long covid immunology – Page 8 – American ME and CFS Society

Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care

Abstract:

Background: Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs).

Methods: Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren’s syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications.

Results: Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42).

Conclusions: SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.

Source: Syed U, Subramanian A, Wraith DC, Lord JM, McGee K, Ghokale K, Nirantharakumar K, Haroon S. Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care. BMC Med. 2023 Sep 21;21(1):363. doi: 10.1186/s12916-023-03049-5. PMID: 37735654; PMCID: PMC10512476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512476/ (Full text)

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Abstract:

The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear.

In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8⁺ T cell-macrophage interactions in maintaining Krt8^hi transitional and ectopic Krt5⁺ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia.

Mechanistically, CD8⁺ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function.

Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.

Source: Narasimhan H, Cheon IS, Qian W, Hu S, Parimon T, Li C, Goplen N, Wu Y, Wei X, Son YM, Fink E, Santos G, Tang J, Yao C, Muehling L, Canderan G, Kadl A, Cannon A, Pramoonjago P, Shim YM, Woodfolk J, Zang C, Chen P, Sun J. Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19. bioRxiv [Preprint]. 2023 Sep 14:2023.09.13.557622. doi: 10.1101/2023.09.13.557622. PMID: 37745354; PMCID: PMC10515929. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10515929/ (Full text)

Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms

Abstract:

Persistence of COVID-19 symptoms may follow SARS-CoV-2 infection. The incidence of long COVID increases with the severity of acute disease, but even mild disease can be associated with sequelae. The symptoms vary widely with fatigue, shortness of breath, and cognitive dysfunction being the most common. Abnormalities of multiple organs have been documented and histopathology has revealed widespread microthrombi. Elevated levels of complement are present in acute COVID-19 patients and may persist at lower levels in long COVID. Evidence supports complement activation with endotheliopathy associated disease as the molecular mechanism causing both acute and long COVID.

Section snippets

Prevalence and Definition: A review and meta-analysis of published results of long COVID studies suggest a global prevalence of the post COVID-19 condition of approximately 43% with a wide range of 9-81%.¹ Using a population-representative survey epidemiologists have estimated the prevalence of long COVID in the United States to be 7.3%.² In an effort to standardize the definition of long COVID the World Health Organization (WHO) established a Clinical Case Definition Working Group on the Post-COVID-19 Condition.³

Symptoms: The symptoms of long COVID are similar to those observed in patients following chronic critical illness and hospitalization in intensive care units.⁴ In the United Kingdom a retrospective matched cohort study was undertaken to determine symptoms beyond 12 weeks in non-hospitalized SARS-CoV-2 infected patients compared with uninfected patients.⁵ A cohort of 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection was compared to 1,944,580 propensity score-matched adults with no record

Evaluation and Testing: The previously referenced study of COVID patients 6 months after discharge from hospital in Wuhan, China enrolled patients in radiographic, pulmonary function, and blood testing.⁷ High resolution computerized tomography (HRCT) was performed on 390 patients and was abnormal in 52% not requiring supplemental oxygen and 54% of patients requiring supplemental oxygen. Lung diffusion impairment was noted in 22% of patients not requiring oxygen and up to 56% of patients requiring supplemental oxygen

Pathology and Histopathology: Autopsy data has contributed considerable information to our understanding of SARS-CoV-2 infection. A review of the histopathological findings in coronavirus disease 2019 reported diffuse alveolar damage (DAD), multiple organ microvasculitis, and lymphocytic infiltration with changes in immune organs and emphasized the observance of microthrombosis in numerous studies.¹⁸ An autopsy study from New York Presbyterian Hospital revealed macroscopic and/or microscopic thrombi in 84% patients.¹⁹

Complement, von Willebrand factor, and Endotheliopathy: A prospective study in the Netherlands was conducted to examine the role of complement as a component of the innate immune response to SARS-CoV-2 infection.²⁹ Investigators found that complement factors C3a, C3c, and the terminal complement complex or membrane attack complex (MAC) were increased in COVID-19 patients compared to healthy controls. Furthermore, these complement factors were more increased in patients who were admitted to intensive care units, died, or experienced thromboembolic

Discussion: Long COVID or post acute sequelae of COVID-19 (PASC) is a frequent occurrence in patients recovering from acute SARS-CoV-2 infection. Estimates of the incidence vary widely with the more recent estimates trending below 10% in the United States. Changes in definition, increasing population immunity, treatment with antivirals and monoclonal antibodies, and newer variants may all play a role in the downward trend. The symptoms of long COVID are numerous and reflect the multi-organ nature of both…

Conclusion: The pathology and histopathology of COVID-19 patients has demonstrated the presence of widespread multi-organ microthrombi as a central feature of SARS-CoV-2 infection. Elevated levels of complement factors and von Willebrand factor have been found in COVID-19 patients and the degree of increases are directly related to the severity of disease and persistent high levels correlate with long COVID symptoms.³⁹ Persisting symptoms following acute COVID-19 occur more often and are more debilitating

Source: Hawley HB. Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms. Am J Med. 2023 Sep 11:S0002-9343(23)00539-9. doi: 10.1016/j.amjmed.2023.08.008. Epub ahead of print. PMID: 37704072. https://www.sciencedirect.com/science/article/abs/pii/S0002934323005399

Analyzing the Interplay between COVID-19 Viral Load, Inflammatory Markers, and Lymphocyte Subpopulations on the Development of Long COVID

Abstract:

The global impact of the SARS-CoV-2 infection has been substantial, affecting millions of people. Long COVID, characterized by persistent or recurrent symptoms after acute infection, has been reported in over 40% of patients. Risk factors include age and female gender, and various mechanisms, including chronic inflammation and viral persistence, have been implicated in long COVID’s pathogenesis. However, there are scarce studies in which multiple inflammatory markers and viral load are analyzed simultaneously in acute infection to determine how they predict for long COVID at long-term follow-up. This study explores the association between long COVID and inflammatory markers, viral load, and lymphocyte subpopulation during acute infection in hospitalized patients to better understand the risk factors of this disease.

This longitudinal retrospective study was conducted in patients hospitalized with COVID-19 in northern Mexico. Inflammatory parameters, viral load, and lymphocyte subpopulation during the acute infection phase were analyzed, and long COVID symptoms were followed up depending on severity and persistence (weekly or monthly) and assessed 1.5 years after the acute infection.

This study analyzed 79 patients, among them, 41.8% presented long COVID symptoms, with fatigue being the most common (45.5%). Patients with long COVID had higher lymphocyte levels during hospitalization, and NK cell subpopulation levels were also associated with long COVID. ICU admission during acute COVID-19 was also linked to the development of long COVID symptoms.

Source: Rivera-Cavazos A, Luviano-García JA, Garza-Silva A, Morales-Rodríguez DP, Kuri-Ayache M, Sanz-Sánchez MÁ, Santos-Macías JE, Romero-Ibarguengoitia ME, González-Cantú A. Analyzing the Interplay between COVID-19 Viral Load, Inflammatory Markers, and Lymphocyte Subpopulations on the Development of Long COVID. Microorganisms. 2023; 11(9):2241. https://doi.org/10.3390/microorganisms11092241 https://www.mdpi.com/2076-2607/11/9/2241 (Full text)

Exploring the mechanisms of long COVID: Insights from computational analysis of SARS-CoV-2 gene expression and symptom associations

Abstract:

Long coronavirus disease (COVID) has emerged as a global health issue, affecting a substantial number of people worldwide. However, the underlying mechanisms that contribute to the persistence of symptoms in long COVID remain obscure, impeding the development of effective diagnostic and therapeutic interventions.

In this study, we utilized computational methods to examine the gene expression profiles of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their associations with the wide range of symptoms observed in long COVID patients. Using a comprehensive data set comprising over 255 symptoms affecting multiple organ systems, we identified differentially expressed genes and investigated their functional similarity, leading to the identification of key genes with the potential to serve as biomarkers for long COVID.

We identified the participation of hub genes associated with G-protein-coupled receptors (GPCRs), which are essential regulators of T-cell immunity and viral infection responses. Among the identified common genes were CTLA4, PTPN22, KIT, KRAS, NF1, RET, and CTNNB1, which play a crucial role in modulating T-cell immunity via GPCR and contribute to a variety of symptoms, including autoimmunity, cardiovascular disorders, dermatological manifestations, gastrointestinal complications, pulmonary impairments, reproductive and genitourinary dysfunctions, and endocrine abnormalities. GPCRs and associated genes are pivotal in immune regulation and cellular functions, and their dysregulation may contribute to the persistent immune responses, chronic inflammation, and tissue abnormalities observed in long COVID.

Targeting GPCRs and their associated pathways could offer promising therapeutic strategies to manage symptoms and improve outcomes for those experiencing long COVID. However, the complex mechanisms underlying the condition require continued study to develop effective treatments. Our study has significant implications for understanding the molecular mechanisms underlying long COVID and for identifying potential therapeutic targets. In addition, we have developed a comprehensive website (https://longcovid.omicstutorials.com/) that provides a curated list of biomarker-identified genes and treatment recommendations for each specific disease, thereby facilitating informed clinical decision-making and improved patient management. Our study contributes to the understanding of this debilitating disease, paving the way for improved diagnostic precision, and individualized therapeutic interventions.

Source: Das S, Kumar S. Exploring the mechanisms of long COVID: Insights from computational analysis of SARS-CoV-2 gene expression and symptom associations. J Med Virol. 2023 Sep;95(9):e29077. doi: 10.1002/jmv.29077. PMID: 37675861. https://pubmed.ncbi.nlm.nih.gov/37675861/

Reactive gliosis and neuroinflammation: prime suspects in the pathophysiology of post-acute neuroCOVID-19 syndrome

Abstract:

Introduction: As the repercussions from the COVID-19 pandemic continue to unfold, an ever-expanding body of evidence suggests that infection also elicits pathophysiological manifestations within the central nervous system (CNS), known as neurological symptoms of post-acute sequelae of COVID infection (NeuroPASC). Although the neurological impairments and repercussions associated with NeuroPASC have been well described in the literature, its etiology remains to be fully characterized.

Objectives: This mini-review explores the current literature that elucidates various mechanisms underlining NeuroPASC, its players, and regulators, leading to persistent neuroinflammation of affected individuals. Specifically, we provide some insights into the various roles played by microglial and astroglial cell reactivity in NeuroPASC and how these cell subsets potentially contribute to neurological impairment in response to the direct or indirect mechanisms of CNS injury.

Discussion: A better understanding of the mechanisms and biomarkers associated with this maladaptive neuroimmune response will thus provide better diagnostic strategies for NeuroPASC and reveal new potential mechanisms for therapeutic intervention. Altogether, the elucidation of NeuroPASC pathogenesis will improve patient outcomes and mitigate the socioeconomic burden of this syndrome.

Source: Saucier J, Comeau D, Robichaud GA, Chamard-Witkowski L. Reactive gliosis and neuroinflammation: prime suspects in the pathophysiology of post-acute neuroCOVID-19 syndrome. Front Neurol. 2023 Aug 24;14:1221266. doi: 10.3389/fneur.2023.1221266. PMID: 37693763; PMCID: PMC10492094. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10492094/ (Full text)

Neuroimmunological Effect of Vitamin D on Neuropsychiatric Long COVID Syndrome: A Review

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). COVID-19 is now recognized as a multiorgan disease with a broad spectrum of manifestations. A substantial proportion of individuals who have recovered from COVID-19 are experiencing persistent, prolonged, and often incapacitating sequelae, collectively referred to as long COVID. To date, definitive diagnostic criteria for long COVID diagnosis remain elusive.

An emerging public health threat is neuropsychiatric long COVID, encompassing a broad range of manifestations, such as sleep disturbance, anxiety, depression, brain fog, and fatigue. Although the precise mechanisms underlying the neuropsychiatric complications of long COVID are presently not fully elucidated, neural cytolytic effects, neuroinflammation, cerebral microvascular compromise, breakdown of the blood–brain barrier (BBB), thrombosis, hypoxia, neurotransmitter dysregulation, and provoked neurodegeneration are pathophysiologically linked to long-term neuropsychiatric consequences, in addition to systemic hyperinflammation and maladaptation of the renin–angiotensin–aldosterone system.

Vitamin D, a fat-soluble secosteroid, is a potent immunomodulatory hormone with potential beneficial effects on anti-inflammatory responses, neuroprotection, monoamine neurotransmission, BBB integrity, vasculometabolic functions, gut microbiota, and telomere stability in different phases of SARS-CoV-2 infection, acting through both genomic and nongenomic pathways.

Here, we provide an up-to-date review of the potential mechanisms and pathophysiology of neuropsychiatric long COVID syndrome and the plausible neurological contributions of vitamin D in mitigating the effects of long COVID.

Source: Chen T-B, Chang C-M, Yang C-C, Tsai I-J, Wei C-Y, Yang H-W, Yang C-P. Neuroimmunological Effect of Vitamin D on Neuropsychiatric Long COVID Syndrome: A Review. Nutrients. 2023; 15(17):3802. https://doi.org/10.3390/nu15173802 https://www.mdpi.com/2072-6643/15/17/3802 (Full text)

Neutrophil Extracellular Traps and Long COVID

Abstract:

Post-acute COVID-19 sequelae, commonly known as long COVID, encompasses a range of systemic symptoms experienced by a significant number of COVID-19 survivors. The underlying pathophysiology of long COVID has become a topic of intense research discussion. While chronic inflammation in long COVID has received considerable attention, the role of neutrophils, which are the most abundant of all immune cells and primary responders to inflammation, has been unfortunately overlooked, perhaps due to their short lifespan.

In this review, we discuss the emerging role of neutrophil extracellular traps (NETs) in the persistent inflammatory response observed in long COVID patients. We present early evidence linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID.

Several uncertainties require investigation in future studies. These include the mechanisms by which SARS-CoV-2 brings about sustained neutrophil activation phenotypes after infection resolution; whether the heterogeneity of neutrophils seen in acute SARS-CoV-2 infection persists into the chronic phase; whether the presence of autoantibodies in long COVID can induce NETs and protect them from degradation; whether NETs exert differential, organ-specific effects; specifically which NET components contribute to organ-specific pathologies, such as pulmonary fibrosis; and whether senescent cells can escape clearance and drive NET formation in long COVID. Answering these questions may pave the way for the development of clinically applicable strategies targeting NETs, providing relief for this emerging health crisis.

Source: Shafqat, A., Omer, M., Albalkhi, I., Alabdul Razzak, G., Abdulkader, H., Abdul Rab, S., … & Yaqinuddin, A. Neutrophil Extracellular Traps and Long COVID. Frontiers in Immunology, 14, 1254310. https://www.frontiersin.org/articles/10.3389/fimmu.2023.1254310/abstract

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

Abstract:

Introduction: Persistent symptoms after COVID-19 infection (“long COVID”) negatively affects almost half of COVID-19 survivors. Despite its prevalence, its pathophysiology is poorly understood, with multiple host systems likely affected. Here, we followed patients from hospital to discharge and used a systems-biology approach to identify mechanisms of long COVID.

Methods: RNA-seq was performed on whole blood collected early in hospital and 4-12 weeks after discharge from 24 adult COVID-19 patients (10 reported post-COVID symptoms after discharge). Differential gene expression analysis, pathway enrichment, and machine learning methods were used to identify underlying mechanisms for post-COVID symptom development.

Results: Compared to patients with post-COVID symptoms, patients without post-COVID symptoms had larger temporal gene expression changes associated with downregulation of inflammatory and coagulation genes over time. Patients could also be separated into three patient endotypes with differing mechanistic trajectories, which was validated in another published patient cohort. The “Resolved” endotype (lowest rate of post-COVID symptoms) had robust inflammatory and hemostatic responses in hospital that resolved after discharge. Conversely, the inflammatory/hemostatic responses of “Suppressive” and “Unresolved” endotypes (higher rates of patients with post-COVID symptoms) were persistently dampened and activated, respectively. These endotypes were accurately defined by specific blood gene expression signatures (6-7 genes) for potential clinical stratification.

Discussion: This study allowed analysis of long COVID whole blood transcriptomics trajectories while accounting for the issue of patient heterogeneity. Two of the three identified and externally validated endotypes (“Unresolved” and “Suppressive”) were associated with higher rates of post-COVID symptoms and either persistently activated or suppressed inflammation and coagulation processes. Gene biomarkers in blood could potentially be used clinically to stratify patients into different endotypes, paving the way for personalized long COVID treatment.

Source: An AY, Baghela A, Zhang PGY, Blimkie TM, Gauthier J, Kaufmann DE, Acton E, Lee AHY, Levesque RC, Hancock REW. Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation. Front Immunol. 2023 Aug 23;14:1243689. doi: 10.3389/fimmu.2023.1243689. PMID: 37680625; PMCID: PMC10482103. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482103/ (Full text)

Severity of neurological long-COVID symptoms correlates with increased level of autoantibodies targeting vasoregulatory and autonomic nervous system receptors

Abstract:

Background: The Long-COVID syndrome constitutes a plethora of persisting symptoms with neurological disorders being the most disabling ones. The pathogenesis of Long-COVID is currently under heavy scrutiny and existing data on the role of auto-immune reaction to G-protein coupled receptors (GPCR) are conflicting.

Methods: This monocentric, cross-sectional study included patients who suffered a mild to moderate SARS-CoV-2 infection up to 12 months prior to enrollment with (n = 72) or without (n = 58) Long-COVID diagnosis according to the German S1 guideline or with no known history of SARS-CoV-2 infection (n = 70). While autoantibodies towards the vasoregulation associated Adrenergic Receptor (ADR) B1 and B2 and the CNS and vasoregulation associated muscarinic acetylcholine receptor (CHR) M3 and M4 were measured by ELISA, neurological disorders were quantified by internationally standardized questionnaires.

Results: The prevalence and concentrations of evaluated autoantibodes were significantly higher in Long-COVID compared to the 2 other groups (p = 2.1*10⁻⁹) with a significantly higher number of patients with simultaneous detection of more than one autoantibody in Long-COVID group (p = 0.0419). Importantly, the overall inflammatory state was low in all 3 groups. ARB1 and ARB2 correlated negatively CERAD Trail Marking A and B (R ≤ −0.26, p ≤ 0.043), while CHRM3 correlated positively with Chadler Fatigue Scale (R = 0.37, p = 0.0087).

Conclusions: Concentrations of autoantibodies correlates to intensity of neurological disorders including psychomotor speed, visual search, attention, and fatigue.

Source: Felix S. Seibert, Ulrik Stervbo, Lea Wiemers, Sarah Skrzypczyk, Maximillian Hogeweg, Sebastian Bertram, Julia Kurek, Moritz Anft, Timm H. Westhoff, Nina Babel. Severity of neurological long-COVID symptoms correlates with increased level of autoantibodies targeting vasoregulatory and autonomic nervous system receptors. Autoimmunity Reviews,2023, 103445, ISSN 1568-9972. https://www.sciencedirect.com/science/article/abs/pii/S1568997223001799 (Full text)