Category: Overlapping Illnesses

Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease

Abstract:

Introduction: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. Patients often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk is the development of lymphoma in some cases. To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry.

Material and methods: An anonymous questionnaire following the recommendations of the Institute of Medicine/National Academy of Medicine for screening of the new SEID criteria was created in French and mailed to 50 patients.

Results: Thirty-nine (78%) contacted patients responded. The studied population was mainly constituted of women (90%) with an average age of 50 (18-59) years. Smoking was a constant factor in all patients. A total of 28/39 (72%) respondents met the SEID symptoms criteria. Severe chronic fatigue for more than 6 months was noted in 36/39 cases (92%). Unrefreshing sleep, post-exertional malaise, cognitive impairment, and orthostatic intolerance were described in 30/39 (77%), 32/39 (82%), 28/39 (72%), and 27/39 (69%) cases, respectively. Pain (arthralgia, myalgia, headache) was present in 26/39 (67%) cases. The most prominent SEID symptoms were fatigue, followed by post-exercise discomfort and cognitive difficulties. The most disabling symptom was non-restorative sleep, followed by pain. An inflammatory and/or autoimmune context was noted in 13 patients (33%), and these comorbidities could have favored the deterioration of the general condition. Three patients also presented with fibromyalgia. However, 3 patients did not mention any complaints.

Conclusion: This survey indicated that patients with PPBL most often initially presented with disabling chronic fatigue, chronic pain, and other symptoms suggestive of SEID but requiring more studies to confirm it. Education of medical staff about the symptoms of PPBL should be encouraged to better assess this peculiar condition.

Source: Morizot R, de Korwin JD, Feugier P, Broséus J, Troussard X, Lesesve JF. Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease. J Clin Med. 2021 Jul 29;10(15):3374. doi: 10.3390/jcm10153374. PMID: 34362156. https://pubmed.ncbi.nlm.nih.gov/34362156/

A common language for Gulf War Illness (GWI) research studies: GWI common data elements

Abstract

Aims: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community.

Main methods: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments.

Key findings: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses.

Significance: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing

Source: Cohen DE, Sullivan KA, McNeil RB, Klimas NG; Gulf War Illness Common Data Elements Working Group; Symptoms Assessment Working Group, McNeil R, Ashford W, Bested A, Bunker J, Cheema A, Cohen D, Cook D, Cournoyer J, Craddock T, Golier J, Hardie A, Helmer D, Lindheimer JB, Lloyd PJ, Kerr K, Krengel M, Nadkarni S, Nugent S, Paris B, Reinhard M, Rumm P, Schneiderman A, Sims KJ, Steele L, Turner M; Systems Assessment Working Group, Sullivan K, Abdullah L, Abreu M, Abu-Donia M, Aenlle K, Arocho J, Balbin E, Baraniuk J, Block K, Block M, DeBeer B, Engdahl B, Filipov N, Fletcher MA, Kalasinsky V, Kokkotou E, Lidie K, Little D, Loging W, Morris M, Nathanson L, Nichols MD, Pasinetti G, Shungu D, Waziry P, VanLeeuwen J, Younger J; GWI CDE Administrative Team, Klimas N. A common language for Gulf War Illness (GWI) research studies: GWI common data elements. Life Sci. 2021 Aug 2:119818. doi: 10.1016/j.lfs.2021.119818. Epub ahead of print. PMID: 34352259. https://pubmed.ncbi.nlm.nih.gov/34352259/

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

Abstract:

Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide.

Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to “off-target”, non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder.

This article is part of the special issue entitled ‘Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield’.

Source: Michalovicz LT, Kelly KA, Sullivan K, O’Callaghan JP. Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans. Neuropharmacology. 2020;171:108073. doi:10.1016/j.neuropharm.2020.108073 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398580/ (Full article)

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)

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)

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/

Post COVID syndrome: a new challenge for medicine

Abstract:

The huge concern raised by SARS-CoV2 pandemic about public health management and social impact is still under debate, particularly because COVID-19 may affect infected people much longer than expected from a typical air-borne viral disease. The scientific community is actually wondering about the etiopathogenesis and clinical development of this “post-COVID” complex symptomatology, very close to symptoms typically observed in chronic fatigue syndrome, so recently named as “post-acute sequelae of COVID-19 (PASC)”. This commentary tries to focus on the most recent news about this issue.

Source: Tirelli U, Taibi R, Chirumbolo S. Post COVID syndrome: a new challenge for medicine. Eur Rev Med Pharmacol Sci. 2021 Jun;25(12):4422-4425. doi: 10.26355/eurrev_202106_26154. PMID: 34227079. https://pubmed.ncbi.nlm.nih.gov/34227079/

Subcortical brain segment volumes in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Aims: There is controversy about brain volumes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI). Subcortical regions were assessed because of significant differences in blood oxygenation level dependent signals in the midbrain between these diseases.

Materials and method: Magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images from 3 Tesla structural magnetic resonance imaging scans from sedentary control (n = 34), CFS (n = 38) and GWI (n = 90) subjects were segmented in FreeSurfer. Segmented subcortical volumes were regressed against intracranial volume and age, then iteratively analyzed by multivariate general linear modeling with disease status, gender and demographics as independent co-variates.

Key findings: The optimal model for all subjects used disease status and gender as fixed factors with independent variables eliminated after iteration. Volumes of anterior and midanterior corpus callosum were significantly larger in GWI than CFS. Gender was a significant variable for many segment volumes, and so female and male subjects were analyzed separately. CFS females had smaller left putamen, right caudate and left cerebellum white matter than control women. CFS males had larger left hippocampus than GWI males. Orthostatic status and posttraumatic distress syndrome were not significant covariates.

Significance: CFS and GWI were appropriate “illness controls” for each other. The different patterns of adjusted segment volumes suggested that sexual dimorphisms contributed to pathological changes. Previous volumetric studies may need to be reevaluated to account for gender differences. The findings are framed by comparison to the spectrum of magnetic resonance imaging outcomes in the literature.

Source: Addiego FM, Zajur K, Knack S, Jamieson J, Rayhan RU, Baraniuk JN. Subcortical brain segment volumes in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Life Sci. 2021 Jun 29:119749. doi: 10.1016/j.lfs.2021.119749. Epub ahead of print. PMID: 34214570. https://pubmed.ncbi.nlm.nih.gov/34214570/

Post-Acute COVID-19 Symptoms, a Potential Link with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A 6-Month Survey in a Mexican Cohort

Abstract:

The aim of this study was to describe the clinical evolution during 6 months of follow-up of adults recovered from COVID-19. We tried to determine how many met the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 130 patients (51.0 ± 14 years, 34.6% female) were enrolled. Symptoms were common, participants reported a median number of 9 (IQR 5-14) symptoms. Fatigue was the most common symptom (61/130; 46.9%). Patients with fatigue were older 53.9 ± 13.5 years compared with 48.5 ± 13.3 years in those without fatigue (p = 0.02) and had a longer length of hospital stay, 17 ± 14 days vs. 13 ± 10 days (p = 0.04). There was no difference in other comorbidities between patients with fatigue and those without it, and no association between COVID-19 severity and fatigue.

After multivariate adjustment of all baseline clinical features, only age 40 to 50 years old was positively associated with fatigue, OR 2.5 (95% CI 1.05-6.05) p = 0.03. In our survey, only 17 (13%) patients met the Institute of Medicine’s criteria for “systemic exertion intolerance disease,” the new name of ME/CFS. In conclusion, in some patients, the features of post-acute COVID-19 syndrome overlap with the clinical features of ME/CFS.

Source: González-Hermosillo JA, Martínez-López JP, Carrillo-Lampón SA, Ruiz-Ojeda D, Herrera-Ramírez S, Amezcua-Guerra LM, Martínez-Alvarado MDR. Post-Acute COVID-19 Symptoms, a Potential Link with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A 6-Month Survey in a Mexican Cohort. Brain Sci. 2021 Jun 8;11(6):760. doi: 10.3390/brainsci11060760. PMID: 34201087. https://pubmed.ncbi.nlm.nih.gov/34201087/