, exercise intolerance, dysautonomia or pain syndromes. The pathophysiology of these symptoms is still under investigation, however, persistent infection or persistent innate immune activation are thought to be the drivers. Our studies suggest that these patients have NK cell and monocyte activation, T cell exhaustion and increased antibody secreting B cells in the cerebrospinal fluid. They may cause microvascular disease, glial cell activation and neuronal injury. Autopsy studies from patients who dies in the acute or subacute stage with minimal lung involvement that there is deposition of antibodies on the brain endothelial cells with platelet aggregates, breakdown of the blood brain barrier, macrophage infiltration, gliosis and neuronophagia. Importantly, there is virtual absence of T cells. These studies suggest that there might be multiple potential therapeutic targets for this population that are worthy of consideration.

Here, we leverage the largest publicly available HIPAA-limited dataset about patients with COVID-19 in the US to examine the heterogeneity of adoption and use of U09.9, the ICD-10-CM code for “Post COVID-19 condition, unspecified.” We undertook a number of analyses to characterize the N3C population with a U09.9 diagnosis code (n = 33,782), including assessing person-level demographics and a number of area-level social determinants of health; diagnoses commonly co-occurring with U09.9, clustered using the Louvain algorithm; and quantifying medications and procedures recorded within 60 days of U09.9 diagnosis. We stratified all analyses by age group in order to discern differing patterns of care across the lifespan., Further, we assessed the impact of inclusion criteria on the representativeness of a multi-site national EHR system along gender, race, healthcare-seeking, and socio-economic lines. We established the diagnoses most commonly co-occurring with U09.9 and algorithmically clustered them into four major categories: cardiopulmonary, neurological, gastrointestinal, and comorbid conditions. Importantly, we discovered that the population of patients diagnosed with U09.9 is demographically skewed toward female, White, non-Hispanic individuals and individuals living in areas with low poverty and unemployment. Our results also characterize common procedures and medications associated with U09.9-coded patients. We also found that typical selection criteria for long COVID research biases patient representation across race and gender.

“Peripheral neuropathy” means abnormalities affecting the nerve cells and their long fibers (axons) that connect our brains and spinal cords to other body-parts and the outside world. The symptoms depend on the nerve-cell types damaged. In ¾ of patients, they start in the feet, sometimes ascending upwards towards the torso and head. Motor neuropathies cause weakness and muscle atrophy, and sensory neuropathies cause tingling, reduced and abnormal sensations including chronic pain and itch. Neuropathies affecting the tiny sensory/autonomic axons that control blood circulation and digestion (small fiber neuropathy/SFN) typically cause hard-to-diagnose chronic fatigue, pain, blood pressure and gastrointestinal symptoms including POTS (postural orthostatic tachycardia syndrome), and irritable bowel/bladder.
If the underlying causes of neuropathy are identified and improved, damaged axons typically heal, otherwise they can degenerate. Viruses and some bacteria occasionally cause neuropathy by infecting nerve cells (e.g. leprosy) or after neurotoxic anti-infective medications. Rarely, infections trigger dysimmune responses that damage neurons, particularly those that infecting organisms bind to. Pathology studies demonstrate that COVID-incident neuropathy is dysimmune––not infectious––and mostly follows mild COVID illnesses.
Case-series particularly link long-COVID with SFN, which is plausible as small-fibers preferentially bind SARS-CoV2 and interact with immune cells. Our multi-center study of 17 patients undergoing neuropathy evaluations (mean age=43.3y, 69% female, 94% Caucasian, 19% Latino) analyzed standardized symptoms, examinations, neurodiagnostic test-results, and outcomes. We identified ≥10 SFN cases. Two had large-fiber neuropathy with weakness. Overall, 59% had ≥1 neuropathy-confirming test. 63% had SFN confirmed by skin biopsy pathology and 50% by autonomic-function results. 17% had abnormal electrodiagnostics. During 1.4y average follow-up, improvement averaged 52% with no complete remissions. Given immunotherapies’ proven effectiveness for other dysimmune neuropathies, they are now increasingly considered for long-COVID-associated neuropathies. In our series, 65% received corticosteroids and/or intravenous immunoglobulins. NIH-sponsored controlled trials of immunoglobulins for COVID-incident dysautonomia begin soon––including at Mass General/Brigham.

CISCO-21 Investigators,

Background: Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection.

Methods: A two-arm randomized, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation as; Group A) not hospitalized due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B) Discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C) Convalescing in hospital after an admission for COVID.
Participants will be randomized to usual care or usual care plus a personalized and pragmatic resistance exercise intervention for 12-weeks. The primary outcome is the incremental shuttle walks test (ISWT) at 3 months after randomization with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalization and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea.

Discussion: The CISCO-21 randomized, controlled trial will provide clinical data on the feasibility, safety and efficacy of resistance-based exercise over a 3-month period on validated measures of physical and psychological function in people recovering from COVID-19.
Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference:GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals.

We gratefully acknowledge the research staff who are supporting this project and the participants. The study is funded by the Chief Scientist Office and the University of Glasgow British Heart Foundation Centre of Research Excellence (RE/18/634217).

During the pandemic, Black and Hispanic individuals have experienced higher rates of COVID-19 hospitalization and death compared to white individuals. Less is known about whether disparities exist with regard to the long-term consequences of infection (long COVID), or whether the prevalence of new or lingering symptoms varies by racial/ethnic groups. Racial/ethnic minority groups have several risk factors for the development of long COVID, including differing levels of vaccination, access to medical care, baseline comorbidities, socioeconomic status, viral exposure, and severity of initial illness.

Recent evidence suggests that there may be meaningful disparities in the incidence of post-acute conditions among both hospitalized and non-hospitalized patients with COVID-19. For example, one study using electronic health record data from health care systems across New York City found that, compared to white patients, Black and Hispanic patients had significantly higher odds of a range of potential long COVID symptoms and conditions, including diabetes, chest pain, headaches, and dyspnea. These findings are consistent with survey data from the US Census Bureau suggesting that Black and Hispanic individuals have the highest rates of lingering symptoms after acute COVID-19.

More research is needed to understand the reasons for these differences and the mechanisms by which they occur. Researchers, clinicians, policymakers, and health systems should also work to ensure representative enrollment in clinical trials and access to comprehensive post-COVID care for individuals of all backgrounds.

Several biological factors have emerged as core potential drivers of inflammation in Long COVID or Post Acute Sequelae of COVID-19 (PASC). One is SARS-CoV-2 reservoir: Some individuals with PASC may not fully clear the SARS-CoV-2 virus after acute infection. Instead, replicating virus and/or viral RNA - potentially capable of being translated to produce viral proteins - persist in patient tissue. These SARS-CoV-2 reservoirs could modulate host immune responses or release viral protein into the circulation. This presentation reviews studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology including inflammatory, coagulation, microbiome, and neuroimmune abnormalities will be delineated. Research priorities and methods to guide the further study of a SARS-CoV-2 reservoir in PASC will also be described, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.

Post-acute sequelae of SARS-CoV-2 (PASC) or Long-COVID can affect 50% COVID-19 patients, who experience fatigue, neuropsychiatric symptoms, and brain fog. Pathogenetic mechanisms of blood-brain barrier disruption, neurovascular inflammation, activation of microglia and neuronal damage occur without viral invasion of the brain, but we hypothesized they derive from SARS-CoV-2 stimulating the perivascular immune cells, mast cells, which can activate microglia and contribute to neurovascular inflammation. We reported that nanomolar amounts of recombinant SARS-CoV-2 Spike protein stimulated cultured human mast cells to secrete the proinflammatory proteases, chymase and tryptase, as well as IL-and CXCL8 via activation not of ACE2, but TLR-4, an action augmented by IL-33. We also reported that Spike protein stimulated cultured human microglia to secrete IL-, IL-8, IL18, TNF-, MMP9 and S100B via activation of different receptors. We show that the luteolin analogue, flavanol eriodictyol, significantly inhibits the effect of the Spike protein. Eriodictyol is combined in a unique dietary supplement (ViralProtek®) with oleuropein, hydroxytyrosol and sulforaphane, which have potent anti-viral and anti-inflammatory actions.
References

Gasparello J et al. Effects of Sulforaphane on SARS CoV 2 infection and NF κB dependent expression of genes involved in the COVID 19 'cytokine storm'. Int J Mol Med. 2023;52(3):76.

Hussain T et al. Oleuropein as a potent compound against neurological complications Llnked with COVID-19: A Computational biology approach. Entropy (Basel). 2022;24(7):881.

Theoharides TC, Kempuraj D. Role of SARS-CoV-2 Spike-Protein-Induced activation of Microglia and Mast Cells in the pathogenesis of Neuro-COVID. Cells. 2023;12(5):688.

Tsilioni I, Theoharides TC. Recombinant SARS-CoV-2 Spike Protein stimulates secretion of chymase, tryptase, and IL-1β from human mast cells, augmented by IL-33. Int J Mol Sci. 2023;30:24(11):9487.

Tsilioni I, Theoharides TC. Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain stimulate release of different pro-Inflammatory mediators via activation of distinct receptors on human microglia cells. Mol Neurobiol. 2023 Jul 21.

COVID-19 remains a major source of concern, particularly as new variants emerge and with recognition that many patients may suffer long-term effects. Mechanisms underlying SARS-CoV-2 mediated vascular endotheliopathy and organ damage remain poorly understood, hindering new drug development. Here, we highlight selected key concepts of how the complement system, a major component of innate immunity that is dysregulated in COVID-19, may participate in the thrombo-inflammatory response, drive the vascular endotheliopathy and the accumulation in various organs of cytotoxic tissue resident memory T-cells. Based on advances in our understanding of the complement system and its multiple interactions with other biological systems, we will discuss potential targeted therapeutic maneuvers and diagnostic strategies.

Organ-Specific Inflammation and Long-COVID

Richard C. Becker, MD, MEd
Professor of Medicine
University of Cincinnati College of Medicine
Adjunct Professor of Medicine
Duke University School of Medicine.

COVID-19 infection is associated with an acute inflammatory state. The terms thrombo-inflammation, immune-inflammation, and immune-thrombosis have been used to describe patients-primarily in the acute phase of infection but increasingly in the subacute phase or during recovery or in patients following even a mild infection. Early observations during the pandemic identified laboratory signatures of inflammation, including IL-6 and CRP that correlated with clinical phenotypes and outcomes. Similarly, tissue biopsies and post-mortem examinations revealed inflammation in many organs and organ systems, including small, medium, and large blood vessels. A common theme in acute COVID-19 infection was the presence of nucleotide-binding oligomerization domain-like receptor containing 3 (NLRP3)- an intracellular innate immune receptor that recognizes a diverse range of stimuli, including pathogens, damage cells and cellular debris. NLRP3 activation promotes assembly of a large, multi-protein complex known as the NLRP3 inflammasome that in turn promotes inflammation, vascular injury, thrombosis, and cell death. Inflammation-related tissue injury can cause irreversible organ damage and dysfunction, contributing to long-COVID phenotypes. An equally or even more common scenario is a heightened state of inflammation or inflammatory signature(s) observed in tissues, blood, and molecular patterns that participates in dysregulation of normal immune, microbiota, vascular endothelial cell, and neurological signaling of the central, peripheral, and autonomic nervous systems. Whether tissue-specific inflammation is a cause of or a response to one or more immune-associated triggers (or both) is an important question that requires careful thought and investigation.

By any name - long COVID, post-COVID conditions, long haul COVID, etc - the effects of SARS-CoV-2 infection that linger after the acute illness has subsided have been recognized almost as long as it has been possible to do so. In the context of hundreds of millions of SARS-CoV-2 infections, even a low incidence of long COVID translates to huge numbers of lives and livelihoods impacted. Understanding long COVID presents some unique and complex challenges that are not true of acute COVID. This presentation will discuss those challenges, some components of the NIH's approaches to meeting those challenges, and will set the stage for thinking about chronic inflammation as a potential key contributor to long COVID. Most importantly, this presentation will attempt to highlight some reasons to have hope for continued progress in the understanding, diagnosis, and treatment of long COVID.