SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2

Abstract:

As of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC).

Compared to RC, participants with respiratory PASC had between 6- and 105-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood, and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea.

Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.

Source: Katherine M. Littlefield,Renée O. Watson,Jennifer M. Schneider,Charles P. Neff,Eiko Yamada,Min Zhang,Thomas B. Campbell,Michael T. Falta,Sarah E. Jolley,Andrew P. Fontenot,Brent E. Palmer. SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2. PLOS Pathogens. Published: May 26, 2022 https://doi.org/10.1371/journal.ppat.1010359  (Full text)

Long-term cardiovascular outcomes of COVID-19

Abstract:

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes.

We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care).

Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

Source: Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022 Mar;28(3):583-590. doi: 10.1038/s41591-022-01689-3. Epub 2022 Feb 7. PMID: 35132265; PMCID: PMC8938267. ncbi.nlm.nih.gov/pmc/articles/PMC8938267/ (Full text)

 

Long COVID-19 and achalasia: a possible relationship?

Abstract:

Achalasia is a rare esophageal motor disorder with a worldwide prevalence of around 10 cases per 100 000 inhabitants, and an incidence of one new case per 100 000 inhabitants per year. It is characterized by loss or decrease of myenteric plexus neurons in the distal esophagus and lower esophageal sphincter, presenting dysphagia and regurgitation. The objective of this work was to show that the presence of type II achalasia could be a sequela of the COVID-19 infection.

Patient histories were reviewed during the 2015-2021 period, the frequencies of achalasia with and without COVID-19 were calculated. Patient profiles were constructed by using cluster analysis based on clinical variables. It was found that frequency of patients with achalasia during the years 2020 and 2021 was higher than that observed in previous years, and by the year 2021, 2/3 of the patients with achalasia had presented COVID-19 infection, in addition, the patients with type I achalasia presented different profiles than patients with type II achalasia according to the cluster analysis, and the frequency of COVID-19 was much lower in patients with type I achalasia. These results seem to indicate achalasia could be a sequela of COVID-19 infection.

Source: Aponte, Raúl, Nefertiti Daulabani, Rosargelis Parra, & Luis Pérez-Ybarra. “Long COVID-19 and achalasia: a possible relationship?.” International Journal Of Community Medicine And Public Health [Online], 9.6 (2022): 2696-2700. Web. 11 Jun. 2022 https://www.ijcmph.com/index.php/ijcmph/article/view/9742 (Full text available as PDF file)

Application of Kampo Medicines for Treatment of General Fatigue Due to Long COVID

Abstract:

Evidence regarding treatment for the acute phase of COVID-19 has been accumulating, but specific treatment for long COVID/post-COVID-19 condition has not yet been established. Treatment with herbal medicine might be one treatment option for long COVID, but there has been little research on the effectiveness of herbal medicine for long COVID. The aim of this study was to clarify the prescription patterns of Kampo medicines, which are herbal medicines that originated in China and were developed in Japan, for the treatment of general fatigue due to long COVID.
A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period from Feb 2021 to Dec 2021 with a focus on symptoms accompanying general fatigue and prescriptions of Kampo medicine. Among the clinical data obtained from medical records of 195 patients, clinical data for 102 patients with general fatigue and accompanying symptoms were analyzed. The patients had various symptoms, and the most frequent symptoms accompanying general fatigue were dysosmia, dysgeusia, headache, insomnia, dyspnea, and hair loss.
Prescriptions of Kampo medicine accounted for 24.1% of the total prescriptions (n = 609). The most frequently prescribed Kampo medicine was hochuekkito (71.6%) and other prescribed Kampo medicines were tokishakuyakusan, ryokeijutsukanto, juzentaihoto, hangekobokuto, kakkonto, ninjin’yoeito, goreisan, rikkunshito, and keishibukuryogan. Since the pathophysiology of general fatigue after an infectious disease is, in general, considered a qi deficiency in Kampo medicine, treatments with such compensation agents can be the major prescription as a complement for the qi. In conclusion, Kampo medicine can be one of the main pharmacological treatments for long COVID accompanying general fatigue.
Source: Tokumasu K, Ueda K, Honda H, Sunada N, Sakurada Y, Matsuda Y, Nakano Y, Hasegawa T, Otsuka Y, Obika M, Hagiya H, Kataoka H, Otsuka F. Application of Kampo Medicines for Treatment of General Fatigue Due to Long COVID. Medicina. 2022; 58(6):730. https://doi.org/10.3390/medicina58060730  https://www.mdpi.com/1648-9144/58/6/730/htm (Full text)

Is there a role for the adrenal glands in long COVID?

Introduction:

After the acute phase of SARS-CoV-2 infection, roughly 20% of patients report one or more complications, which are particularly apparent during mental or physical stress. These complications include extreme chronic fatigue, shortness of breath, sleep abnormalities, headache, brain fog, joint pains, nausea, cough and abdominal pain. When symptoms persist for more than four weeks after initial infection and cannot be attributed to other known diseases, they are described as long COVID. When comparing the clinical presentation of long COVID and chronic adrenal insufficiency, overlap between the conditions can be seen, suggesting that long COVID might be related to some form of adrenal dysfunction. Here we discuss the role of the adrenal glands in long COVID.

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Source: Kanczkowski W, Beuschlein F, Bornstein SR. Is there a role for the adrenal glands in long COVID? Nat Rev Endocrinol. 2022 May 30:1–2. doi: 10.1038/s41574-022-00700-8. Epub ahead of print. PMID: 35637413; PMCID: PMC9150041. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9150041/ (Full text)

High Prevalence of Both Previous Infection with SARS-CoV-2 and Persistent Symptoms

Abstract:

Introduction: Universities are unique settings with large populations, congregate housing, and frequent attendance of events in large groups. However, the current prevalence of previous COVID-19 infection in university students, including symptomatic and asymptomatic disease, is unknown. Our goal therefore was to determine the prevalence of previous infection, risk factors for infection, and the prevalence of persistent symptoms following infection among university students.

Methods: This was a cross-sectional study set in a large public university between January 22 and March 22, 2021. We surveyed students about demographics, risk factors, and symptoms, and simultaneously tested their saliva for IgA antibodies to SARS-CoV-2. To estimate the prevalence of previous infection we adjusted our intentional sample of a diverse student population for year in school and age to resemble the composition of the entire student body and adjusted for the imperfect sensitivity and specificity of the antibody test. Univariate and multiple regression analysis was used to identify independent risk factors for infection, and the proportion of students with persistent symptoms following acute infection was determined.

Results: A total of 488 students completed the survey, 432 had a valid antibody result, and 428 had both. The estimated prevalence of previous infection for 432 participants with valid antibody results was 41%. Of 145 students in our sample with a positive antibody test, 41.4% denied having a previous positive polymerase chain reaction (PCR) test for SARS-CoV-2 and presumably had an asymptomatic infection; in our adjusted analysis we estimate that approximately 2-thirds of students had asymptomatic infections. Independent risk factors for infection included male sex, having a roommate with a known symptomatic infection, and having two or fewer roommates. More frequent attendance of parties and bars was a univariate risk factor, but not in the multiple regression analysis. Of 122 students reporting a previous symptomatic infection, 14 (11.4%) reported persistent symptoms consistent with postacute COVID-19 a median of 132 days later.

Conclusions and relevance: Previous COVID-19 infection, both symptomatic and asymptomatic, was common at a large university. Measures that could prevent resurgence of the infection when students return to campus include mandatory vaccination policies, mass surveillance testing, and testing of sewage for antigen to SARS-CoV-2.

Source: Ebell MH, Forgacs D, Shen Y, Ross TM, Hulme C, Bentivegna M, Hanley HB, Jefferson AM, Hainess L. High Prevalence of Both Previous Infection with SARS-CoV-2 and Persistent Symptoms. J Am Board Fam Med. 2022 May-Jun;35(3):570-578. doi: 10.3122/jabfm.2022.03.210348. PMID: 35641057. https://www.jabfm.org/content/35/3/570 (Full text)

Is the number of long-term post-COVID symptoms relevant in hospitalized COVID-19 survivors?

Dear editor,

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease-2019 (COVID-19) is associated with heterogeneous symptoms at its acute phase but also at post-acute phase. Current evidence suggests that 50% of survivors experience post-COVID symptoms the following months after the acute infection [,]. The presence of post-COVID symptoms is associated with worse quality of life . In fact, up to 50 diffferent post-COVID symptoms have been described, and patients usually exhibit more than one symptom . Similarly, the number of symptoms at onset is also heterogeneous, and patients can exhibit several number of symptoms. It has been found that a higher number of onset symptoms at the acute phase (high viral load) is associated with a greater number of post-COVID symptoms . Previous studies focussing on post-COVID symptoms did not use machine learning analysis. Here we present the use of a network analysis for investigating the associations between COVID-19 onset symptoms at hospital admission and the presence of post-COVID symptoms at a long-term follow-up in previously hospitalised COVID-19 survivors recruited from different hospitals.

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Source: Fernández-de-Las-Peñas C, Varol U, Fuensalida-Novo S, Plaza-Canteli S, Valera-Calero JA. Is the number of long-term post-COVID symptoms relevant in hospitalized COVID-19 survivors? Eur J Intern Med. 2022 Jun;100:133-136. doi: 10.1016/j.ejim.2022.02.013. Epub 2022 Feb 14. PMID: 35181183; PMCID: PMC8841158. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841158/ (Full text)

Mechanistic factors contributing to pain and fatigue in fibromyalgia and ME/CFS: autonomic and inflammatory insights from an experimental medicine study

Abstract:

Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathoaetiological mechanisms are complex and debated(2), however there is a strong association with features of hereditary disorders of connective tissue (hypermobility) and autonomic and inflammatory abnormalities (1,2).

Objectives: To determine potential autonomic and inflammatory mechanisms of pain and fatigue in fibromyalgia and ME/CFS

Methods: After excluding participants with WCC higher than 10 (suggesting acute infection) baseline markers of inflammation (CRP and ESR) were available for 60 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 23 matched controls. Participants then underwent full research diagnostic evaluation including a hypermobility assessment(1) and autonomic challenge (60 degree head up tilt, ISRCTN78820481). Subjective pain and fatigue were assessed before and after challenge (VAS). Linear regression models were used to explore predictors, with adjustment for confounders as appropriate. Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1)pain and 2)fatigue induced by challenge and mediatiors 1)no of connective tissue features in hypermobility diagnostic criteria endorsed by participant; 2)baseline inflammatory markers.

Results: ESR and CRP were significantly higher in patients rather than controls, even after correcting for BMI, age and sex (B=5.15, t=2.05, p=0.044; B=1.77, t=2.15, p=0.044 respectively). Adjusted ESR and CRP correlated with both subjective fatigue (B=0.44, t=2.09, p=0.04; B=1.63, t=2.60, p=0.011) and pain severity (B=0.13, t=2.51, p=0.014; B=0.45, t=3.01, p=0.004) at baseline. Autonomic challenge amplified pain (B=14.20, t=2.87, p=0.005) and fatigue (B=31.48, t=5.95, p=<0.001) in patients to a significantly greater degree than controls, controlling for baseline levels. Baseline ESR and CRP also predicted challenge-induced increase in fatigue (B=0.78, t=370, p=<0.001; B=1.91, t=3.36, p=<0.001) and ESR challenge-induced increases in pain (B=0.46, t=2.35, p=0.021).

Mediation analysis demonstrated that number of connective tissue features expressed in hypermobility criteria mediated the degree to which subjective pain was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero, 0.1572 – 6.8171). ESR mediated the degree to which subjective fatigue was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero,0.7541 – 7.3888).

Conclusion: To our knowledge this is the first study to directly explore autonomic and inflammatory mechanisms of pain and fatigue in a combined population of Fibromyalgia and ME/CFS. This study this adds to the evidence-base of baseline inflammatory abnormalities in fibromyalgia and ME/CFS. It highlights their potential role in predicting symptom severity and their potential mechanistic role in autonomic induced pain and fatigue, suggesting future treatment strategies.

Source: Eccles J, Thompson C, Thompson B, et al. AB1209 MECHANISTIC FACTORS CONTRIBUTING TO PAIN AND FATIGUE IN FIBROMYALGIA AND ME/CFS: AUTONOMIC AND INFLAMMATORY INSIGHTS FROM AN EXPERIMENTAL MEDICINE STUDY. Annals of the Rheumatic Diseases 2022;81:1719 https://ard.bmj.com/content/annrheumdis/81/Suppl_1/1719.2.full.pdf (Full text available as PDF file)

Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice

Abstract:

Purpose: This report describes the clinical manifestations of 35 patients sent to a University Immunology clinic with a diagnosis of fatigue and exercise intolerance who were identified to have low carnitine palmitoyl transferase activity on muscle biopsies.

Recent findings: All of the patients presented with fatigue and exercise intolerance and many had been diagnosed with fibromyalgia. Their symptoms responded to treatment of the metabolic disease. Associated symptoms included bloating, diarrhea, constipation, gastrointestinal reflux symptoms, recurrent infections, arthritis, dyspnea, dry eye, visual loss, and hearing loss. Associated medical conditions included Hashimoto thyroiditis, Sjogren’s syndrome, seronegative arthritis, food hypersensitivities, asthma, sleep apnea, and vasculitis. This study identifies clinical features that should alert physicians to the possibility of an underlying metabolic disease. Treatment of the metabolic disease leads to symptomatic improvement.

Source: Bax K, Isackson PJ, Moore M, Ambrus JL Jr. Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice. Curr Rheumatol Rep. 2020 Feb 14;22(3):8. doi: 10.1007/s11926-020-0879-9. PMID: 32067119. https://pubmed.ncbi.nlm.nih.gov/32067119/

Preparing for the long-haul: Autonomic complications of COVID-19

Abstract:

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

Source: Larsen NW, Stiles LE, Miglis MG. Preparing for the long-haul: Autonomic complications of COVID-19. Auton Neurosci. 2021;235:102841. doi:10.1016/j.autneu.2021.102841  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254396/ (Full text)