Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib.

INTRODUCTION: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. CONCLUSION: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.

Phaeohyphomycosis in Solid Organ Transplant Recipients: A Case Series and Narrative Review of the Literature.

Phaeohyphomycosis comprises a variety of infections caused by pigmented fungi. Solid organ transplant (SOT) recipients are particularly at risk of invasive infections due to their prolonged immunosuppression. Here, we describe three cases of phaeohyphomycosis in SOT recipients who were successfully treated with surgical excision and/or antifungal therapy. We additionally carried out a narrative review of the literature on phaeohyphomycosis in 94 SOT recipients from 66 published studies describing 40 different species of fungi. The most reported fungus was Alternaria (21%). The median time from transplant to diagnosis was 18 months (IQR 8.25-48), and kidney transplants were the most reported. Antifungal regimens were not homogeneous, though there was a prevalence of itraconazole- and voriconazole-based treatments. Clinical outcomes included recovery in 81% and death in 5% of infected SOT recipients. Susceptibility testing was done in 26.6% of the cases, with heterogeneous results due to the variety of species isolated. While the wide diversity of dematiaceous fungi and their host range make it difficult to offer a uniform approach for phaeohyphomycosis, an early diagnosis and therapy are critical in preventing the dissemination of disease in the immunocompromised host.

The Test of Masticating and Swallowing Solids (TOMASS): Reliability and validity in patients with dysphagia.

BACKGROUND: The Test of Masticating and Swallowing Solids (TOMASS) is an international standardized swallowing assessment tool. However, its psychometric characteristics have not been analysed in patients with dysphagia. AIMS: To analyse TOMASS's (1) inter- and intra-rater reliability in a clinical population of patients with dysphagia, (2) known-group validity, (3) concurrent validity and (4) correlation with meal duration. METHODS & PROCEDURES: Two age- and gender-matched groups of 39 participants each were recruited: A group of patients with dysphagia and a control group with no history of dysphagia. The TOMASS was carried out in both populations, video-recorded and scored offline by two speech and language therapists (SLT 1 and SLT 2) (inter-rater reliability) and twice by the same SLT (intra-rater reliability). In the clinical group, the TOMASS was carried out three times: (1) to verify understanding of the required tasks, (2) performed concurrently during fibreoptic endoscopic evaluation of swallowing (FEES) to assess validity and (3) during clinical assessment to assess reliability. TOMASS under endoscopic control was recorded and the number of white-out events was counted to compare with the number of observed swallows per cracker during standard TOMASS as a measure of concurrent validity. As additional measures of TOMASS validity, oral dental status, classified as 'functional' or 'partially functional', and duration of a standard meal were assessed by an SLT (SLT 1 or SLT 2), and then correlated with TOMASS. OUTCOME & RESULTS: TOMASS's inter- and intra-rater reliability were high (intraclass correlation coefficient (ICC) > 0.95) in both the clinical and the control groups. The number of masticatory cycles (p = 0.020), swallows (p = 0.013) and total time (p = 0.003) of TOMASS were significantly lower in the control group than in the clinical group. Patients with 'partially functional' oral dental status showed a significantly higher number of masticatory cycles per cracker and a longer duration of ingestion than patients with a 'functional' one. Concurrent validity suggested a substantial agreement between TOMASS and FEES in defining the number of swallows per cracker. The mean difference of the two measures was -0.02 (95% confidence interval (CI) = -1.7 to 1.2). Meal duration significantly correlated with the 'number of swallows per cracker' (r = 0.49; p = 0.002) and 'total time' (r = 0.41; p = 0.011). CONCLUSIONS & IMPLICATIONS: Preliminary psychometric analysis of TOMASS in a clinical sample of outpatients with dysphagia suggests that it is a reliable and valid (specifically related to the number of swallows per cracker) tool. TOMASS's application in clinical practice to quantitatively measure solid bolus ingestion is recommended. What this paper adds What is already known on the subject The Test of Masticating and Swallowing Solids (TOMASS) is an international standardized swallowing assessment tool to evaluate oral preparation and oral phase of solids. The TOMASS' reliability and validity were tested on healthy subjects and normative data were gained. What this paper adds to existing knowledge The study provides the first data on the validity and reliability of the TOMASS in a clinical population. The TOMASS was proved to be a reliable and valid tool also in patients with dysphagia and to distinguish between patients with dysphagia and healthy subjects. What are the potential or actual clinical implications of this work? The use of the TOMASS in clinical practice is recommended as a valid and reliable tool to quantitatively measure the ingestion of solid in patients with dysphagia.

Signal transducer and activator of transcription gain-of-function primary immunodeficiency/immunodysregulation disorders.

PURPOSE OF REVIEW: To describe primary immunodeficiencies caused by gain-of-function (GOF) mutations of signal transducer and activator of transcription (STAT) genes, a group of genetically determined disorders characterized by susceptibility to infections and, in many cases, autoimmune manifestations. RECENT FINDINGS: GOF mutations affecting STAT1 result in increased STAT tyrosine phosphorylation and secondarily increased response to STAT1-signaling cytokines, such as interferons. In contrast, STAT3 hyperactivity is not usually related to hyperphosphorylation but rather to increased STAT3-mediated transcriptional activity. In both cases, heterozygous STAT1 and STAT3 GOF mutations trigger a distinct set of genes in target cells that lead to abnormal functioning of antimicrobial response and/or autoimmunity and result in autosomal dominant diseases. SUMMARY: Clinical manifestations of patients with STAT1 GOF are characterized by mucocutaneous candidiasis and recurrent lower tract respiratory infections. In addition, many patients have thyroiditis, type 1 diabetes mellitus, autoimmune cytopenias, cancer or aneurysms. Patients with germline STAT3 GOF mutations have an increased frequency of early-onset multiorgan autoimmunity (i.e. autoimmune enteropathy, type 1 diabetes mellitus, autoimmune interstitial lung disease and autoimmune cytopenias), lymphoproliferation, short stature and, less frequently, severe recurrent infections. Treatment options range from antimicrobial therapy, intravenous or subcutaneous immunoglobulin and immunosuppressive drugs. Some patients with STAT1 GOF disorder have undergone hematopoietic stem cell transplantation, although these have been difficult because of the underlying proinflammatory milieu from the mutation.