Tag: Klimas

Remission of severe forms of long COVID following monoclonal antibody (MCA) infusions: A report of signal index cases and call for targeted research

Abstract:

Objective: Long COVID has afflicted tens of millions globally leaving many previously-healthy persons severely and indefinitely debilitated. The objective here was to report cases of complete, rapid remission of severe forms of long COVID following certain monoclonal antibody (MCA) infusions and review the corresponding pathophysiological implications.

Design: Case histories of the first three index events (among others) are presented. Unaware of others with similar remissions, each subject independently completed personal narratives and standardized surveys regarding demographics/occupation, past history, and the presence and respective severity grading of 33 signs/symptoms associated with long COVID, comparing the presence/severity of those symptoms during the pre-COVID, long-COVID, post-vaccination, and post-MCA phases.

Setting: Patient interviews, e-mails and telephone conversations.

Subjects: Three previously healthy, middle-aged, highly-functioning persons, two women and one man (ages 60, 43, and 63 years respectively) who, post-acute COVID-19 infection, developed chronic, unrelenting fatigue and cognitive impairment along with other severe, disabling symptoms. Each then independently reported incidental and unanticipated complete remissions within days of MCA treatment.

Interventions: The casirivimab/imdevimab cocktail.

Measurements and main results: Irrespective of sex, age, medical history, vaccination status, or illness duration (18, 8 and 5 months, respectively), each subject experienced the same complete remission of their persistent disabling disease within a week of MCA infusion. Each rapidly returned to normal health and previous lifestyles/occupations with normalized exercise tolerance, still sustained to date over two years later.

Conclusions: These index cases provide compelling clinical signals that MCA infusions may be capable of treating long COVID in certain cases, including those with severe debilitation. While the complete and sustained remissions observed here may only apply to long COVID resulting from pre-Delta variants and the specific MCA infused, the striking rapid and complete remissions observed in these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions and long COVID from other variants.

Source: Scheppke KA, Pepe PE, Jui J, Crowe RP, Scheppke EK, Klimas NG, Marty AM. Remission of severe forms of long COVID following monoclonal antibody (MCA) infusions: A report of signal index cases and call for targeted research. Am J Emerg Med. 2023 Oct 4;75:122-127. doi: 10.1016/j.ajem.2023.09.051. Epub ahead of print. PMID: 37944296. https://www.sciencedirect.com/science/article/pii/S073567572300534X (Full text)

Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: To examine ocular symptoms and signs of veterans with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnosis, ME/CFS symptoms, and controls.

Methods: This was a prospective, cross-sectional study of 124 South Florida veterans in active duty during the Gulf War era. Participants were recruited at an ophthalmology clinic at the Miami Veterans Affairs Hospital and evaluated for a diagnosis of ME/CFS, or symptoms of ME/CFS (intermediate fatigue, IF) using the Canadian Consensus criteria. Ocular symptoms were assessed via standardised questionnaires and signs via comprehensive slit lamp examination. Inflammatory blood markers were analysed and compared across groups.

Results: Mean age was 55.1 ± 4.7 years, 88.7% identified as male, 58.1% as White, and 39.5% as Hispanic. Ocular symptoms were more severe in the ME/CFS (n = 32) and IF (n = 48) groups compared to controls (n = 44) across dry eye (DE; Ocular Surface Disease Index [OSDI]: 48.9 ± 22.3 vs. 38.8 ± 23.3 vs. 19.1 ± 17.8, p < 0.001; 5 item Dry Eye Questionnaire [DEQ-5]: 10.8 ± 3.9 vs. 10.0 ± 4.6 vs. 6.6 ± 4.2, p < 0.001) and pain-specific questionnaires (Numerical Rating Scale 1-10 [NRS] right now: 2.4 ± 2.8 vs. 2.4 ± 2.9 vs 0.9 ± 1.5; p = 0.007; Neuropathic Pain Symptom Inventory modified for the Eye [NPSI-E]: 23.0 ± 18.6 vs. 19.8 ± 19.1 vs. 6.5 ± 9.0, p < 0.001). Ocular surface parameters and blood markers of inflammation were generally similar across groups.

Conclusion: Individuals with ME/CFS report increased ocular pain but similar DE signs, suggesting that mechanisms beyond the ocular surface contribute to symptoms.

Source: Victor Sanchez BS, Colin K. Kim BS, Elyana V. T. Locatelli BS, Adam K. Cohen, Kimberly Cabrera MS, Kristina Aenlle PhD, Nancy G. Klimas MD, Robert O’Brien PhD, Anat Galor MD, MSPH. Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome. First published: 12 November 2023 https://doi.org/10.1111/ceo.14313 https://onlinelibrary.wiley.com/doi/10.1111/ceo.14313 (Full text)

COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), could affect brain structure and function. SARS-CoV-2 can enter the brain through different routes, including the olfactory, trigeminal, and vagus nerves, and through blood and immunocytes. SARS-CoV-2 may also enter the brain from the peripheral blood through a disrupted blood-brain barrier (BBB).
The neurovascular unit in the brain, composed of neurons, astrocytes, endothelial cells, and pericytes, protects brain parenchyma by regulating the entry of substances from the blood. The endothelial cells, pericytes, and astrocytes highly express angiotensin converting enzyme 2 (ACE2), indicating that the BBB can be disturbed by SARS-CoV-2 and lead to derangements of tight junction and adherens junction proteins. This leads to increased BBB permeability, leakage of blood components, and movement of immune cells into the brain parenchyma. SARS-CoV-2 may also cross microvascular endothelial cells through an ACE2 receptor–associated pathway.
The exact mechanism of BBB dysregulation in COVID-19/neuro-COVID is not clearly known, nor is the development of long COVID. Various blood biomarkers could indicate disease severity and neurologic complications in COVID-19 and help objectively diagnose those developing long COVID. This review highlights the importance of neurovascular and BBB disruption, as well as some potentially useful biomarkers in COVID-19, and long COVID/neuro-COVID.
Source: Kempuraj D, Aenlle KK, Cohen J, Mathew A, Isler D, Pangeni RP, Nathanson L, Theoharides TC, Klimas NG. COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions. Neuroscientist. 2023 Sep 11:10738584231194927. doi: 10.1177/10738584231194927. Epub ahead of print. PMID: 37694571. https://pubmed.ncbi.nlm.nih.gov/37694571/

Cardiovascular risk factors predict who should have echocardiographic evaluation in long COVID

Abstract:

Background: The need for echocardiograms among patients with long COVID is debatable. Our aim was to evaluate the prevalence of left ventricular (LV) dysfunction and identify predictors.
Methods: We conducted a cross-sectional study and included all consecutive patients enrolled in our post-COVID clinic. We included patients who had an echocardiogram and had no previous known heart disease. We defined LV dysfunction as a low ejection fraction or grade II to grade III diastolic dysfunction on an echocardiogram with evidence of elevated filling pressures. We calculated the prevalence of heart disease and predictors of heart disease using logistic regression.
Results: We included 217 post-COVID patients enrolled in the clinic. The prevalence of LV dysfunction is 24%;95% CI 18-30. Predictors of heart disease include older age and a previous history of hypertension and diabetes or having a intermediate or high ASCVD score. Patients with low ASCVD score did not have low ejection fraction on the screening echocardiograms.
Conclusion: Our study found a considerable number of patients with LV dysfunction. Older patients with cardiovascular risk factors are at risk of long COVID associated heart disease.
Source: Leonardo Tamariz, Mathew Ryan, George Marzouka R, et al. Cardiovascular risk factors predict who should have echocardiographic evaluation in long COVID. Authorea. August 23, 2023. https://www.authorea.com/doi/full/10.22541/au.169277562.22633945 (Full text available as download)

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect 0.4%-2.5% of the global population. Most cases are unexplained; however, some patients describe an antecedent viral infection or response to antiviral medications.

We report here a multicenter study for the presence of viral nucleic acid in blood, feces, and saliva of patients with ME/CFS using polymerase chain reaction and high-throughput sequencing.

We found no consistent group-specific differences other than a lower prevalence of anelloviruses in cases compared to healthy controls. Our findings suggest that future investigations into viral infections in ME/CFS should focus on adaptive immune responses rather than surveillance for viral gene products.

Source: Briese T, Tokarz R, Bateman L, Che X, Guo C, Jain K, Kapoor V, Levine S, Hornig M, Oleynik A, Quan PL, Wong WH, Williams BL, Vernon SD, Klimas NG, Peterson DL, Montoya JG, Ian Lipkin W. A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome. J Med Virol. 2023 Aug;95(8):e28993. doi: 10.1002/jmv.28993. PMID: 37526404. https://pubmed.ncbi.nlm.nih.gov/37526404/ 

The Potential Role of Ocular and Otolaryngological Mucus Proteins in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness associated with a constellation of other symptoms. While the most common symptom is unrelenting fatigue, many individuals also report suffering from rhinitis, dry eyes and a sore throat.

Mucin proteins are responsible for contributing to the formation of mucosal membranes throughout the body. These mucosal pathways contribute to the body’s defense mechanisms involving pathogenic onset. When compromised by pathogens the epithelium releases numerous cytokines and enters a prolonged state of inflammation to eradicate any particular infection.

Based on genetic analysis, and computational theory and modeling we hypothesize that mucin protein dysfunction may contribute to ME/CFS symptoms due to the inability to form adequate mucosal layers throughout the body, especially in the ocular and otolaryngological pathways leading to low grade chronic inflammation and the exacerbation of symptoms.

Source: Kaylin Huitsing, Tara Tritsch, Francisco J. Carrera Arias et al. The Potential Role of Ocular and Otolaryngological Mucus Proteins in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, 24 July 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3171709/v1] https://www.researchsquare.com/article/rs-3171709/v1 (Full text)

 

Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multi-symptom illness characterized by debilitating fatigue and post-exertional malaise (PEM). Numerous studies have reported sex differences at the epidemiological, cellular, and molecular levels between male and female ME/CFS patients. To gain further insight into these sex-dependent changes, we evaluated differential gene expression by RNA-sequencing (RNA-Seq) in 33 ME/CFS patients (20 female, 13 male) and 34 matched healthy controls (20 female and 14 male) before, during, and after an exercise challenge intended to provoke PEM.
Our findings revealed that pathways related to immune-cell signaling (including IL-12) and natural killer cell cytotoxicity were activated as a result of exertion in the male ME/CFS cohort, while female ME/CFS patients did not show significant enough changes in gene expression to meet the criteria for the differential expression. Functional analysis during recovery from an exercise challenge showed that male ME/CFS patients had distinct changes in the regulation of specific cytokine signals (including IL-1β). Meanwhile, female ME/CFS patients had significant alterations in gene networks related to cell stress, response to herpes viruses, and NF-κβ signaling. The functional pathways and differentially expressed genes highlighted in this pilot project provide insight into the sex-specific pathophysiology of ME/CFS.
Source: Gamer J, Van Booven DJ, Zarnowski O, Arango S, Elias M, Kurian A, Joseph A, Perez M, Collado F, Klimas N, et al. Sex-Dependent Transcriptional Changes in Response to Stress in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Project. International Journal of Molecular Sciences. 2023; 24(12):10255. https://doi.org/10.3390/ijms241210255 https://www.mdpi.com/1422-0067/24/12/10255 (Full text)

The impact of post-traumatic stress on quality of life and fatigue in women with Gulf War Illness

Abstract:

Background: Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder characterized by fatigue, muscle pain, cognitive problems, insomnia, rashes, and gastrointestinal issues affecting an estimated 30% of the ~ 750,000 returning military Veterans of the 1990-1991 Persian Gulf War. Female Veterans deployed to combat in this war report medical symptoms, like cognition and respiratory troubles, at twice the rate compared to non-deployed female Veterans of the same era. The heterogeneity of GWI symptom presentation complicates diagnosis as well as the identification of effective treatments. This is exacerbated by the presence of co-morbidities. Defining subgroups of the illness may help alleviate these complications. One clear grouping is along the lines of gender. Our aim is to determine if women with GWI can be further subdivided into distinct subgroups based on post-traumatic stress disorder (PTSD) symptom presentation.

Methods: Veterans diagnosed with GWI (n = 35) and healthy sedentary controls (n = 35) were recruited through the Miami Veterans Affairs Medical Health Center. Symptoms were assessed via the RAND short form health survey, the multidimensional fatigue inventory, and the Davidson trauma scale. Hierarchal regression modeling was performed on measures of health and fatigue with PTSD symptoms as a covariate. This was followed by univariate analyses conducted with two separate GWI groups based on a cut-point of 70 for their total Davidson trauma scale value and performing heteroscedastic t-tests across all measures.

Results: Based on the distinct differences found in PTSD symptomology regarding all health and trauma symptoms, two subgroups were derived within female GWI Veterans. Hierarchical regression models displayed the comorbid effects of GWI and PTSD, as both conditions had measurable impacts on quality of life and fatigue (ΔR2 = 0.08-0.672), with notable differences in mental and emotional measures. Overall, a cut point analysis indicated poorer quality of life and greater fatigue within all measures for women with GWI and PTSD symptoms in comparison to those women with GWI without PTSD symptoms and healthy controls.

Conclusions: Our current findings support the understanding that comorbid symptoms of GWI and PTSD subsequently result in poorer quality of life and fatigue, along with establishing the possibility of varying clinical presentations.

Source: Shastry N, Sultana E, Jeffrey M, Collado F, Kibler J, DeLucia C, Fletcher MA, Klimas N, Craddock TJA. The impact of post-traumatic stress on quality of life and fatigue in women with Gulf War Illness. BMC Psychol. 2022 Feb 25;10(1):42. doi: 10.1186/s40359-022-00752-5. PMID: 35216624; PMCID: PMC8876751. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876751/ (Full text)

TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model

Abstract:

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive.

Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro.

Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.

Source: Bose D, Mondal A, Saha P, Kimono D, Sarkar S, Seth RK, Janulewicz P, Sullivan K, Horner R, Klimas N, Nagarkatti M, Nagarkatti P, Chatterjee S. TLR Antagonism by Sparstolonin B Alters Microbial Signature and Modulates Gastrointestinal and Neuronal Inflammation in Gulf War Illness Preclinical Model. Brain Sci. 2020 Aug 8;10(8):532. doi: 10.3390/brainsci10080532. PMID: 32784362; PMCID: PMC7463890. https://www.mdpi.com/2076-3425/10/8/532 (Full text)

Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms

Abstract:

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.

Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.

Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

Source: Cheng Guo, Xiaoyu Che, Thomas Briese, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, Brent L. Williams. Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms. medRxiv 2021.10.27.21265575; doi: https://doi.org/10.1101/2021.10.27.21265575 https://www.medrxiv.org/content/10.1101/2021.10.27.21265575v1?fbclid=IwAR16pb6by73xZx5lZM3j-5dOc_YT2JapILaRS-DcUZj5EHZxnoSa2fAAIuE (Full text available to download)