Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome

Abstract:

Context: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe chronic illness which reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.

Objective: To investigate the occurrence of anti-pituitary (APA) and anti-hypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Design, setting, patients and other participants: This is a case-control study conducted in University Hospital setting (Stanford, Naples). Thirty women with ME/CSF (Group 1) diagnosed according to Fukuda, Canadian, and IOM criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls.

Main outcome measures: APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands and plasma and urinary osmolality. Both APA and AHA titers were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results: Patients in Group 1 showed a high prevalence of AHA (33%) and APA (56%) and a significant lower levels of ACTH/cortisol, and GH peak/IGF1 vs controls (all AHA/APA negative). Patients in Group 1A (13 patients positive at high titers, ≥1:32) showed ACTH/cortisol and GH peak/ IGF1 levels significantly lower and more severe forms of ME/CFS with respect to patients in Group 1B (7 positive at middle/low titers,1:16-1:8) and 1C (10 Ab negative patients).

Conclusions: Both AHA and/or APA at high titers associated with hypothalamic/pituitary dysfunction suggest that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Source: De Bellis A, Bellastella G, Pernice V, Cirillo P, Longo M, Maio A, Scappaticcio L, Maiorino MI, Bellastella A, Esposito K, Montoya JG. Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome. J Clin Endocrinol Metab. 2021 Jul 13:dgab429. doi: 10.1210/clinem/dgab429. Epub ahead of print. PMID: 34254637. https://pubmed.ncbi.nlm.nih.gov/34254637/

Chronic fatigue syndrome and epigenetics: The case for hyperbaric oxygen therapy in biomarker identification

Abstract:

Chronic fatigue syndrome (CFS) is a poorly-understood respiratory condition that affects millions of individuals. Hyperbaric oxygen therapy (HBOT) is a treatment option being considered to address CFS as it is suggested to combat fatigue and increase oxygenation. HBOT provides two opportunities in advancing research of CFS: it may provide data on symptom amelioration and be utilized in the search for a biomarker. By either identifying biomarkers before using HBOT to compare epigenomes of patients before and after treatment or using HBOT to find epigenetic discrepancies between patients with and without treatment, matching epigenetic regulation with symptom amelioration may significantly advance the understanding of the etiology and treatment mechanism for CFS. EPAS1/HIF-2α is a leading candidate for an epigenetic biomarker as it responds differentially to hypoxic and normoxic conditions, which degrades more slowly in hypoxic conditions. Epigenetic regulation of EPAS1/HIF-2α in such differential conditions may be explored in HBOT experiments. In addition to HBOT as a promising treatment option for CFS symptoms, it may aid the identification of biomarkers in CFS. Further research into both outcomes is strongly encouraged.

Source: Shah RJ. Chronic fatigue syndrome and epigenetics: The case for hyperbaric oxygen therapy in biomarker identification. J Pulmonol Respir Res. 2021; 5: 027-030. DOI: 10.29328/journal.jprr.1001020 https://www.heighpubs.org/jprr/jprr-aid1020.php (Full text)

My experience of chronic fatigue syndrome

Anonymous 16-year-old:

Chronic fatigue syndrome (CFS) is exactly what it says on the tin: it is an extreme tiredness (loss of energy and motivation) which can lead to extreme difficulty or an inability to complete basic functions. Other symptoms include sleep problems, problems thinking/remembering, headaches, dizziness and heart palpitations. As you can imagine, these symptoms have a severe impact on a person’s life and often lead to a sudden or extreme change in lifestyle (eg, time outside, time in bed, time seeing friends, etc).

The severity of CFS can often fluctuate and people with CFS typically experience a ‘boom and bust’ cycle, in which they have ‘boom’, a sudden burst of energy and (as a result) activity followed by a bust, a period of worse than usual fatigue and extremely low levels of activity.

CFS isolated me to my bed where I often had no energy to move, to talk or even to think. If I ever had enough energy to leave my bed, it would only be for an hour or two and I would often spend double or triple that time resting up again before I could consider leaving my bed again. The fact that I spent basically all day in bed meant that by night-time, although I still had no energy to do anything, I was not physically worn out enough to sleep, meaning for some time I was practically nocturnal. It also meant that school was almost impossible to attend: I missed several terms and had an attendance rate of 20%. Schoolwork—which I could rarely attempt to complete—would take three times as long as usual; it was as if I were mentally trudging through treacle in subjects in which I was previously able to sprint through.

Source: My experience of chronic fatigue syndrome. BMJ Paediatr Open. 2021 Jun 25;5(1):e001165. doi: 10.1136/bmjpo-2021-001165. PMID: 34250274; PMCID: PMC8237727. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237727/ (Full text)

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Abstract:

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive.

This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis

Source: Proal AD, VanElzakker MB. Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front Microbiol. 2021 Jun 23;12:698169. doi: 10.3389/fmicb.2021.698169. PMID: 34248921; PMCID: PMC8260991. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260991/ (Full study)

Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality.

In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.

Source: Sfera A, Osorio C, Zapata Martín Del Campo CM, Pereida S, Maurer S, Maldonado JC, Kozlakidis Z. Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis. Front Cell Neurosci. 2021 Jun 25;15:673217. doi: 10.3389/fncel.2021.673217. PMID: 34248502; PMCID: PMC8267916. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267916/ (Full study)

Impacts of online support groups on quality of life, and perceived anxiety and depression in those with ME/CFS: A survey

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition that can negatively affect physical and mental health [1,2]. People with ME/CFS report lower perceived levels of social support, which further exacerbate challenges with mental health and has been linked to a higher prevalence of depression and anxiety in this population [3]. There are many mental health benefits associated with participation in in-person support groups; however, it is unknown if these benefits translate to online support groups [5].

Purpose: To examine the perceived impacts of participation in online support groups on depression, anxiety and quality of life among people with ME/CFS.

Results: Responses (n = 76) to an online survey indicated positive and negative experiences with participation in online support groups. Positive experiences included a sense of belonging, validation, supportive friendships and feelings of positively impacting others. Negative experiences included jealousy, decreased hope and optimism and disagreement regarding treatment strategies.

Conclusion: Participation in online support groups was believed to decrease perceived feelings of depression and increase the quality of life in those with ME/CFS. No significant impacts on anxiety were found. Overall, participants reported engagement in online support groups to be a positive experience.

Source: Samantha Morehouse, Krystal Schaible, Olivia Williams, Ellen Herlache-Pretzer & Stacey Webster (2021) Impacts of online support groups on quality of life, and perceived anxiety and depression in those with ME/CFS: a survey, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2021.1950406

Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection

Introduction: Long-term COVID symptoms marked by autonomic dysfunction1 and cardiac damage2 following COVID-19 infection have been noted for up to 6 months after symptom onset,3 but to date have not been quantified, to our knowledge. Previous studies have found that wearable data can improve real-time detection of viral illness4 or discrimination of individuals with COVID-19 vs other viral infections.5 Wearable devices provide a way to continuously track an individual’s physiological and behavioral metrics beginning when healthy (ie, before infection), during the course of infection, and recovery back to baseline. In this cohort study, we aimed to examine the duration and variation of recovery among COVID-19–positive vs COVID-19–negative participants.
Methods: DETECT (Digital Engagement and Tracking for Early Control and Treatment) is a remote, app-based, longitudinal research study enrolling adult participants from all over the US and collecting their wearable data to better understand individual changes associated with viral illness, including COVID-19. All participants provided informed consent electronically. The protocol for this study was reviewed and approved by the Scripps Office for the Protection of Research Subjects. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

From March 25, 2020, through January 24, 2021, 37 146 participants were enrolled. This analysis focuses on 875 individuals who reported symptoms of an acute respiratory illness and underwent swab testing for COVID-19 and were found to be either positive (234 individuals) or negative (641 individuals) (eFigure in the Supplement).

The following calculation was used for resting heart rate (RHR): deviation from baseline = daily RHR − baseline RHR mean. Individuals with COVID-19 were also grouped by their mean RHR deviation from baseline 28 to 56 days after symptom onset (<1, 1-5, or >5 beats per minute).

Data analysis was conducted in SAS statistical software version 9.4 (SAS Institute). Significance was set at P < .05. P values were calculated with 1-way ANOVA (for mean age) or χ2 tests. Additional details about our methods can be found in the eAppendix in the Supplement.

Results: For this analysis, our study population consisted of 234 COVID-19–positive individuals (mean [range] age, 45.3 [18-76] years; 164 women [70.9%]) and 641 COVID-19–negative symptomatic individuals (mean [range] age, 44.7 [19-75] years; 455 women [71.1%]). Individuals with COVID-19 took longer to return to their RHR (Figure, A and B), sleep (Figure, C and D), and activity (Figure, E and F) baselines compared with symptomatic individuals who were COVID-19 negative. This difference was most marked for RHR, with COVID-19–positive individuals initially experiencing a transient bradycardia followed by a prolonged relative tachycardia that did not return to baseline, on average, until 79 days after symptom onset. Step count and sleep quantity returned to baseline sooner than RHR at 32 and 24 days, respectively. During recovery, individuals with COVID-19 experienced different trajectories in the return of their RHR to their normal compared with COVID-19–negative individuals (Figure, B). A small subset of COVID-19–positive participants (32 participants [13.7%]) maintained an RHR more than 5 beats per minute greater than their baseline RHR that did not return to their normal for more than 133 days. During the acute phase of COVID-19, individuals in this group reported higher frequencies of cough (27 participants [84.4%] vs 57 participants [55.3%] in the <1 beat per minute group and 57 participants [57.6%] in the 1-5 beats per minute group), body ache (20 participants [62.5%] vs 42 participants [40.8%] in the <1 beat per minute group and 35 participants [35.4%] in the 1-5 beats per minute group), and shortness of breath (9 participants [28.1%] vs 9 participants [8.7%] in the <1 beat per minute group and 6 participants [6.1%] in the 1-5 beats per minute group) compared with the other groups (Table).
Discussion: To our knowledge, this is the first study to examine longer duration wearable sensor data. We found a prolonged physiological impact of COVID-19 infection, lasting approximately 2 to 3 months, on average, but with substantial intraindividual variability, which may reflect various levels of autonomic nervous system dysfunction or potentially ongoing inflammation. Transient bradycardia has been noted in a case study6 approximately 9 to 15 days after symptom onset, which was also seen in our population. Our data suggest that early symptoms and larger initial RHR response to COVID-19 infection may be associated with the physiological length of recovery from this virus.

Symptom data were collected only during the acute phase of infection, which limited our ability to compare long-term physiological and behavioral changes with long-term symptoms. In the future, with larger sample sizes and more comprehensive participant-reported outcomes, it will be possible to better understand factors associated with interindividualized variability in COVID-19 recovery.

Source: Radin JM, Quer G, Ramos E, et al. Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection. JAMA Netw Open. 2021;4(7):e2115959. doi:10.1001/jamanetworkopen.2021.15959 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781687 (Full article)

Functional somatic syndromes and joint hypermobility: A systematic review and meta-analysis

Abstract:

Objective: There have been multiple reports of increased joint hypermobility (JH) in functional somatic syndromes (FSS). We sought to evaluate the evidence for an association.

Methods: A systematic search of the databases Medline and PsycINFO was conducted to identify all controlled studies from inception to February 2020 measuring the association of an FSS and JH. Records were identified and screened, and full-text articles assessed for eligibility by two independent authors. Meta-analysis was performed using random-effects modelling with the DerSimonian and Laird method.

Results: We found 220 studies initially, which yielded 11 studies for inclusion in the qualitative review and 10 in the quantitative analysis – 5 studies on fibromyalgia, 3 on chronic fatigue syndrome and 3 on functional gastrointestinal disorder. Nine of the 11 studies found increased rates of JH in FSS compared to controls, though most studies were fair to poor in quality. Meta-analysis showed a weighted summary effect odds ratio of 3.27 (95% CI: 1.83, 5.84; p < 0.001) of JH in FSS, suggesting greater odds of FSS in individuals with JH than in those without.

Conclusions: There is some evidence for an association between FSS and JH, but this is limited by the generally poor quality of studies and the narrow range of FSS studied. Better research is needed to confirm these findings as well as evaluate causation using prospective cohort studies.

Source: Chen G, Olver JS, Kanaan RA. Functional somatic syndromes and joint hypermobility: A systematic review and meta-analysis. J Psychosom Res. 2021 Jun 24;148:110556. doi: 10.1016/j.jpsychores.2021.110556. Epub ahead of print. PMID: 34237584. https://pubmed.ncbi.nlm.nih.gov/34237584/

Incidence of chronic Q fever and chronic fatigue syndrome: a six year follow-up of a large Q fever outbreak

Abstract:

Objectives: Acute Q fever is a generally self-limiting infection caused by the intracellular gram-negative bacterium Coxiella (C.) burnetii. For yet unknown reasons, a subset of patients develops chronic a infection. Furthermore, a Chronic Fatigue Syndrome (CFS) as post-acute Q fever sequelae has been described. We here investigated the rates of chronic Q fever and incidences of CFS six years after one of the largest European Q fever outbreaks that occurred in Jena, Germany in 2005 with 331 reported cases, who lived in proximity of a grazing sheep herd.

Methods: A total of 80 patients and 52 non-diseased household members from the former outbreak, were enrolled six years after the outbreak, blood samples collected and tested for a chronic Q fever were determined by seroprevalence using referenced immunofluorescence tests. Also, the presence of a CFS was assessed using the Short Form Symptom Inventory developed by the Centers (United States) for Disease Control and Prevention (SF CDC- SI).

Results: In 80 out of 132 (60.6%) study participants, previous Q fever infection was confirmed serologically, while no previous infection was detected in the 52 household members. None of the participants fulfilled the serological criteria of chronic Q fever. The evaluation of the CDC-SI did not show any differences between the two groups. Also, there was no difference between both groups regarding fulfillment of CFS-defining criteria (n = 3 (3.8 %; sero-positive) vs. n = 2 (3.8 %; sero-negative), p = 0.655).

Conclusion: Our six-year follow-up study of a large Q fever outbreak did not find evidence for chronic Q fever or post Q fever CFS. There was no asymptomatic sero-positivity in household members of Q fever patients.

Source: Ankert J, Frosinski J, Weis S, Boden K, Pletz MW. Incidence of chronic Q fever and chronic fatigue syndrome: a six year follow-up of a large Q fever outbreak. Transbound Emerg Dis. 2021 Jul 9. doi: 10.1111/tbed.14224. Epub ahead of print. PMID: 34240822. https://pubmed.ncbi.nlm.nih.gov/34240822/

Efficacy of Qigong Exercise for Treatment of Fatigue: A Systematic Review and Meta-Analysis

Abstract:

Objective: Several studies suggested that Qigong exercise (QE) can relieve fatigue in patients diagnosed with various diseases. Our review aimed to evaluate the efficacy of QE for alleviating fatigue.

Methods: A related literature search was performed in the PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang, and VIP data bases from inception to November 2020. Information on fatigue, malaise, tiredness, and Qigong research data was collected.

Results: Sixteen randomized controlled trials (RCTs) were reported in patients with cancer (n = 4), chronic fatigue syndrome (n = 2), and other diseases (n = 10). The QE groups showed significant improvements in total fatigue intensity [15 RCTs, p < 0.00001; standard mean difference (SMD) -0.69 (-0.95 to -0.44)]. The QE groups did not show significant improvement in quality of life [4 RCTs, p = 0.08; SMD 0.53 (-0.07 to 1.14)]. The statistically significant difference of the subgroup analyses (different primary diseases, QE types, and study quality) also remained unchanged.

Conclusion: The findings of this meta-analysis indicate that QE may be beneficial for improving fatigue in patients diagnosed with various diseases. Considering the limitations of the study, we draw a very cautious conclusion regarding the resulting estimate of the effect. Further studies are warranted to better understand the benefits of QE in primary medical care.

Source: Wang R, Huang X, Wu Y, Sun D. Efficacy of Qigong Exercise for Treatment of Fatigue: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021 Jun 22;8:684058. doi: 10.3389/fmed.2021.684058. PMID: 34239889; PMCID: PMC8257957. https://pubmed.ncbi.nlm.nih.gov/34239889/