Tag: 2022

Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review

Abstract:

Long COVID is an emergent, heterogeneous, and multisystemic condition with an increasingly important impact also on the pediatric population. Among long COVID symptoms, patients can experience chronic gastrointestinal symptoms such as abdominal pain, constipation, diarrhea, vomiting, nausea, and dysphagia.
Although there is no standard, agreed, and optimal diagnostic approach or treatment of long COVID in children, recently compounds containing multiple micronutrients and lactoferrin have been proposed as a possible treatment strategy, due to the long-standing experience gained from other gastrointestinal conditions. In particular, lactoferrin is a pleiotropic glycoprotein with antioxidant, anti-inflammatory, antithrombotic, and immunomodulatory activities. Moreover, it seems to have several physiological functions to protect the gastrointestinal tract.
In this regard, we described the resolution of symptoms after the start of therapy with high doses of oral lactoferrin in two patients referred to our post-COVID pediatric unit due to chronic gastrointestinal symptoms after SARS-CoV-2 infection.
Source: Morello R, De Rose C, Cardinali S, Valentini P, Buonsenso D. Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review. Children. 2022; 9(10):1446. https://doi.org/10.3390/children9101446 (Full text)

Post-COVID myalgic encephalomyelitis in chronic heart disease patient: A case series

Abstract

Purpose of Study: Myalgic encephalomyelitis (ME), also called chronic fatigue syndrome, is a condition characterized by severe fatigue that impairs a patient’s ability to perform common daily activities.

Criteria for ME include 6 months of fatigue-limited daily activities, unrefreshing sleep, and symptom exacerbation following physical or mental strain, and orthostatic intolerance.

New reports indicate that ME incidence may be higher in specific patient populations. This study was designed to investigate the association between ME and Cardiovascular disease in patients recovering from COVID-19 infection.

Methods: Used The patient population used for this study includes 19 patients that were referred to the Amarillo Heart Group in Amarillo, TX who also tested positive for Covid-19 at least 6 months prior to September 1, 2021.

The patients that fit this timeline were asked a series of standardized questions and rate the severity of their symptoms on a scale of 0 to 5, with 0 being the absence of symptoms and 5 being the most severe. Two sets of questions were created and named Life Spheres Criteria (4 questions) and Symptoms Criteria (3 questions) based on the 2015 IOM Diagnostic Criteria for CFS. Rating more than 1 Life Spheres question as a 3 or higher or rating all 3 Symptoms Criteria questions as a 3 or higher indicated Chronic Fatigue Syndrome. Information from the survey, including time since infection, demographics, and question scores, were analyzed.

Summary of Results: Our study included 10 women and 10 men, with the average amount of time since Covid-19 infection being 328.17 ± 41.36 days. Worsening of symptoms with mild exertion was the most commonly endorsed criteria (3.58 ± 1.64) and the least common criterion was fatigue reducing activity in school (2.00 ± 1.94).

Women scored higher in every category except reduced activity in school when compared to men. However, there was no significant difference in symptom scores between the two groups with the Combined Fatigue Score being 2.89 ± 1.47 for women and 2.67 ± 1.59 for men.

Nearly all symptom scores significantly positively correlated with one another, meaning if one category was high it was likely for other categories to be high as well.

Ultimately, when looking at the Cumulative Pearson Correlation Scores, reduced social life, difficulty concentrating, and symptoms worsening with mild exertion were found to be most predictive of a high Combined Fatigue Score.

Conclusions: In this case series, over 80% of patients met the criteria for Post-COVID Myalgic Encephalomyelitis. While the link between ME and both COVID-19 and cardiovascular disease has been established, little is known about the severity of ME in patients who have a history of both cardiovascular disease and COVID-19 infection.

To our knowledge, this is the first study to examine ME in patients with both of these predisposing conditions. A high degree of clinical suspicion for ME should be used when screening and treating cardiac patients who have been infected with COVID-19.

Source: Holder, K. G.; Vemulapalli, V.; Daines, B.; Kankam, A.; Galvan, B.; Nambiar, R. Post-COVID myalgic encephalomyelitis in chronic heart disease patient: A case series. Journal of Investigative Medicine ; 70(2):475, 2022. https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-1705710

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?

Abstract:

A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation.

We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders.

Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition.

Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals.

Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, “dysfunction of the autonomic nervous system”, “neurological sensory / motor disorders” and “pain syndromes”.

Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing.

The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02).  There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group.

Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls.  The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.

Source: Ryabkova, V.A.; Gavrilova, N.Y.; Fedotkina, T.V.; Churilov, L.P.; Shoenfeld, Y. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?. Preprints 2022, 2022090289 (doi: 10.20944/preprints202209.0289.v1) https://www.preprints.org/manuscript/202209.0289/v1 (Full study available as PDF file)

Polyphenols as possible alternative agents in chronic fatigue: a review

Abstract:

Chronic fatigue syndrome (CFS) is a pathological state of extreme tiredness that lasts more than six months and may possess an impact on the social, emotional, or occupational functioning of an individual. CFS is characterized by profound disabling fatigue associated with infectious, rheumatological, and neurological symptoms.

The current pharmacological treatment for CFS does not offer a complete cure for the disease, and none of the available treatments show promising results.

The exact mechanism of the pathogenesis of the disease is still unknown, with current suggestions indicating the overlapping roles of the immune system, central nervous system, and neuroendocrine system.

However, the pathological mechanism revolves around inflammatory and oxidative stress markers.

Polyphenols are the most abundant secondary metabolites of plant origin, with potent antioxidant and anti-inflammatory effects, and can exert protective activity against a whole range of disorders.

The current review is aimed at highlighting the emerging role of polyphenols in CFS from both preclinical and clinical studies. Numerous agents of this class have shown promising results in different in vitro and in vivo models of chronic fatigue/CFS, predominantly by counteracting oxidative stress and the inflammatory cascade.

The clinical data in this regard is still very limited and needs expanding through randomized, placebo-controlled studies to draw final conclusions on whether polyphenols may be a class of clinically effective nutraceuticals in patients with CFS.

Source: Ullah, H., Khan, A., Riccioni, C. et al. Polyphenols as possible alternative agents in chronic fatigue: a review. Phytochem Rev (2022). https://doi.org/10.1007/s11101-022-09838-9 (Full text)

Circadian skin temperature rhythm and dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the role of endothelin-1 in the vascular dysregulation

Abstract:

Purpose: There is accumulating evidence of autonomic dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, little is known about its association with circadian rhythms and endothelial dysfunction. This study aimed to explore the relationship between autonomic responses using an orthostatic test, skin temperature circadian variations, and circulating endothelial biomarkers in ME/CFS.

Methods: Sixty-seven adult female ME/CFS patients and 48 matched healthy controls were enrolled. Demographic and clinical characteristics suggestive of autonomic disturbances were assessed using validated self-reported outcome measures. Postural changes in blood pressure [BP], heart rate [HR], and wrist temperature (WT) were recorded during the orthostatic test. Actigraphy during one week was used to determine the 24-hour profile of peripheral temperature and motor activity. Circulating endothelial biomarkers were also measured as indicators of endothelial functioning.

Results: ME/CFS patients showed higher BP and HR values than healthy controls at rest (p < 0.05 for both), and also higher amplitude of the circadian activity rhythm (p < 0.01). Circulating levels of endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in ME/CFS (p < 0.05). In ME/CFS, ET-1 levels were associated with the stability and amplitude of the temperature rhythm, (p < 0.01), and also with the self-reported questionnaires (p < 0.001).

Conclusions: ME/CFS patients exhibited alterations in circadian rhythms and hemodynamic measures that are associated with endothelial dysfunction, supporting previous evidence of dysautonomia in ME/CFS. Future investigation in this area is needed to assess vascular tone abnormalities and dysautonomia which may provide therapeutic targets for ME/CFS.

Source: Trinitat Cambras, Maria Fernanda Zerón-Rugerio, Antoni Díez-Noguera et al. Circadian skin temperature rhythm and dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the role of endothelin-1 in the vascular dysregulation, 21 September 2022, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2044838/v1 (Full text)

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR).

In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups.

We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients.

Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

Source: Franziska Sotzny, Igor Salerno Filgueiras, Claudia Kedor, Helma Freitag, Kirsten Wittke, Sandra Bauer, Nuno Sepúlveda, Dennyson Leandro Mathias da Fonseca, Gabriela Crispim Baiocchi, Alexandre H. C. Marques, Myungjin Kim, Tanja Lange, Desirée Rodrigues Plaça, Finn Luebber, Frieder M. Paulus, Roberta De Vito, Igor Jurisica, Kai Schulze-Forster, Friedemann Paul, Judith Bellmann-Strobl, Rebekka Rust, Uta Hoppmann, Yehuda Shoenfeld, Gabriela Riemekasten, Harald Heidecke, Otavio Cabral-Marques, Carmen Scheibenbogen. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Front. Immunol., 27 September 2022
Sec. Autoimmune and Autoinflammatory Disorders https://doi.org/10.3389/fimmu.2022.981532 (Full text)

Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19

Abstract:

Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets.

To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC.

A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fcγ receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.

Source: Jonathan D. Herman, Caroline Atyeo, Yonatan Zur, Claire E. Cook, Naomi J. Patel, Kathleen M. Vanni, Emily N. Kowalski, Grace Qian, Nancy A. Shadick, Douglas Laffenburger, Zachary S. Wallace, Jeffrey A. Sparks, Galit Alter. Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19. medRxiv 2022.09.25.22280335; doi: https://doi.org/10.1101/2022.09.25.22280335 https://www.medrxiv.org/content/10.1101/2022.09.25.22280335v1.full-text (Full text)

Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis

Abstract:

The epipharynx, located behind the nasal cavity, is responsible for upper respiratory tract immunity; however, it is also the site of frequent acute and chronic inflammation. Previous reports have suggested that chronic epipharyngitis is involved not only in local symptoms such as cough and postnasal drip, but also in systemic inflammatory diseases such as IgA nephropathy and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID.

Epipharyngeal Abrasive Therapy (EAT), which is an effective treatment for chronic epipharyngitis in Japan, is reported to be effective for these intractable diseases. The sedation of chronic epipharyngitis by EAT induces suppression of the inflammatory cytokines and improves systemic symptoms, which is considered to be one of the mechanisms, but there is no report that has proved this hypothesis. The purpose of this study was to clarify the anti-inflammatory effect of EAT histologically.

The study subjects were 8 patients who were not treated with EAT and 11 patients who were treated with EAT for chronic epipharyngitis for 1 month or more. For immunohistochemical assessment, the expression pattern of IL-6 mRNA, which plays a central role in the human cytokine network, was analyzed using in situ hybridization. The expression of IL-6 in the EAT-treated group was significantly lower than those in the EAT nontreated group (p = 0.0015). In addition, EAT suppressed the expression of tumor necrosis factor alpha (TNFα), a crucial proinflammatory cytokine. As a result, continuous EAT suppressed submucosal cell aggregation and reduced inflammatory cytokines. Thus, EAT may contribute to the improvement of systemic inflammatory diseases through the suppression of IL-6 expression.

Source: Nishi K, Yoshimoto S, Nishi S, Nishi T, Nishi R, Tanaka T, Tsunoda T, Imai K, Tanaka H, Hotta O, Tanaka A, Hiromatsu K, Shirasawa S, Nakagawa T, Yamano T. Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis. Int J Mol Sci. 2022 Aug 16;23(16):9205. doi: 10.3390/ijms23169205. PMID: 36012469; PMCID: PMC9409341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409341/ (Full text)

Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study

Abstract:

Background: Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households.

Methods: 1267 members of 341 households (404 children aged <14 years, 140 adolescents aged 14-18 years and 723 adults) were categorized as having had either a SARS-CoV-2 infection or household exposure to SARS-CoV-2 without infection, based on three serological assays and history of laboratory-confirmed infection. Participants completed questionnaires assessing the presence of long COVID symptoms 11-12 months after infection in the household using online questionnaires.

Findings: The prevalence of moderate or severe persistent symptoms was statistically significantly higher in infected than in exposed women (36.4% [95% CI: 30.7-42.4%] vs 14.2% [95% CI: 8.7-21.5%]), infected men (22.9% [95% CI: 17.9-28.5%] vs 10.3% [95% CI: 5.8-16.9%]) and infected adolescent girls (32.1% 95% CI: 17.2-50.5%] vs 8.9% [95%CI: 3.1-19.8%]). However, moderate or severe persistent symptoms were not statistically more common in infected adolescent boys aged 14-18 (9.7% [95% CI: 2.8-23.6%] or in infected children <14 years (girls: 4.3% [95% CI: 1.2-11.0%]; boys: 3.7% [95% CI: 1.1-9.6%]) than in their exposed counterparts (adolescent boys: 0.0% [95% CI: 0.0-6.7%]; girls < 14 years: 2.3% [95% CI: 0·7-6·1%]; boys < 14 years: 0.0% [95% CI: 0.0-2.0%]). The number of persistent symptoms reported by individuals was associated with the number of persistent symptoms reported by their household members (IRR=1·11, p=·005, 95% CI [1.03-1.20]).

Interpretation: In this controlled, multi-centre study, infected men, women and adolescent girls were at increased risk of negative outcomes 11-12 months after SARS-CoV-2 infection. Amongst non-infected adults, prevalence of negative outcomes was also high. Prolonged symptoms tended to cluster within families, suggesting family-level interventions for long COVID could prove useful.

Funding: Ministry of Science, Research and the Arts, Baden-Württemberg, Germany.

Source: Haddad A, Janda A, Renk H, Stich M, Frieh P, Kaier K, Lohrmann F, Nieters A, Willems A, Huzly D, Dulovic A, Schneiderhan-Marra N, Jacobsen EM, Fabricius D, Zernickel M, Stamminger T, Bode SFN, Himpel T, Remppis J, Engel C, Peter A, Ganzenmueller T, Hoffmann GF, Haase B, Kräusslich HG, Müller B, Franz AR, Debatin KM, Tönshoff B, Henneke P, Elling R. Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study. EBioMedicine. 2022 Sep 22;84:104245. doi: 10.1016/j.ebiom.2022.104245. Epub ahead of print. PMID: 36155957; PMCID: PMC9495281. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495281/ (Full text)

Tunneling nanotubes provide a route for SARS-CoV-2 spreading

Abstract:

Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represent a major issue in long coronavirus disease. How SARS-CoV-2 gains access to the brain and how infection leads to neurological symptoms are not clear because the principal means of viral entry by endocytosis, the angiotensin-converting enzyme 2 receptor, are barely detectable in the brain.

We report that human neuronal cells, nonpermissive to infection through the endocytic pathway, can be infected when cocultured with permissive infected epithelial cells. SARS-CoV-2 induces the formation of tunneling nanotubes (TNTs) and exploits this route to spread to uninfected cells. In cellulo correlative fluorescence and cryo-electron tomography reveal that SARS-CoV-2 is associated with TNTs between permissive cells. Furthermore, multiple vesicular structures such as double-membrane vesicles, sites of viral replication, are observed inside TNTs between permissive and nonpermissive cells.

Our data highlight a previously unknown mechanism of SARS-CoV-2 spreading, likely used as a route to invade nonpermissive cells and potentiate infection in permissive cells.

Source: Pepe A, Pietropaoli S, Vos M, Barba-Spaeth G, Zurzolo C. Tunneling nanotubes provide a route for SARS-CoV-2 spreading. Sci Adv. 2022 Jul 22;8(29):eabo0171. doi: 10.1126/sciadv.abo0171. Epub 2022 Jul 20. PMID: 35857849; PMCID: PMC9299553.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299553/ (Full text)