Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome

OBJECTIVES: One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses. METHODS: Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS. RESULTS: The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19\u27s hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors\u27 treated MCAS patients with Covid-19 suffered severe infection, let alone mortality. CONCLUSIONS: Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications

Post-HPV-vaccination mast cell activation syndrome: Possible vaccine-triggered escalation of undiagnosed pre-existing mast cell disease?

For nearly a decade, case reports and series have emerged regarding dysautonomias-particularly postural orthostatic tachycardia syndrome (POTS)-presenting soon after vaccination against human papilloma virus (HPV). We too have observed a number of such cases (all following vaccination with the Gardasil product), and have found several to have detectable mast cell activation syndrome (MCAS) as well as histories suggesting that MCAS was likely present long before vaccination. We detail 11 such cases here, posing a hypothesis that HPV vaccination (at least with the Gardasil product) may have triggered or exacerbated MCAS in teenagers previously not recognized to have it. Only recently recognized, MCAS is being increasingly appreciated as a prevalent and chronic multisystem disorder, often emerging early in life and presenting with inflammatory ± allergic phenomena following from known mast cell (MC) mediator effects. There is rising recognition, too, of associations of MCAS with central and peripheral neuropathic disorders, including autonomic disorders such as POTS. Given the recognized potential for many antigens to trigger a major and permanent escalation of baseline MC misbehavior in a given MCAS patient, we hypothesize that in our patients described herein, vaccination with Gardasil may have caused pre-existing (but not yet clinically recognized) MCAS to worsen to a clinically significantly degree, with the emergence of POTS and other issues. The recognition and management of MCAS prior to vaccinations in general may be a strategy worth investigating for reducing adverse events following HPV vaccinations and perhaps even other types of vaccinations

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

Restless legs syndrome shows increased silent postmortem cerebral microvascular disease with gliosis

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T-cell marker); (3) CD19 (a B-cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease

Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome

Background & AimsFew treatments have demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). A phase 3, randomized, double-blind, placebo-controlled trial was performed to evaluate the safety and efficacy of repeat treatment with the nonsystemic antibiotic rifaximin.MethodsThe trial included adults with IBS-D, mean abdominal pain and bloating scores of 3 or more, and loose stool, located at 270 centers in the United States and Europe from February 2012 through June 2014. Those responding to a 2-week course of open-label rifaximin 550 mg 3 times daily, who then relapsed during an observation phase (up to 18 weeks), were randomly assigned to groups given repeat treatments of rifaximin 550 mg or placebo 3 times daily for 2 weeks. The primary end point was percentage of responders after first repeat treatment, defined as a decrease in abdominal pain of ≥30% from baseline and a decrease in frequency of loose stools of ≥50% from baseline, for 2 or more weeks during a 4-week post-treatment period.ResultsOf 1074 patients (44.1%) who responded to open-label rifaximin, 382 (35.6%) did not relapse and 692 (64.4%) did; of these, 636 were randomly assigned to receive repeat treatment with rifaximin (n = 328) or placebo (n = 308). The percentage of responders was significantly greater with rifaximin than placebo (38.1% vs 31.5%; P = .03). The percentage of responders for abdominal pain (50.6% vs 42.2%; P = .018) was significantly greater with rifaximin than placebo, but not stool consistency (51.8% vs 50.0%; P = .42). Significant improvements were also noted for prevention of recurrence, durable response, and bowel movement urgency. Adverse event rates were low and similar between groups.ConclusionsIn a phase 3 study of patients with relapsing symptoms of IBS-D, repeat rifaximin treatment was efficacious and well tolerated. ClinicalTrials.gov ID: NCT01543178

Decreasing recurrent bowel obstructions, improving quality of life with physiotherapy: Controlled study

AIM: To compare (1) quality of life and (2) rate of recurrent small bowel obstructions (SBO) for patients treated with novel manual physiotherapy METHODS: One hundred and three subjects (age 19-89) with a history of recurrent adhesive SBO were treated with a manual physiotherapy called the Clear Passage Approach (CPA) which focused on decreasing adhesive crosslinking in abdominopelvic viscera. Pre- and post-therapy data measured recurring obstructions and quality of life, using a validated test sent 90 d after therapy. Results were compared to 136 untreated control subjects who underwent the same measurements for subjects who did not receive any therapy, which is the normal course for patients with recurring SBO. Comparison of the groups allowed us to assess changes when the physiotherapy was added as an adjunct treatment for patients with recurring SBO. RESULTS: Despite histories of more prior hospitalizations, obstructions, surgeries, and years impacted by bowel issues, the 103 CPA-treated subjects reported a significantly lower rate of repeat SBO than 136 untreated controls (total obstructions CONCLUSION: CPA physical therapy was effective for patients with adhesive SBO with significantly lower recurrence rate, improvement in reported symptoms and overall quality of life of subjects

Association of the infant gut microbiome with early childhood neurodevelopmental outcomes: An ancillary study to the VDAART randomized clinical trial

Importance: In animal models, the early life gut microbiome influences later neurodevelopment. Corresponding data in human populations are lacking. Objective: To study associations between the gut microbiome in infants and development at preschool age measured by the Ages and Stages Questionnaire, third edition (ASQ-3). Design, Setting, and Participants: This ancillary cohort study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART) used data from 715 participants who had development assessed at 3 years of age by the ASQ-3, which included scores in 5 domains (gross motor skills, fine motor skills, problem solving, communication, and personal and social skills). A total of 309 stool samples were collected from infants aged 3 to 6 months for microbiome analysis using 16S rRNA gene sequencing. Exposures: Infant gut microbiome. Main Outcomes and Measures: Continuous ASQ-3 scores and typical vs potential delay in the 5 developmental domains. Factor scores for bacterial coabundance groups were used as predictors in regression models of continuous ASQ-3 scores. Logistic regression was used to examine bacterial coabundance scores and odds of scoring below the threshold for typical development. Multivariate analysis examined the abundance of individual taxa and ASQ-3 scores. Results: The 309 participants (170 [55.0%] male) with ASQ-3 scores and stool samples were ethnically diverse (136 [44.0%] black, 41 [13.3%] Hispanic, 86 [27.8%] white, and 46 [14.9%] other race/ethnicity); the mean (SD) age at ASQ-3 assessment was 3.0 (0.07) years. Coabundance scores dominated by Clostridiales (Lachnospiraceae genera and other, unclassified Clostridiales taxa) were associated with poorer ASQ-3 communication (β, -1.12; 95% CI, -2.23 to -0.01; P = .05) and personal and social (β, -1.44; 95% CI, -2.47 to -0.40; P = .01) scores and with increased odds of potential delay for communication (odds ratio [OR], 1.69; 95% CI, 1.06 to 2.68) and personal and social skills (OR, 1.96; 95% CI, 1.22 to 3.15) per unit increase in coabundance score. The Bacteroides-dominated coabundance grouping was associated with poorer fine motor scores (β, -2.42; 95% CI, -4.29 to -0.55; P = .01) and with increased odds of potential delay for fine motor skills (OR, 1.52; 95% CI, 1.07 to 2.16) per unit increase in coabundance score. Multivariate analysis detected similar family-level and order-level associations. Conclusions and Relevance: These findings suggest an association between infant gut microbiome composition and communication, personal and social, and fine motor skills at age 3 years. The majority of associations were driven by taxa within the order Clostridiales

Remodeling of Retinal Fatty Acids in an Animal Model of Diabetes: A Decrease in Long-Chain Polyunsaturated Fatty Acids Is Associated With a Decrease in Fatty Acid Elongases Elovl2 and Elovl4

OBJECTIVE: The results of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort study revealed a strong association between dyslipidemia and the development of diabetic retinopathy. However, there are no experimental data on retinal fatty acid metabolism in diabetes. This study determined retinal-specific fatty acid metabolism in control and diabetic animals. RESEARCH DESIGN AND METHODS: Tissue gene and protein expression profiles were determined by quantitative RT-PCR and Western blot in control and streptozotocin-induced diabetic rats at 3-6 weeks of diabetes. Fatty acid profiles were assessed by reverse-phase high-performance liquid chromatography, and phospholipid analysis was performed by nano-electrospray ionization tandem mass spectrometry. RESULTS: We found a dramatic difference between retinal and liver elongase and desaturase profiles with high elongase and low desaturase gene expression in the retina compared with liver. Elovl4, an elongase expressed in the retina but not in the liver, showed the greatest expression level among retinal elongases, followed by Elovl2, Elovl1, and Elovl6. Importantly, early-stage diabetes induced a marked decrease in retinal expression levels of Elovl4, Elovl2, and Elovl6. Diabetes-induced downregulation of retinal elongases translated into a significant decrease in total retinal docosahexaenoic acid, as well as decreased incorporation of very-long-chain polyunsaturated fatty acids (PUFAs), particularly 32:6n3, into retinal phosphatidylcholine. This decrease in n3 PUFAs was coupled with inflammatory status in diabetic retina, reflected by an increase in gene expression of proinflammatory markers interleukin-6, vascular endothelial growth factor, and intercellular adhesion molecule-1. CONCLUSIONS: This is the first comprehensive study demonstrating diabetes-induced changes in retinal fatty acid metabolism. Normalization of retinal fatty acid levels by dietary means or/and modulating expression of elongases could represent a potential therapeutic target for diabetes-induced retinal inflammation