Clinical features of Japanese patients with gastrointestinal long-COVID symptoms

Introduction:

Although the development of new therapeutic approaches and vaccines has decreased coronavirus disease 2019 (COVID-19)-associated mortality, prolonged systemic symptoms after COVID-19, termed long-COVID, have been a major concern, considering their potential impact on health-related quality of life (QOL). Gastrointestinal (GI) symptoms, including diarrhea and abdominal pain, have been reported in patients with long-COVID even months after the initial COVID-19 symptoms have resolved.

Although emerging evidence suggests that GI symptoms in long-COVID are affected by the dysregulation of the immune system or ongoing inflammation and damage to the GI tract caused by the initial COVID-19 infection, the clinical features of patients with GI long-COVID symptoms remain elusive. Our study aimed to clarify these features.

Source: Kazuma Yagi, Takanori Asakura, Hideki Terai, Keiko Ohgino, Katsunori Masaki, Ho Namkoong, Shotaro Chubachi, Jun Miyata, Ichiro Kawada, Nobuhiro Kodama, Satoshi Sakamoto, Akira Umeda, Takashi Ishiguro, Makoto Ishii, Koichi Fukunaga. JGH Open. First published: 06 December 2023 https://doi.org/10.1002/jgh3.13006 https://onlinelibrary.wiley.com/doi/full/10.1002/jgh3.13006 (Full text)

Mechanisms of long COVID: An updated review

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic has been ongoing for more than 3 years, with an enormous impact on global health and economies. In some patients, symptoms and signs may remain after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which cannot be explained by an alternate diagnosis; this condition has been defined as long COVID.

Long COVID may exist in patients with both mild and severe disease and is prevalent after infection with different SARS-CoV-2 variants. The most common symptoms include fatigue, dyspnea, and other symptoms involving multiple organs. Vaccination results in lower rates of long COVID. To date, the mechanisms of long COVID remain unclear. In this narrative review, we summarized the clinical presentations and current evidence regarding the pathogenesis of long COVID.

Source: Yan Liu, Xiaoying Gu, Haibo Li, Hui Zhang, Jiuyang Xu. Mechanisms of long COVID: An updated review. Chinese Medical Journal Pulmonary and Critical Care Medicine, Volume 1, Issue 4, December 2023, Pages 231-240. https://www.sciencedirect.com/science/article/pii/S2772558823000580 (Full text)

Investigating the Human Intestinal DNA Virome and Predicting Disease-Associated Virus-Host Interactions in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Understanding how the human virome, and which of its constituents, contributes to health or disease states is reliant on obtaining comprehensive virome profiles. By combining DNA viromes from isolated virus-like particles (VLPs) and whole metagenomes from the same faecal sample of a small cohort of healthy individuals and patients with severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we have obtained a more inclusive profile of the human intestinal DNA virome.

Key features are the identification of a core virome comprising tailed phages of the class Caudoviricetes, and a greater diversity of DNA viruses including extracellular phages and integrated prophages. Using an in silico approach, we predicted interactions between members of the Anaerotruncus genus and unique viruses present in ME/CFS microbiomes. This study therefore provides a framework and rationale for studies of larger cohorts of patients to further investigate disease-associated interactions between the intestinal virome and the bacteriome.

Source: Hsieh SY, Savva GM, Telatin A, Tiwari SK, Tariq MA, Newberry F, Seton KA, Booth C, Bansal AS, Wileman T, Adriaenssens EM, Carding SR. Investigating the Human Intestinal DNA Virome and Predicting Disease-Associated Virus-Host Interactions in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Mol Sci. 2023 Dec 8;24(24):17267. doi: 10.3390/ijms242417267. PMID: 38139096. https://www.mdpi.com/1422-0067/24/24/17267 (Full text)

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation

Abstract:

One in ten SARS-CoV-2 infections result in prolonged symptoms termed long COVID, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 previously hospitalised adults with long COVID grouped by symptoms. Elevated markers of myeloid inflammation and complement activation were associated with long COVID; elevated IL1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while MATN2 and DPP10 were elevated in gastrointestinal (GI) symptoms, and C1QA in cognitive impairment.
Proteins suggestive of neurodegeneration were elevated in cognitive impairment, whilst SCG3 (indicative of brain-gut axis disturbance) was specific to GI symptoms. Nasal inflammation was apparent after COVID-19 but did not associate with symptoms. Although SARS-CoV-2 specific IgG was elevated with some long COVID symptoms, virus was not detected from sputum. Thus, systemic inflammation is evident in long COVID and could be targeted in therapeutic trials tailored to pathophysiological differences between symptom groups.

Source: Peter Openshaw, Felicity Liew, Claudia Efstathiou et al. Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation, 04 December 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3427282/v1] https://www.researchsquare.com/article/rs-3427282/v1 (Full text)

Compelled loneliness and necessitated social isolation: “It’s like being on the other side of a mirror, just looking in”

Abstract:

This article develops the conceptualisation of loneliness by drawing on 42 accounts of myalgic encephalomyelitis (ME). While illness experience is a central concern of the sociology of health and illness, experiences of loneliness alongside contested and chronic illness have received less attention. The analysis illustrates how loneliness can be an integral part of living with ME and offers two novel conceptual contributions – necessitated social isolation and compelled loneliness.

Necessitated social isolation concerns how ME symptoms can make social lives increasingly restricted. Compelled loneliness highlights how the combined experiences of both stigma and contested illness can lead to social withdrawal and rejection, which create a sense of loneliness. The article argues that loneliness and social isolation can be conceptually distinct yet recursive and overlapping.

With the worsening of ME, the participants experienced a cycle of loneliness, in which social isolation and loneliness reproduced each other. Three key themes draw attention to how loneliness is affected by the situational aspects of living with a chronic and contested illness: (1.) spatial and temporal restrictedness (2.) communicative alienation and (3.) discreditation. The article highlights how health challenges can impact on loneliness and how the stigma of contested illness exacerbates loneliness.

Source: Wotherspoon, N. (2023). Compelled loneliness and necessitated social isolation: “It’s like being on the other side of a mirror, just looking in”. Sociology of Health & Illness, 1–18. https://doi.org/10.1111/1467-9566.13732 https://onlinelibrary.wiley.com/doi/10.1111/1467-9566.13732 (Full text)

Augmentation of Anaerobic Pentose Phosphate Pathway Dysregulates Tetrahydrobiopterin Metabolism in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) Patients with Orthostatic Intolerance: A Pilot Study

Abstract:

Tetrahydrobiopterin (BH4), an essential cofactor of amino acid metabolism, was found to be strongly elevated in ME/CFS patients with Orthostatic intolerance (ME + OI). However, the molecular mechanism of BH4 upregulation is poorly understood in ME + OI patients. Here, we report that the activation of the non-oxidative pentose phosphate pathway (PPP) plays a critical role in the biosynthesis of BH4 in ME + OI patients.

Microarray-based gene screening followed by real-time PCR-based validation, ELISA assay, and finally enzyme kinetic studies of glucose-6-phosphate dehydrogenase (G6PDH), transaldolase (TALDO1), and transketolase (TK) enzymes revealed that the augmentation of anaerobic PPP is critical in the pathogenesis of ME + OI. Along with the upregulated anaerobic PPP enzymes, we observed that biopterin metabolites such as BH4 and dihydrobiopterin (BH2) are strongly upregulated suggesting the disruption of biopterin homeostasis in ME + OI patients.

To explore the molecular role of anaerobic PPP in biopterin metabolism, we devised a novel cell culture strategy to induce non-oxidative PPP by treating human microglial cells with ribose-5-phosphate (R5P) under a hypoxic condition of 85%N2/10%CO2/5%O2 followed by the analysis of BH4 and BH2 upregulation via ELISA, immunoblot and dual immunocytochemical analyses.

These results confirmed that the activation of non-oxidative PPP is indeed required for the upregulation of both BH4 and BH2. Moreover, the siRNA knocking down of the taldo1 gene strongly inhibited the expression of GTP cyclohydrolase 1 (GTPCH1) and subsequent production of BH4 and its metabolic conversion to BH2 in R5P-treated and hypoxia-induced C20 human microglia cells. To test the functional role of ME + OI plasma-derived biopterins, exogenously added plasma samples of ME + OI plasma with high BH4 upregulated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in human microglial cells indicating that the non-oxidative PPP-induced-biopterins could stimulate inflammatory response in ME + OI patients.

Source: Sarojini Bulbule, Carl Gunnar Gottschalk, Molly E Drosen et al. Augmentation of Anaerobic Pentose Phosphate Pathway Dysregulates Tetrahydrobiopterin Metabolism in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) Patients with Orthostatic Intolerance: A Pilot Study, 11 December 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3716093/v1] https://www.researchsquare.com/article/rs-3716093/v1 (Full text)

COVID-19 mRNA Vaccination Reduces the Occurrence of Post-COVID Conditions in U.S. Children Aged 5-17 Years Following Omicron SARS-CoV-2 Infection, July 2021-September 2022

Abstract:

Background An estimated 1-3% of children with SARS-CoV-2 infection will develop Post-COVID Conditions (PCC). This study evaluates mRNA COVID-19 vaccine impact on likelihood of PCC in children.
Methods A multi-site cohort of children enrolled 7/21/2021-9/1/2022 underwent weekly SARS-CoV-2 screening tests and were surveyed via self- or parental report 12/1/2022-5/31/2023 regarding PCC (defined as ≥1 new or on-going symptoms lasting ≥ 1 month after infection). Multivariable logistic regression was performed to estimate the occurrence of PCC by vaccination status among children aged 5–17 years whose first PCR-confirmed SARS-CoV-2 infection occurred in-study with Omicron variant, who completed the survey >60 days from infection, and who were vaccine age-eligible at time of infection per ACIP recommendations. Vaccination status was categorized as vaccinated (at least primary series completed >14 days before infection) and unvaccinated (no vaccine doses before infection). Vaccination status was verified through vaccine registry and/or medical records.
Results Of 622 participants surveyed, 5% (n=28) had PCC (Table 1) and 67% (n=474) were vaccinated (Table 2). Surveys were completed a median (IQR) of 203.7 days (119.0–293.0) after infection. Children with non-Hispanic Black race/ethnicity and good/fair/poor self-rated baseline health were more likely to report PCC. Children aged 12-18 years, Non-Hispanic Asian and White children, those reporting symptomatic SARS-CoV-2 infection, and those with excellent/very good self-rated baseline health were more likely to report vaccination When comparing children with and without PCC symptoms, COVID-19 mRNA vaccination was associated with a decreased likelihood of >1 PCC symptom (aOR 0.66, 95% CI 0.43-0.99), >2 PCC symptoms (aOR 0.52, 95% 0.32-0.83), and respiratory PCC symptoms (aOR 0.53, 95% CI 0.33-0.87) (Table 3).
Conclusion In this study, mRNA COVID-19 vaccination appeared to be protective against PCC in children following Omicron SARS-CoV-2 infection. The adjusted ORs correspond to an estimated 34%, 48%, and 47% reduced likelihood of >1, >2, and respiratory PCC symptoms among vaccinated children, respectively. These findings support COVID-19 vaccination for children and may encourage increased pediatric vaccine uptake.
Source: Anna R Yousaf, Josephine Mak, Lisa Gwynn, Robin Bloodworth, Ramona Rai, Zuha Jeddy, Lindsay B LeClair, Laura Edwards, Lauren E W Olsho, Gabriella Newes-Adeyi, Alexandra F Dalton, Manjusha Gaglani, Sarang K Yoon, Kurt Hegmann, Katherine Ellingson, Leora R Feldstein, Angela P Campbell, Amadea Britton, Sharon Saydah, 1935. COVID-19 mRNA Vaccination Reduces the Occurrence of Post-COVID Conditions in U.S. Children Aged 5-17 Years Following Omicron SARS-CoV-2 Infection, July 2021-September 2022, Open Forum Infectious Diseases, Volume 10, Issue Supplement_2, December 2023, ofad500.2466, https://doi.org/10.1093/ofid/ofad500.2466 https://academic.oup.com/ofid/article/10/Supplement_2/ofad500.2466/7448254 (Full text available as PDF file)

Post-Traumatic Stress Disorder and Complex Post-Traumatic Stress Disorder in people with long COVID, ME/CFS, and controls

Abstract:

Background: Prevalences of Post-Traumatic Stress Disorder (PTSD) and Complex Post-Traumatic Stress Disorder (CPTSD) have not previously been compared between individuals with long COVID and individuals with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), and healthy age-matched controls. For these reasons, this study aimed to determine the prevalence of PTSD and CPTSD in individuals with long COVID (n=21) and ME/CFS (n=20) and age-matched controls (n=20).

Methods: A case-case-control approach was employed, participants completed the International Trauma Questionnaire (ITQ), a self-report measure of the International Classification of Diseases (ICD-11) of PTSD and CPTSD consisting of 18 items. Scores were calculated for each PTSD and Disturbances in Self-Organization (DSO) symptom cluster and summed to produce PTSD and DSO scores. PTSD was diagnosed if the criteria for PTSD were met but not DSO, and CPTSD was diagnosed if the criteria for PTSD and DSO were met. Moreover, each cluster of PTSD and DSO were compared among individuals with long COVID, ME/CFS and healthy controls.

Results: Individuals with long COVID (PTSD= 5%, CPTSD= 33%) had more prevalence of PTSD and CPTSD than individuals with ME/CFS (PTSD= 0%, CPTSD= 20%) and healthy controls (PTSD= 0%, CPTSD= 0%). PTSD and CPTSD prevalence was greater in individuals with long COVID and ME/CFS than controls. Individuals with long COVID had greater values controls for all PTSD values. Moreover, individuals with long COVID had greater values than controls for all DSO values. Individuals with ME/CFS had greater values than controls for all DSO values. Both long COVID and ME/CFS groups differed in overall symptom scores compared to controls.

Conclusion: Findings of this study demonstrated that individuals with long COVID generally had more cases of PTSD and CPTSD than individuals with ME/CFS and healthy controls.

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Berry ECJ, Sculthorpe NF. Post-Traumatic Stress Disorder and Complex Post-Traumatic Stress Disorder in people with long COVID, ME/CFS, and controls. Am J Med. 2023 Dec 15:S0002-9343(23)00756-8. doi: 10.1016/j.amjmed.2023.12.006. Epub ahead of print. PMID: 38104642. https://pubmed.ncbi.nlm.nih.gov/38104642/

Systems thinking, subjective findings and diagnostic “pigeonholing” in ME/CFS: A mainly qualitative public health study from a patient perspective

Abstract:

in English, German

Background: ME/CFS (Myalgic encephalomyelitis/chronic fatigue syndrome) is an illness that is predominantly viewed as a neuroimmunological multisystem disease, which is still unknown to many doctors in Germany or which they classify as a psychosomatic disease. From their perspective, ME/CFS patients report significant deficits in terms of medical treatment and a doctor-patient relationship (DP relationship) that is perceived as problematic. The aim of the present study is to more precisely analyse the process of finding a diagnosis as an influencing factor on the DP relationship in ME/CFS from the point of view of those affected.

Method: As part of an explorative qualitative survey, 544 ME/CFS patients (> 20 years; 455 ♀, 89 ♂) with a medical diagnosis of ME/CFS were asked in writing about their experiences with regard to the process of finding a diagnosis. The sampling was previously done by self-activation and via the snowball principle. The questionnaire to be answered was structured analogously to a focused, standardized guideline interview. The evaluation was carried out as part of a qualitative content analysis according to Mayring. Some of the results were subsequently quantified.

Results: The participants described what they saw as the inadequate process of making a diagnosis as a central factor in a problematic DP relationship in ME/CFS. From their point of view, many doctors deny the existence of ME/CFS or classify it as a solely psychosomatic illness, insist on their level of knowledge, ignore patient knowledge and disregard scientific information provided. They follow the standard program, think in “pigeonholes” and are incapable of systemic thinking. This has a significant impact on the DP relationship.

Discussion: From the point of view of ME/CFS patients, the process of making a diagnosis and the recognition of ME/CFS as a neuroimmunological multisystem disease are the central aspects of a DP relationship that they experience as problematic. In the past, findings classified as “subjective” and thus ignored, the pigeonholing that is characteristic of biomedically oriented medicine and a healthcare system that opposes systemic thinking when making a diagnosis have all been identified as factors that may have a significant impact on the DP relationship.

Source: Habermann-Horstmeier L, Horstmeier LM. Systemisches Denken, subjektive Befunde und das diagnostische „Schubladendenken“ bei ME/CFS – Eine vorwiegend qualitative Public-Health-Studie aus Patientensicht [Systems thinking, subjective findings and diagnostic “pigeonholing” in ME/CFS: A mainly qualitative public health study from a patient perspective]. Dtsch Med Wochenschr. 2023 Dec 14. German. doi: 10.1055/a-2197-6479. Epub ahead of print. PMID: 38096913. https://pubmed.ncbi.nlm.nih.gov/38096913/

Differential Cardiopulmonary Hemodynamic Phenotypes in PASC Related Exercise Intolerance

Abstract:

Background Post-acute sequelae of COVID-19 (PASC) affects a significant portion of patients who have previously contracted SARS-CoV-2, with exertional intolerance being a prominent symptom.

Study Objective This study aimed to characterize the invasive hemodynamic abnormalities of PASC-related exertional intolerance using a larger data set from invasive cardiopulmonary exercise testing (iCPET).

Study Design & Intervention Fifty-five patients were recruited from the Yale Post-COVID-19-Recovery-Program, with most experiencing mild acute illness. Supine right heart catheterization (RHC) and iCPET were performed on all participants.

Main results The majority (75%) of PASC patients exhibited impaired peak systemic oxygen extraction (pEO2) during iCPET in conjunction with supranormal cardiac output (CO) (i.e., PASC alone group), On average, the PASC alone group exhibited a “normal” peak exercise capacity, VO2 (89±18% predicted). Approximately 25% of patients had evidence of central cardiopulmonary pathology (i.e., 12 with resting and exercise HFpEF and 2 with exercise PH). PASC patient with HFpEF (i.e., PASC HFpEF group) exhibited similarly impaired pEO2 with well compensated PH (i.e., peak VO2 and cardiac output >80% respectively) despite aberrant central cardiopulmonary exercise hemodynamics. PASC patients with HFpEF also exhibited increased body mass index of 39±7 kg·m−2. To examine the relative contribution of obesity to exertional impairment in PASC HFpEF, a control group compromising of obese non-PASC group (n=61) derived from historical iCPET cohort was used. The non-PASC obese patients with preserved peak VO2 (>80% predicted) exhibited a normal peak pulmonary artery wedge pressure (17±14 versus 25±6 mmHg; p=0.03) with similar maximal voluntary ventilation (90±12 versus 86±10%predicted; p=0.53) compared to PASC HFpEF patients. Impaired pEO2 was not significantly different between PASC patients who underwent supervised rehabilitation and those who did not (p=0.19).

Conclusions This study highlights the importance of considering impaired pEO2 in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of current study also highlights the prevalence of a distinct high output failure HFpEF phenotype in PASC with a primary peripheral limitation to exercise.

Source: Peter A. Kahn, Phillip Joseph, Paul M. Heerdt, Inderjit Singh. Differential Cardiopulmonary Hemodynamic Phenotypes in PASC Related Exercise Intolerance. ERJ Open Research Jan 2023, 00714-2023; DOI: 10.1183/23120541.00714-2023 https://openres.ersjournals.com/content/early/2023/12/07/23120541.00714-2023 (Full text available as PDF file)