Tag: 2023

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS.
New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure.
Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion.
The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance – capillary ischemia-reperfusion – which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.
Source: Wirth, K.J.; Löhn, M. Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome. Preprints 2023, 2023120791. https://doi.org/10.20944/preprints202312.0791.v1  https://www.preprints.org/manuscript/202312.0791/v1 (Full text available as PDF file)

Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing.
Materials and Methods: First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published.
Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at follow-up (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001).
Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.
Source: van Campen CMC, Rowe PC, Visser FC. Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Medicina. 2023; 59(12):2153. https://doi.org/10.3390/medicina59122153 https://www.mdpi.com/1648-9144/59/12/2153 (Full text)
Source:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021-2022

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem illness characterized by activity-limiting fatigue, worsening of symptoms after activity, and other symptoms (1). It affects all age, sex, and racial and ethnic groups and costs the U.S. economy about $18-$51 billion annually (2-5). This report describes the percentage of adults who had ME/CFS at the time of interview by selected demographic and geographic characteristics based on data from the 2021-2022 National Health Interview Survey (NHIS).

Source: Vahratian A, Lin JS, Bertolli J, Unger ER. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults: United States, 2021-2022. NCHS Data Brief. 2023 Dec;(488):1-8. PMID: 38085820. https://www.cdc.gov/nchs//data/databriefs/db488.pdf (Full text)

A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial

Abstract:

Background: Post-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms.

Methods: In this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803.

Findings: Between June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520-3·397, p=0·0001), memory loss (1·967, 1·271-3·044, p=0·0024), difficulty in concentration (2·644, 1·687-4·143, p<0·0001), gastrointestinal upset (1·995, 1·304-3·051, p=0·0014), and general unwellness (2·360, 1·428-3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036).

Interpretation: Treatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions.

Source: Lau RI, Su Q, Lau ISF, Ching JYL, Wong MCS, Lau LHS, Tun HM, Mok CKP, Chau SWH, Tse YK, Cheung CP, Li MKT, Yeung GTY, Cheong PK, Chan FKL, Ng SC. A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2023 Dec 7:S1473-3099(23)00685-0. doi: 10.1016/S1473-3099(23)00685-0. Epub ahead of print. PMID: 38071990. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00685-0/fulltext (Full text)

Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patient perspective

Abstract:

in English, German

Background: Most patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are dissatisfied with medical care. They complain about e. g. the lack of medical recognition of ME/CFS as a neuroimmunological disease and the medical perception of those affected as “difficult patients”.

Method: As part of an exploratory qualitative survey, 544 medically diagnosed ME/CFS patients (> 20 years; 455 ♀, 89 ♂) were asked about their subjective experiences with regard to the doctor-patient relationships (DP relationship) to their treating physicians. The questionnaire was structured analogously to a focused, standardized guideline interview. The written answers were evaluated using a qualitative content analysis according to Mayring.

Results: The participants reported a significant deterioration in their health situation and their quality of life as a result of misdiagnoses and incorrect treatments, the strained DP relationship and the lack of support from the physicians. All of this leads to fear of visiting the doctor, a general loss of trust in physicians, a feeling of helplessness up to bitterness and resignation – with suicide as the last mental option for some patients to escape from this precarious situation. During medical consultations, other participants only addressed health problems that were not related to ME/CFS, or only went to the doctor in an emergency, or refrained from contacting doctors entirely.

Conclusions: The DP relationship described by the participants as problematic in their opinion has significant negative health consequences for them. It is therefore of great urgency to develop a patient-centred treatment concept that focuses on ME/CFS patients as experts on their own illness.

Source: Habermann-Horstmeier L, Horstmeier LM. Auswirkungen der Qualität der Arzt-Patient-Beziehung auf die Gesundheit von erwachsenen ME/CFS-Erkrankten : Eine qualitative Public-Health-Studie aus Patientensicht [Implications of the quality of the doctor-patient relationship on health in adult ME/CFS patients. A qualitative public health study from a patien perspective]. MMW Fortschr Med. 2023 Dec;165(Suppl 5):16-27. German. doi: 10.1007/s15006-023-2894-z. PMID: 38062324.

Long-term symptom profiles after COVID-19 vs other acute respiratory infections: a population-based observational study (COVIDENCE UK)

Abstract:

Summary:

Background: Long COVID is a well recognised, if heterogeneous, entity. Acute respiratory infections (ARIs) due to other pathogens may cause long-term symptoms, but few studies compare post-acute sequelae between SARS-CoV-2 and other ARIs. We aimed to compare symptom profiles between people with previous SARS-CoV-2 infection, people with previous non-COVID-19 ARIs, and contemporaneous controls, and to identify clusters of long-term symptoms.

Methods: COVIDENCE UK is a prospective, population-based UK study of ARIs in adults. We analysed data on 16 potential long COVID symptoms and health-related quality of life (HRQoL), reported in January, 2021, by participants unvaccinated against SARS-CoV-2. We classified participants as having previous SARS-CoV-2 infection or previous non-COVID-19 ARI (≥4 weeks prior) or no reported ARI. We compared symptoms by infection status using logistic and fractional regression, and identified symptom clusters using latent class analysis (LCA).

Findings: We included 10,203 participants (1343 [13.2%] with SARS-CoV-2 infection, 472 [4.6%] with non-COVID-19 ARI). Both types of infection were associated with increased prevalence/severity of most symptoms and decreased HRQoL compared with no infection. Participants with SARS-CoV-2 infection had increased odds of taste/smell problems and hair loss compared with participants with non-COVID-19 ARIs. Separate LCA models identified three symptom severity groups for each infection type. In the most severe groups (including 23% of participants with SARS-CoV-2, and 21% with non-COVID-19 ARI), SARS-CoV-2 infection presented with a higher probability of memory problems, difficulty concentrating, hair loss, and taste/smell problems than non-COVID-19 ARI.

Interpretation: Both SARS-CoV-2 and non-COVID-19 ARIs are associated with a wide range of long-term symptoms. Research on post-acute sequelae of ARIs should extend from SARS-CoV-2 to include other pathogens.

Source: Vivaldi G, Pfeffer PE, Talaei M, et al. Long-term symptom profiles after COVID-19 vs other acute respiratory infections: a population-based observational study (COVIDENCE UK). medRxiv; 2023. DOI: 10.1101/2023.07.06.23292296. https://europepmc.org/article/PPR/ppr687749 (Full text)

In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS

Abstract:

Disturbances of energy metabolism contribute to clinical manifestations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Previously we found that B cells from ME/CFS patients have increased expression of CD24, a modulator of many cellular functions including those of cell stress.

The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand were compared. CD24, the ectonucleotidases CD39, CD73, the NAD-degrading enzyme CD38 and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor (BCR) and co-stimulation with either T cell dependent or Toll-like receptor-9 dependent agonists. Levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analysed in relation to cell growth and immunophenotype.

Proliferating B cells from patients with ME/CFS showed lower mitochondrial mass and a significantly increased usage of essential amino acids compared those from HC, with a significantly delayed loss of CD24 and increased expression of CD38 following stimulation. Immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.

Source: Christopher Armstrong, Fane F. Mensah, Maria Leandro, Venkat Reddy, Paul R. Gooley, Saul Berkovitz, Geraldine Cambridge. In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS. Front. Immunol. Sec. B Cell Biology, Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1178882 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1178882/abstract

Comparison of post-acute sequelae following hospitalization for COVID-19 and influenza

Abstract

Background: Few studies have directly compared the risk and magnitude of post-acute sequelae following COVID-19 and influenza, and most of these studies were conducted before emergence of the Omicron. This study investigated the prevalence of post-COVID conditions and the long-term risk of emergency department (ED) visits, hospitalizations, and deaths in patients with COVID-19 and compared their risk with that of patients with influenza.

Methods: A retrospective study based on the TriNetX databases, a global health research network. We identified patients with COVID-19 and influenza who required hospitalization between January 1, 2022, and January 1, 2023. We compared the risk of developing any post-COVID conditions between the two groups and also analyzed each post-COVID-19 condition and all-cause ED visits, hospitalizations, and deaths in both populations during the follow-up 90-180 days.

Results: Before matching, 7,187 patients with COVID-19 were older (63.9 ± 16.7 vs. 55.4 ± 21.2) and were predominantly male (54.0% vs. 45.4%), and overweight/obese (16.1% vs. 11.2%) than 11,266 individuals with influenza. After propensity score matching, 6,614 patients were identified in each group, resulting in well-balanced baseline characteristics. During follow-up, the COVID-19 group had a higher incidence of any post-COVID-19 condition when compared with the influenza group (17.9% vs. 13.0%), with a hazard ratio (HR) of 1.398 (95% CI, 1.251-1.562). Compared to the influenza group, the COVID-19 group had a significantly higher incidence of abnormal breathing (HR, 1.506; 95% CI, 1.246-1.822), abdominal symptoms (HR, 1.313; HR, 1.034-1.664), fatigue (HR, 1.486; 95% CI, 1.158-1.907), and cognitive symptoms (HR, 1.815; 95% CI, 1.235-2.668). Moreover, the COVID-19 group had a significantly higher risk of the composite outcomes during all-cause ED visits, hospitalizations, and deaths when compared with the influenza group (27.5% vs. 21.7; HR, 1.303; 95% CI, 1.194-1.422).

Conclusions: This study indicates that hospitalized COVID-19 patients are at a higher risk of long-term complications when compared with influenza survivors.

Source: Liu TH, Huang PY, Wu JY, Chuang MH, Hsu WH, Tsai YW, Lai CC. Comparison of post-acute sequelae following hospitalization for COVID-19 and influenza. BMC Med. 2023 Dec 5;21(1):480. doi: 10.1186/s12916-023-03200-2. PMID: 38049876; PMCID: PMC10696681. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696681/ (Full text)

Incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms: A systematic review and meta-analysis

Abstract:

Background: Persistent symptoms are reported in patients who survive the initial stage of COVID-19, often referred to as “long COVID” or “post-acute sequelae of SARS-CoV-2 infection” (PASC); however, evidence on their incidence is still lacking, and symptoms relevant to pain are yet to be assessed.

Methods: A literature search was performed using the electronic databases PubMed, EMBASE, Scopus, and CHINAL and preprint servers MedRχiv and BioRχiv through January 15, 2021. The primary outcome was pain-related symptoms such as headache or myalgia. Secondary outcomes were symptoms relevant to pain (depression or muscle weakness) and symptoms frequently reported (anosmia and dyspnea). Incidence rates of symptoms were pooled using inverse variance methods with a DerSimonian-Laird random-effects model. The source of heterogeneity was explored using meta-regression, with follow-up period, age and sex as covariates.

Results: In total, 38 studies including 19,460 patients were eligible. Eight pain-related symptoms and 26 other symptoms were identified. The highest pooled incidence among pain-related symptoms was chest pain (17%, 95% confidence interval [CI], 11%-24%), followed by headache (16%, 95% CI, 9%-27%), arthralgia (13%, 95% CI, 7%-24%), neuralgia (12%, 95% CI, 3%-38%) and abdominal pain (11%, 95% CI, 7%-16%). The highest pooled incidence among other symptoms was fatigue (44%, 95% CI, 32%-57%), followed by insomnia (27%, 95% CI, 10%-55%), dyspnea (26%, 95% CI, 17%-38%), weakness (25%, 95% CI, 8%-56%) and anosmia (19%, 95% CI, 13%-27%). Substantial heterogeneity was identified (I2, 50-100%). Meta-regression analyses partially accounted for the source of heterogeneity, and yet, 53% of the symptoms remained unexplained.

Conclusions: The current meta-analysis may provide a complete picture of incidence in PASC. It remains unclear, however, whether post-COVID symptoms progress or regress over time or to what extent PASC are associated with age or sex.

Source: Hoshijima H, Mihara T, Seki H, Hyuga S, Kuratani N, Shiga T. Incidence of long-term post-acute sequelae of SARS-CoV-2 infection related to pain and other symptoms: A systematic review and meta-analysis. PLoS One. 2023 Nov 29;18(11):e0250909. doi: 10.1371/journal.pone.0250909. PMID: 38019841; PMCID: PMC10686440. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686440/ (Full text)

Molecular Mechanisms Involved in the Occurrence and Progression of Long COVID and Associated Analysis Techniques

Abstract:

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), has emerged as a significant health concern following the COVID-19 pandemic. Molecular mechanisms underlying the occurrence and progression of long COVID include viral persistence, immune dysregulation, endothelial dysfunction, and neurological involvement, and highlight the need for further research to develop targeted therapies for this condition.
While a clearer picture of the clinical symptomatology is shaping, many molecular mechanisms are yet to be unraveled, given their complexity and high level of interaction with other metabolic pathways. This review summarizes some of the most important symptoms and associated molecular mechanisms that occur in long COVID, as well as the most relevant molecular techniques that can be used in understanding the viral pathogen, its affinity towards the host and the possible outcomes of host-pathogen interaction.
Source: Constantinescu-Bercu, A.; Lobiuc, A.; Caliman Sturdza, O.A.; Oita, R.; Iavorschi, M.; Paval, N.; Soldanescu, I.; Dimian, M.; Covasa, M. Molecular Mechanisms Involved in the Occurrence and Progression of Long COVID and Associated Analysis Techniques. Preprints 2023, 2023111865. https://doi.org/10.20944/preprints202311.1865.v1 https://www.preprints.org/manuscript/202311.1865/v1 (Full text available as PDF file)