Tag: case series

Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series

Highlights:

• Both Long COVID and ME/CFS are characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα.

• In a small Long COVID and ME/CFS case series, patients’ immune deficiency and health improve during treatment period with a nebulized antioxidant, anti-pathogen and immune-modulatory pharmacological agent.

• This work provides evidence of a useful biomarker, CD8 T-cell dysfunction reminiscent of T cell exhaustion, that may assist diagnosis and have utility for tracking disease outcome during therapy, including response to a potential new treatment.

Abstract:

Background: Patients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system.

Methods and Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3–15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients.

Conclusions: Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.

Source: Gil, A., Hoag, G.E., Salerno, J.P., Hornig, M., Klimas, N., Selin, L.K. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/antipathogen agent in a retrospective case series. Brain, Behavior, & Immunity – Health (2024), doi: https://doi.org/10.1016/j.bbih.2023.100720 https://www.sciencedirect.com/science/article/pii/S2666354623001345 (Full text)

Successful treatment of myalgic encephalomyelitis/chronic fatigue syndrome using hydrogen gas: four case reports

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue and malaise that persist for more than 6 months with neuropsychiatric symptoms, including slight fever, headache, weakness, impaired thinking, and depression.[1,2] The onset and severity of these symptoms vary and reduce the quality of life as well as social, occupational, and personal activities of those affected, with some becoming bedridden.[1,2] The number of ME/CFS patients in the United States is estimated to be between 836,000 and 2.5 million.[3]

Although it currently remains unclear whether there are objective and biological abnormalities in ME/CFS, recent neuroimaging, blood marker analyses, and energy metabolism and mitochondrial studies detected these abnormalities in ME/CFS patients.[4] ME/CFS may be caused by the activation of the immune system, both within and outside the brain, which induces the release of inflammatory cytokines. ME/CFS is presumed to cause abnormalities in the central and autonomic nervous systems, systemic energy metabolism, and immune system and also involve oxidative and nitrosative stress.[4,5,6] Dysfunctions in systemic energy metabolism may be related to abnormalities in the structure and function of mitochondria.[7,8,9,10]

Molecular hydrogen (H2) is a gaseous molecule that selectively scavenges reactive oxygen and nitrogen species with strong oxidizing power, namely, hydroxyl radicals (·OH) and peroxynitrite, respectively.[11,12] H2 easily crosses the blood-brain barrier and biological membranes, reaches mitochondria, and protects cells from ·OH-induced cell damage.[11,12] A recent literature review revealed that H2 attenuated acute or chronic fatigue in animals and healthy subjects.[13] We also reported that the anti-fatigue effects of H2 involved the protection of mitochondria, which may also ameliorate the pathogenesis of ME/CFS.[13] Therefore, we conducted this case study to test this hypothesis by examining the efficacy of H2 gas inhalation in four patients with ME/CFS.

Source: Hirano, Shin-ichi*; Ichikawa, Yusuke; Sato, Bunpei; Takefuji, Yoshiyasu; Satoh, Fumitake. Successful treatment of myalgic encephalomyelitis/chronic fatigue syndrome using hydrogen gas: four case reports. Medical Gas Research 14(2):p 84-86, June 2024. | DOI: 10.4103/2045-9912.385441 https://journals.lww.com/mgar/fulltext/2024/14020/successful_treatment_of_myalgic.7.aspx (Full text)

Chronic Fatigue Syndrome and Multiple Sclerosis have Reduced Craniospinal Compliance and Dilated Pressurized Bridging Cortical Veins: A Hypothesis Illustrated with Two Case Studies

Abstract:

Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) share similarities regarding their epidemiology, symptomatology and craniospinal physiology. Indeed, the cardinal feature of CFS, fatigue, is also a major factor in the symptomatology of the majority of MS patients.

Recently, we have found that there is a significant reduction in the craniospinal compliance in MS which affects both the stiffness of the walls of the spinal canal and the walls of the cerebral venous system. This change in compliance brings about an alteration in the effectiveness of the pulse wave dampening in the craniospinal system. The result is an impedance mismatch between the cortical veins and their draining sinuses, leading to dilatation of these upstream veins.

We deduce this dilatation can only be brought about by an increase in the pressure gradient between the vein lumen and the subarachnoid space (i.e. the transmural pressure gradient). We hypothesise that given the similarities between MS and CFS, a similar mechanism underlies the physiology of CFS. We present two case studies to highlight the expected findings in CFS patients if this hypothesis were proven to be correct.

Source: Bateman, G.; Bateman, A. Chronic Fatigue Syndrome and Multiple Sclerosis have Reduced Craniospinal Compliance and Dilated Pressurized Bridging Cortical Veins: A Hypothesis Illustrated with Two Case Studies. Preprints.org 2023, 2023052264. https://doi.org/10.20944/preprints202305.2264.v1 https://www.preprints.org/manuscript/202305.2264/v1 (Full text available as PDF file)

Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies

Abstract:

Forty-four patients, including 26 adults and 18 children under 15 years of age, were referred for evaluation of recurrent or persistent illnesses, with symptoms including pharyngitis, lymphadenopathy, fever, headaches, arthralgia, fatigue, depression, dyslogia, and myalgia. Thirty-nine patients were positive for Epstein-Barr virus antibody with antibody levels compatible with active infection for at least 1 year. Antiviral capsid antigen and anti-early antigen titers of patients were significantly greater (p less than 0.001) than age-group-matched controls. The frequency, number, duration, and patterns of symptoms, as well as patient sex, were compared by age in study patients seropositive and seronegative for Epstein-Barr virus. Illness patterns were not associated with changes in specific antibody titers or clinical findings. Lymphocyte phenotype and function analyses were done in 11 of the 39 patients positive for Epstein-Barr virus antibody; no consistent differences from normal were found. Only 1 of 32 patients had circulating interferon, in contrast to 7 of 7 patients with acute infectious mononucleosis. There were many adverse consequences of the illness. Epstein-Barr virus infection may not be self-limiting, and the virus may be associated with clinically recognizable illness other than infectious mononucleosis in children as well as in adults.

Source:Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985 Jan;102(1):1-7. doi: 10.7326/0003-4819-102-1-. PMID: 2578266. https://pubmed.ncbi.nlm.nih.gov/2578266/

Assessment and Management of Long COVID

Abstract:

Almost two years into the pandemic, the scientific and healthcare communities continue to learn a great deal regarding COVID-19, the disease produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Broad variability during acute COVID-19 infection is seen, ranging from asymptomatic presentation to death. The vast majority of individuals who develop COVID-19 return to their pre-COVID-19 baseline within several weeks.

However, a portion of patients will develop a post-COVID-19 syndrome of persistent cognitive, somatic, and behavioral symptoms. This syndrome, designated as post-acute sequelae of SARS-CoV-2 infection, is more commonly known as long COVID. The objectives of this paper are to inform psychologists regarding our current understanding of the underlying pathophysiology of COVID-19, review criteria for range of severity during acute illness, present clinical manifestations of long haul phenomena, and discuss the emerging literature base of evidence-based treatment and management approaches.

Source: Rivas-Vazquez, R.A., Rey, G., Quintana, A. et al. Assessment and Management of Long COVID. J Health Serv Psychol 48, 21–30 (2022). https://doi.org/10.1007/s42843-022-00055-8  (Full study)

Stellate ganglion block reduces symptoms of Long COVID: A case series

Abstract:

After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble “sickness behavior,” the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to “reboot.” In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.

Source: Liu LD, Duricka DL. Stellate ganglion block reduces symptoms of Long COVID: A case series. J Neuroimmunol. 2021 Dec 8;362:577784. doi: 10.1016/j.jneuroim.2021.577784. Epub ahead of print. PMID: 34922127. https://www.jni-journal.com/article/S0165-5728(21)00311-8/fulltext (Full text)

Severe ME in Children

Abstract:

A current problem regarding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is the large proportion of doctors that are either not trained or refuse to recognize ME/CFS as a genuine clinical entity, and as a result do not diagnose it. An additional problem is that most of the clinical and research studies currently available on ME are focused on patients who are ambulant and able to attend clinics and there is very limited data on patients who are very severe (housebound or bedbound), despite the fact that they constitute an estimated 25% of all ME/CFS cases.

This author has personal experience of managing and advising on numerous cases of severe paediatric ME, and offers a series of case reports of individual cases as a means of illustrating various points regarding clinical presentation, together with general principles of appropriate management.

Source: Speight N. Severe ME in Children. Healthcare (Basel). 2020;8(3):E211. Published 2020 Jul 14. doi:10.3390/healthcare8030211 https://www.mdpi.com/2227-9032/8/3/211/htm (Full text)

Reply to Comment on Detection of Mycotoxin in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617″ by Mark J. Mendell

The authors of [1] have received further correspondence from Mark J. Mendell [2] concerning the above paper. We strongly disagree that the case series, which is reported by Brewer, et al., has flawed methodologies and is unsuitable for publication in a peer-reviewed journal. We also disagree that the control group selected was inappropriate and thus results invalidate comparison and findings.

Mendell emphasizes throughout his document that this is in essence a case-control study. This is simply not true. In reviewing his comments, we must emphasize that he is reviewing this paper as an epidemiologist and not as a M.D. As many, if not all, epidemiologists are aware, the purpose of epidemiology is to establish associations, which may be causative or may reveal clues to causation [3]. Wang and Attia (2010) stated: “to study causes or exposures known to be harmful, it is not ethical nor feasible to use an experimental design; for example, one cannot ask one group to start smoking and another to abstain from smoking to study if smoking causes age-related macular degeneration. Observational studies do not interfere in human subjects’ choice of exposure and assess outcomes in subjects who were exposed or not exposed to the factors of interest; these are surveys, case-control, cohort studies (all with controls) or case series (without controls)” [3]. Kempen, in 2011, stated the uncontrolled case series may suffer from a fundamental defect of lacking a contemporaneous comparison group which then leaves authors and readers to resort to historical controls [4]. He continues to state that observational case series make up a substantial proportion of publications submitted to journals (in his case, ophthalmic journals), which aspire to promulgate generalizable knowledge. When these studies are appropriately used, they serve an important and legitimate purpose in furthering medical knowledge, particularly when a question of importance cannot be addressed by other methods because of ethical or logistical constraints.

The Brewer paper reports a case series from a clinician who treats patients. Thus, reporting of a case series, such as the Brewer paper, adds to generalizable knowledge. Brewer et al. made no causal inferences from this case series.

Kempen states that observational case series receive very little attention among epidemiologists because of the limitations of no control [4]. This does not mean in any way that the observations reported are not meaningful and potentially helpful to care givers and their patients.

Kooistra et al. furthermore stated that case reports and case series that lack comparison groups might present data that is biased and incomplete [5]. Despite that, studies like this one are useful for generating hypotheses for future studies.

We understand the issues that Mendell cites but strongly disagree with his assessment. Mendell gives his points as an epidemiologist, the authors of Brewer, et al., point out the medical interpretation of such data and do not emphasize that this is an epidemiology study. To not publish these data or other case series would be limiting further future hypotheses and future studies in the area of chronic fatigue and mycotoxins.

 

Source: Brewer J, Thrasher JD, Hooper D. Reply to Comment on Detection of Mycotoxin in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617″ by Mark J. Mendell. Toxins (Basel). 2016 Nov 7;8(11). pii: E325. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127122/ (Full article)

 

Adrenal histoplasmosis: a case series and review of the literature

Abstract:

Adrenal histoplasmosis is an uncommon mycotic disease typically caused by Histoplasma capsulatum. The objective was to determine the clinicopathological findings in adrenal histoplasmosis.

Pathological records were searched from the database at the Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University from 1993 to 2008 for cases of adrenal histoplasmosis. The keywords were “histoplasmosis” and “adrenal gland”.

Adrenal histoplasmosis was diagnosed by histopathology and Gomori-Grocott methenamine silver staining. Histoplasma capsulatum was confirmed by tissue culture and/or serology. The authors report seven cases of adrenal histoplasmosis in immunocompetent patients. The mean age at diagnosis was 67 years. All patients presented as chronic fatigue syndrome.

The onset of symptoms ranged from one to three months. Addison’s disease was found in adrenal histoplasmosis in one case (14.3%). The computed tomography revealed adrenal nodules measuring 1.2 to 7.8 cm in diameter.

The histopathology showed granulomatous inflammation with caseous necrosis. Culture of adrenal tissue from two patients revealed Histoplasma capsulatum. Serum Histoplasma antibodies were positive in four cases. A cure was accomplished in 6 out of 7 cases (85.7%). The patients were followed up for 2.5 to 16.5 years.

 

Source: Larbcharoensub N, Boonsakan P, Aroonroch R, Rochanawutanon M, Nitiyanant P, Phongkitkarun S, Poonvutikul S, Watcharananan SP, Ngarmukos C. Adrenal histoplasmosis: a case series and review of the literature. Southeast Asian J Trop Med Public Health. 2011 Jul;42(4):920-5. https://www.ncbi.nlm.nih.gov/pubmed/22299474

 

Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. A patient with CFS had unexpected, marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for Hodgkin’s disease. We reasoned that the transient CFS recovery was related to methotrexate treatment, which induces immunomodulation in part through B-cell depletion.

METHODS: In a case series, this patient and two additional CFS patients were B-cell depleted by infusion of the monoclonal anti-CD20 antibody rituximab.

RESULTS: All three had improvement of all CFS symptoms. Patients 1 and 2 had major amelioration from 6 weeks after intervention, patient 3 slight improvement from the same time, but then improved markedly from 26 weeks after intervention. The symptomatic effect lasted until weeks 16, 18 and 44, respectively. At relapse, all were retreated with a single (patient 1) or double rituximab infusion (patients 2 and 3). Again, all three had marked symptom improvement, mimicking their first response. After new symptom recurrence, patients 1 and 2 were given weekly oral methotrexate, patient 1 having effect also from this agent. Patients 1 and 2 were again treated for a third rituximab infusion after new relapse, again with a marked clinical benefit. No unexpected toxicity was seen.

CONCLUSION: These observations suggest that B-lymphocytes are involved in CFS pathogenesis for a subset of patients. Benefit for all CFS symptoms, the delayed symptom relief following B-cell depletion, the kinetics of relapses, and the effect also from methotrexate treatment, provide suggestive evidence that B-cells play a significant role in the ongoing clinical features, and that CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function. More systematic investigations of this therapeutic strategy, and of its biological basis, are now needed.

 

Source: Fluge Ø, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711959/ (Full article)