MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet (preprint)

Long Covid (LC), Chronic Fatigue Syndrome (CFS), Postural Orthostatic Tachycardia Syndrome (POTS), Mast Cell Activation Syndrome (MCAS), Small Intestine Bacterial Overgrowth (SIBO), and Ehlers-Danlos Syndrome (EDS) are all loosely connected, some poorly defined, some with overlapping symptoms. The female preponderance, the prominence of fatigue and chronic inflammation, and methylenetetrahydrofolate reductase (MTHFR) abnormalities may connect them all. Indeed differential methylation may lie at the root. Two - EDS and MTHFR - are genetic. But epigenetic factors may ultimately determine their phenotypic expression. Oxidative stress, overloaded mitochondria, an antioxidant and nutrient shortfall, and suboptimal gut microbiome appear to be the primary determinants. A deep dive into the folate and methionine cycles is undertaken in an attempt to connect these syndromes. The active forms of vitamin D and vitamins B2,3,6,9,12 are shown to be biochemically integral to optimal methylation and control of the epigenome. Their status largely determines the symptoms of abnormal MTHFR in all its phenotypes. The wider implications for aging, cancer, cardiovascular disease, neurodegenerative disease, and autoimmune disease are briefly explored.

Internal tremors and vibrations in long COVID: a cross-sectional study (preprint)

Background: Internal tremors and vibrations symptoms have been described as part of neurologic disorders but have not been fully described as a part of long COVID. We compared demographics, socioeconomic characteristics, pre-pandemic comorbidities, and new-onset conditions between people with internal tremors and vibrations as part of their long COVID symptoms and people with long COVID but without these symptoms. Methods: A cross-sectional study, Listen to Immune, Symptom and Treatment Experiences Now (LISTEN), collected data from adults with long COVID. The study sample included 423 participants enrolled between May 2022 and June 2023. Results: The 423 participants had a median age of 46 years (interquartile range, 38-56), 74% were female, 87% were Non-Hispanic White, and 158 (37%) reported "internal tremors, or buzzing/vibration" as a long COVID symptom. Before long COVID, the groups had similar comorbidities. Post-COVID, participants with internal tremors and vibrations had significantly worse health as measured by the Euro-QoL visual analogue scale (median: 40 vs. 50 points, P = 0.007), higher rates of financial difficulties caused by the pandemic and housing insecurity (P < 0.001 for each), and were significantly more likely to have new-onset conditions of mast cell disorders (11% vs. 2.6%), neurologic conditions (22% vs. 8.3%), anxiety (20% vs. 8.7%), and trauma- or stress-related mental health disorders (12% vs. 3.4%) compared with those without internal tremors (Bonferroni-adjusted P < 0.05 for each). Participants with internal tremors also reported significantly higher rates of cardiovascular, gastrointestinal, integumentary, and neurologic long COVID symptoms compared with those without internal tremors (Bonferroni-adjusted P < 0.05 for each). Conclusions and Relevance: Among people with long COVID, those with internal tremors and vibrations have more associated symptoms and worse health status, suggesting it may be associated with a severe phenotype of the condition.

Incidence of symptomatic Covid-19 infections in patients with mastocytosis and chronic myeloid leukemia: A comparison with the general Austrian population.

BACKGROUND: The SARS-COV-2 (Covid-19) pandemic has impacted the management of patients with hematologic disorders. In some entities, an increased risk for Covid-19 infections was reported, whereas others including chronic myeloid leukemia (CML) had a lower mortality. We have analyzed the prevalence of Covid-19 infections in patients with mastocytosis during the Covid-19 pandemic in comparison to data from CML patients and the general Austrian population. MATERIALS AND METHODS: The prevalence of infections and PCR-proven Covid-19 infections was analyzed in 92 patients with mastocytosis. As controls, we used 113 patients with CML and the expected prevalence of Covid-19 in the general Austrian population. RESULTS: In 25% of the patients with mastocytosis (23/92) signs and symptoms of infection, including fever (n = 11), dry cough (n = 10), sore throat (n = 12), pneumonia (n = 1), and dyspnea (n = 3) were recorded. Two (8.7%) of these symptomatic patients had a PCR-proven Covid-19 infection. Thus, the prevalence of Covid-19 infections in mastocytosis was 2.2%. The number of comorbidities, subtype of mastocytosis, regular exercise, smoking habits, age, or duration of disease at the time of interview did not differ significantly between patients with and without Covid-19 infections. In the CML cohort, 23.9% (27/113) of patients reported signs and symptoms of infection (fever, n = 8; dry cough, n = 17; sore throat, n = 11; dyspnea, n = 5). Six (22.2%) of the symptomatic patients had a PCR-proven Covid-19 infection. The prevalence of Covid-19 in all CML patients was 5.3%. The observed number of Covid-19 infections neither in mastocytosis nor in CML patients differed significantly from the expected number of Covid-19 infections in the Austrian population. CONCLUSIONS: Our data show no significant difference in the prevalence of Covid-19 infections among patients with mastocytosis, CML, and the general Austrian population and thus, in mastocytosis, the risk of a Covid-19 infection was not increased compared to the general population.

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis (preprint)

Long COVID describes an array of often debilitating symptoms in the aftermath of SARS-CoV-2 infection, with similar symptomatology affecting some people post-vaccination. With an estimated > 200 million Long COVID patients worldwide and cases still rising, the effects on quality of life and the economy are significant, thus warranting urgent attention to understand the pathophysiology. Herein we describe our perspective that Long COVID is a continuation of acute COVID-19 pathology, whereby coagulopathy is the main driver of disease and can cause or exacerbate other pathologies common in Long COVID, such as mast cell activation syndrome and dysautonomia. Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID. We discuss several treatment targets to address the coagulopathy, and predict that (particularly early) treatment with combination anticoagulant and antiplatelet drugs will bring significant relief to many patients, supported by a case study. To help focus attention on such treatment targets, we propose Long COVID should be referred to as Spike protein Induced Thrombotic Vasculitis (SITV). These ideas require urgent testing, especially as the world tries to co-exist with COVID-19.

Pathophysiology of Post-COVID syndromes: a new perspective.

Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as "long-COVID" or "Post-COVID syndrome" (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence.

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can affect almost all systems and organs of the human body, including those responsible for reproductive function in women. The multisystem inflammatory response in COVID-19 shows many analogies with mast cell activation syndrome (MCAS), and MCAS may be an important component in the course of COVID-19. Of note, the female sex hormones estradiol (E2) and progesterone (P4) significantly influence mast cell (MC) behavior. This review presents the importance of MCs and the mediators from their granules in the female reproductive system, including pregnancy, and discusses the mechanism of potential disorders related to MCAS. Then, the available data on COVID-19 in the context of hormonal disorders, the course of endometriosis, female fertility, and the course of pregnancy were compiled to verify intuitively predicted threats. Surprisingly, although COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as significantly increasing the risk of abnormal female reproductive function, including pregnancy. Further studies in the context of post COVID-19 condition (long COVID), where inflammation and a procoagulative state resemble many aspects of MCAS, are needed.

Effective Anti-SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders.

BACKGROUND: Mast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published. OBJECTIVE: To study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting. METHODS: Clinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti-SARS-CoV-2-specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies. RESULTS: Overall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2-specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2-specific, IFN-γ-producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden). CONCLUSIONS: Patients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.

Absence of severe COVID-19 in patients with clonal mast cells activation disorders: effective anti-SARS-CoV-2 immune response. (preprint)

Mast cells are key actors of innate immunity and Th2 adaptive immune response which counterbalance Th1 response, critical for anti-viral immunity. Clonal Mast Cells Activation Disorders (cMCADs) such as mastocytosis and clonal mast cells activation syndrome are characterized by an abnormal mast cells accumulation and/or activation. No data have been published on the anti-viral immune response of patients with cMCADs. The aims of the study were to collected, in a comprehensive way, outcomes of cMCADs patients who experienced a biologically-proven COVID-19 and to characterize both anti-endemic coronaviruses and specific anti-SARS-CoV-2 immune responses in these patients. Clinical follow-up and outcome data were collected prospectively for one year within the French rare disease network CEREMAST encompassing patients from all over the country. Anti-SARS-CoV-2 and anti-endemic coronaviruses specific T-cells were assessed with an enzyme-linked immunospot assay (EliSpot) and anti-SARS-CoV-2 humoral response with dosage of circulating levels of specific IgG, IgA and neutralizing antibodies. Overall, 32 cMCADs patients were identified. None of them required non-invasive or mechanical ventilation; two patients were hospitalized to receive oxygen and steroid therapy. In 21 patients, a characterization of the SARS-CoV-2-specific immune response has been performed. A majority of patients showed a high proportion of circulating SARS-CoV-2-specific interferon (IFN)-{gamma} producing T-cells and high levels of anti-Spike IgG antibodies with neutralizing activity. In addition, no defects in anti-endemic coronaviruses responses were found in patients with cMCADs compared to non-cMCADs controls. Patients with cMCADs frequently showed a spontaneous IFN-{gamma} T-cell production in absence of any stimulation that correlated with circulating basal tryptase levels, a marker of mast cells burden. These findings underscore that patients with cMCADs might be not at risk of severe COVID-19 and the spontaneous IFN-{gamma} production might explain this observation. Author SummaryMast cells are immune cells involved in many biological processes including the anti-microbial response. However, previous studies suggest that mast cells may have a detrimental role in the response against viruses such as SARS-CoV-2, responsible for COVID-19. When a mutation occurs in mast cells, it can lead to a group of diseases called clonal mast cells activation disorders (cMCADs), characterized by deregulated activation of these cells. Hence, patients with cMCADs might be more susceptible to severe COVID-19 than general population. We therefore conducted a 1-year study in France to collect data from all cMCADs patients included in the CEREMAST rare disease French network and who experienced COVID-19. Interestingly, we did not find any severe COVID-19 (i.e. requiring non-invasive or mechanical ventilation) in spite of well-known risk factors for severe COVID-19 in a part of cMCADs patients. We then have studied the immune response against SARS-CoV-2 and other endemic coronaviruses in these patients. We did not observe any abnormalities in the immune response either at the level of T and B lymphocytes. These findings underscore that these patients might not be at risk of severe COVID-19 as one might have feared.

Impact of mental health on disease activity in mastocytosis during COVID-19 pandemic.

BACKGROUND: Mast cell-related symptoms might be influenced by mental health status in mastocytosis. In this study, we aimed to investigate the influence of mental health problems developed during the COVID-19 pandemic on the course of mastocytosis. METHODS: Mental health status in 60 adult patients with mastocytosis was prospectively evaluated with the total Depression-Anxiety-Stress Scale (tDASS-21) and Fear of COVID-19 Scale (FCV-19S) in the lockdown period (LP) and the return to normal period (RTNP) during the pandemic. The disease course was assessed from emergency and outpatient medical reports, including Scoring Mastocytosis (SCORMA) index and serum baseline tryptase levels, by telephone interviews and clinical visits. RESULTS: The mean FCV-19S and median tDASS-21 scores were significantly higher in LP than RTNP (p < 0.001) and there was a positive correlation between FCV-19S and tDASS-21 in LP (r = 0.820, p < 0.001) and in RTNP (r = 0.572 p= <0.001). Disease-related symptoms including skin lesions, flushing and anaphylaxis attacks increased in 22 patients in LP, and in this group, mean FCV-19S and median tDASS-21 were higher than those without symptom exacerbation (p < 0.001). During the study period, four (6.7%) patients who experienced COVID-19 recovered without any requirement for hospitalization and had not experienced symptom exacerbation. CONCLUSIONS: Fear of COVID-19 can be a reason for mental health changes, including depression, anxiety and stress which may further increase mast cell-related symptoms. Therefore, psychological support is important to control the severity of mast cell-related symptoms in mastocytosis during a pandemic.

Recommendations for the Recognition, Diagnosis, and Management of Patients with Post COVID-19 Condition ('Long COVID'): A Delphi Study (preprint)

Background: The present work aims to provide a rapid expert guide for Post Covid-19 Condition (“long covid”) clinical services. In the absence of research into mechanisms, therapies and care pathways, yet faced with an urgent need, guidance based on “emerging experience” is required.Methods: The authors generated 33 recommendations pertaining to the recognition, investigation, and management of long covid. These were distributed online to a Delphi panel of UK doctors (any specialty) with an interest in, lived experience of, and/or experience treating long covid. Over two rounds of Delphi testing, panellists indicated their agreement with each recommendation (a 5-point Likert scale) and gave comments. Recommendations eliciting a response of “strongly agree”, “agree”, or “neither agree nor disagree” from ≥90% of respondents were taken as showing consensus. Findings: Thirty-three UK-based clinicians representing 14 specialties completed both rounds of the Delphi. Twenty-nine (88%) had lived experience of long covid and five (15%) were clinicians developing services for long covid. Of the 33 recommendations presented in Round 1, 18 were incorporated into the final list, 13 were amended to reflect respondents’ feedback, and two were excluded. Of the 19 presented in Round 2, 17 were added to the final list and two were excluded. The final list thus comprised 35 recommendations: six pertaining to clinic organisation, 13 to diagnosis of the underlying disorder, and 16 to management.Interpretation: Long covid clinics need to operate not in isolation but in the context of rapidly evolving practice amongst both GPs and specialists. Care pathways in holistic care, investigation of specific complications, management of potential symptom clusters in cardiac disease, dysautonomia and mast cell disorder, and individualised rehabilitation are needed.Funding: The first author is funded by the NIHR Imperial PSTRC; however, this research received no specific grant from any funding agency.Declaration of Interest: There are no conflicts of interest.Ethical Approval: As this is considered service development, ethical approval was not required for this study. Delphi participants gave informed consent before taking part. All aspects of the study were conducted in the UK in January-March 2021.

COVID-19 Vaccination in Mastocytosis: Recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM).

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Coronavirus disease 2019 (COVID-19) is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against COVID-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of COVID-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of COVID-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and postvaccination observation, should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations, and expert opinion that form the basis of these recommendations.

Mast Cells and COVID-19: a case report implicating a role of mast cell activation in the prevention and treatment of Covid-19 (preprint)

Coronavirus disease (COVID-19) is a heterogeneous syndrome following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the upper respiratory tract. ln adults, the clinical condition can range from asymptomatic cases to severe acute respiratory syndrome and multi-organ dysfunction. Those at risk of developing COVID-19 related hyperinflammatory syndrome likely had an ineffective, innate immune response to this novel pathogen. Mast cells are associated with the epithelium, contributing to tissue homeostasis and epithelial barrier defense. Equipped with an array of pathogen receptors, mast cells exhibit distinct cytokine profiles, dependent on the tissue and the triggered pathogen receptors. Following viral infections, mast cells produce pro-inflammatory chemical mediators, such as interleukin-1 (IL-1) and IL-6, and these cytokines has been shown to be elevated in severe COVID-19 cases. Here, we present a case of a patient with a longstanding history of signs and symptoms, worrisome for a mast cell activation syndrome (MCAS), but never had laboratory confirmation of this non-clonal mast cell activation disorder, until she contracted COVID-19. This case illustrates the need to recognize the rate of mast cell activation in SARS-CoV-2 infection, not only to optimize anti-SARS-CoV-2 therapy, including the development of vaccine, but to potentially curb the risk of SARS­ CoV-2 triggered hyperinflammatory syndrome.

Unmasked: an insight into three patients' rare disease experiences during the COVID-19 pandemic.

This article describes my reflections of speaking with three patients and their families living with mastocytosis, who I was introduced to through the UK Mastocytosis Support Group. I discuss the various ways in which the condition affects their day-to-day lives and how this has changed during the Covid-19 pandemic. I have tried to give an insight into the particular difficulties that this patient group faces, both during and before the pandemic, whilst also considering how these challenges may resonate more widely with other patient groups in the rare disease community. Pseudonyms are used throughout to protect patient anonymity.

Removing Fuel from Coronavirus Fire: Blocking Superoxide with Apocynin and Paeonol (preprint)

Background: The toll of the coronavirus pandemic needs little introduction. The commencement of vaccination is both impressive and welcome but insufficient to achieve herd immunity. Consequently, additional approaches are urgently needed for pandemic abatement.Hypothesis: Inhibiting the human NADPH oxidase enzyme can reduce the morbidly and mortality of severe coronavirus infection by preventing excess production of superoxide free radicals, the reason behind severe infection. This can be accomplished with apocynin, a historic natural well-researched compound, and its derivative paeonol, present in the readily available peony root.Evidence: The common denominator of who dies from coronavirus (the aged, males, post-menopausal females, African Americans, obesity, diabetics, hypertensives, chronic heart, liver, kidney disease patients) is oxidative stress. Moreover, the source can be traced specifically to a higher endogenous production of the reactive oxygen species superoxide from NADPH-oxidase activity shared by these groups. In addition, interventions for coronavirus infection that act on the host (Vitamins C, D, B3, melatonin, estrogen, nicotine) all decrease NADPH oxidase activity even when not the stated reason for use. Finally, apocynin’s well-studied use as a highly effective NADPH inhibitor is covered. Implications: The direct implication is reduction in serious infections and deaths. especially in COVID-vulnerable groups. Apocynin may also be capable of targeting other lethal viruses that co-evolved with bats in the same oxygen-rich milieu, such as Ebola. An intriguing potential application is in Chronic Fatigue Syndrome, Mast Cell Activation Syndrome, and dysautonomia, all with symptoms resembling the COVID long-hauler syndrome. Finally, as the role of NADPH oxidase in conditions of aging such as cardiovascular disease and neurodegeneration is being increasingly recognized, apocynin as “vitamin of the 21st century” for longevity warrants investigation.Conclusion: Oxidative bursts kill pathogens but can be exploited by viruses to replicate. By removing this fuel from coronavirus fire, apocynin and peony root are safe available compounds dating to antiquity that become attractive contenders for rapid pandemic relief.