Efficacy and toxicity of hydroxyurea in mast cell activation syndrome patients refractory to standard medical therapy: retrospective case series.

Determine efficacy and adverse events (AEs) of hydroxyurea (HU) in mast cell activation syndrome (MCAS) patients who were refractory to standard medical therapy. An electronic chart review was performed to find MCAS patients who received HU in a MCAS medical practice. Diagnosis of MCAS was established on the basis of mast cell (MC) activation symptoms in ≥ 5 systems plus ≥ 1 abnormal MC mediators and/or ≥ 20 MC/high power field on duodenal biopsies. Medicines not providing significant clinical improvement prior to HU were tabulated. The following symptoms were evaluated by patients on a 0-10 scale prior to and at the study conclusion: bone pain, abdominal pain, diarrhea, bloating, and nausea. Safety labs were obtained on a regular basis. Twenty out of three hundred ten (8.4%) MCAS patients received HU. Patients included 22 females, average age 42.4 years. Dysautonomia was present in 60%. An average of 10.6 (SD 1.7, range 8-13) medications were used prior to adding HU to various concomitant medications. Average dose of HU was 634 mg. In 20 patients who continued therapy for ≥ 2 months, there was statistically significant reduction of bone pain, abdominal pain, diarrhea, bloating, and nausea. Fourteen patients noted prolonged success with therapy. Six patients stopped HU within 6 weeks owing to AEs. Four patients treated ≥ 2 months had AEs and 2 led to HU cessation. All AEs were reversible. Refractory MCAS patients showed clear significant improvement in bone pain and gastrointestinal symptoms on HU. Systematic monitoring was effective in preventing the occurrence of severe HU-induced adverse events.

Restless legs syndrome is associated with long-COVID in women.

STUDY OBJECTIVES: Sleep disturbance is common in long-COVID (LC). Restless legs syndrome (RLS) is characterized by sleep disturbance and has been reported after viral infections. Therefore, we evaluated RLS symptoms cross-sectionally in individuals with LC at both current and pre-coronavirus disease 2019 (pre-COVID-19) time points. METHODS: Adults on LC-focused Facebook pages were recruited for an online assessment of symptoms before COVID-19 infection and during their present LC state in a cross-sectional manner. The LC group documented baseline symptoms retrospectively. Questions were included about the presence/severity of RLS symptoms and assessments of fatigue, quality of life, and sleep apnea. A control group was recruited and included individuals ≥ 18 years of age who never had overt symptoms of COVID-19. Pregnancy was an exclusion criterion for both groups. RESULTS: There were 136 participants with LC (89.7% females, age 46.9 ± 12.9 years) and 136 controls (65.4% females, age 49.2 ± 15.5). RLS prevalence in females with LC was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (P < .01) vs 6.7% in control females. Severity of RLS was moderate in both groups. Logistic regression predicting post-COVID-19 RLS among females with LC failed to find significant effects of hospitalization, sleep apnea, neuropathic pain severity, or use of antihistamines and antidepressants. CONCLUSIONS: The baseline prevalence of RLS in females with LC was similar to the general population group as well as to patients in epidemiological studies. The prevalence significantly increased in the LC state. Postinfectious immunological mechanisms may be at play in the production for RLS symptoms. CITATION: Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Restless legs syndrome is associated with long-COVID in women. J Clin Sleep Med. 2022;18(5):1413-1418.

Mast cell activation symptoms are prevalent in Long-COVID.

OBJECTIVES: Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms. We determined prevalence/severity of MCA symptoms in LC. METHODS: Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms. RESULTS: There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis. CONCLUSIONS: MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.

Diagnosis of mast cell activation syndrome: a global "consensus-2".

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Restless legs syndrome is associated with mast cell activation syndrome.

STUDY OBJECTIVES: Mast cell activation syndrome (MCAS) is an inflammatory and allergic disorder. We determined the prevalence of restless legs syndrome (RLS) in MCAS because each common syndrome may be inflammatory in nature and associated with dysautonomia. METHODS: Individuals with MCAS were evaluated for RLS by two standard questionnaires. Prevalence comparisons included spouse control patients and two prevalence publications. MCAS diagnosis required mast cell (MC) symptoms in ≥ 2 organs plus ≥ 1 elevated MC mediators, improvement with MC therapy, and/or increased intestinal MC density. Clinical variables were studied. RESULTS: There were 174 patients with MCAS (146 female, 28 male, mean age 44.8 years) and 85 spouse control patients (12 female, 73 male, mean age 50.9 years). Patients with MCAS as a whole had a higher prevalence of RLS (40.8%) than spouse control (12.9%) (P < .0001) Male patients with MCAS had a higher prevalence of RLS (32.1%) than male controls (12.3%, odds ratio [OR] 3.4, confidence interval [CI] 1.2-9.7, P = .025), American men (8.4%, OR 5.2, CI 2.2-12.0, P < .001), and French men (5.8%, OR 7.7, CI 3.4-17.1, P < .001). Female patients with MCAS also had a higher prevalence of RLS (42.5%) than female controls (16.7%) but this did not reach statistical significance perhaps because of the sample size of the female controls. However, female patients with MCAS had a statistically higher prevalence of RLS than American women (10.0%, OR 6.7, CI 4.5-9.7, P < .0001) and French women (10.8%, OR 6.1, CI 4.4-8.6, P < .0001). CONCLUSIONS: RLS appears to be associated with MCAS. Effects of mast cell mediators, inflammation, immune mechanisms, dysautonomia, or hypoxia may theoretically activate RLS in MCAS.

Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment.

A patient with severe postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS) received immunotherapy with low-dose naltrexone (LDN) and intravenous immunoglobulin (IVIg) and antibiotic therapy for small intestinal bacterial overgrowth (SIBO). A dramatic and sustained response was documented. The utility of IVIg in autoimmune neuromuscular diseases has been published, but clinical experience with POTS is relatively unknown and has not been reported in MCAS. As a short-acting mu-opioid antagonist, LDN paradoxically increases endorphins which then bind to regulatory T cells which regulate T-lymphocyte and B-lymphocyte production and this reduces cytokine and antibody production. IVIg is emerging as a promising therapy for POTS. Diagnosis and treatment of SIBO in POTS is a new concept and appears to play an important role.