Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib.

Mutations in the coiled-coil and DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and subsequently gain-of-function. The associated clinical phenotype is broad and can include chronic mucocutaneous candidiasis (CMC) and/or combined immunodeficiency (CID). We report a case of CMC/CID in a 10-year-old boy due to a novel mutation in the small ubiquitin molecule (SUMO) consensus site at the C-terminal region of STAT1 leading to gain-of-function by impaired sumoylation. Immunodysregulatory features of disease improved after Janus kinase inhibitor (jakinib) treatment. Functional testing after treatment confirmed reversal of the STAT1 hyper-phosphorylation and downstream transcriptional activity. IL-17 and IL-22 production was, however, not restored with jakinib therapy (ruxolitinib), and the patient remained susceptible to opportunistic infection. In conclusion, a mutation in the SUMO consensus site of STAT1 can lead to gain-of-function that is reversible with jakinib treatment. However, full immunocompetence was not restored, suggesting that this treatment strategy might serve well as a bridge to definitive therapy such as hematopoietic stem cell transplant rather than a long-term treatment option.

Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC).

Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. We also assessed how GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/c-Myc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies.

Prevalence and predictors of out-of-range cuff pressure of endotracheal and tracheostomy tubes: a prospective cohort study in mechanically ventilated patients.

BACKGROUND: Maintaining the cuff pressure of endotracheal tubes (ETTs) within 20-30 cmH2O is a standard practice. The aim of the study was to evaluate the effectiveness of standard practice in maintaining cuff pressure within the target range. METHODS: This was a prospective observational study conducted in a tertiary-care intensive care unit, in which respiratory therapists (RTs) measured the cuff pressure 6 hourly by a handheld manometer. In this study, a research RT checked cuff pressure 2-4 h after the clinical RT measurement. Percentages of patients with cuff pressure levels above and below the target range were calculated. We identified predictors of low-cuff pressure. RESULTS: We analyzed 2120 cuff-pressure measurements. The mean cuff pressure was 27 ± 2 cmH2O by the clinical RT and 21 ± 5 cmH2O by the research RT (p < 0.0001). The clinical RT documented that 98.0 % of cuff pressures were within the normal range. The research RT found the cuff pressures to be within the normal range in only 41.5 %, below the range in 53 % and above the range in 5.5 %. Low cuff pressure was found more common with lower ETT size (OR, 0.34 per 0.5 unit increase in ETT size; 95 % CI, 0.15-0.79) and with lower peak airway pressure (OR per one cm H2O increment, 0.93; 95 % CI, 0.87-0.99) on multivariate analysis. CONCLUSIONS: Cuff pressure is frequently not maintained within the target range with low-cuff pressure being very common approximately 3 h after routine measurements. Low cuff pressure was associated with lower ETT size and lower peak airway pressure. There is a need to redesign the process for maintaining cuff pressure within the target range.

Impact of a national collaborative project to improve the care of mechanically ventilated patients.

This prospective quasi-experimental study from the NASAM (National Approach to Standardize and Improve Mechanical Ventilation) collaborative assessed the impact of evidence-based practices including subglottic suctioning, daily assessment for spontaneous awakening trial (SAT), spontaneous breathing trial (SBT), head of bed elevation, and avoidance of neuromuscular blockers unless otherwise indicated. The study outcomes included VAE (primary) and intensive care unit (ICU) mortality. Changes in daily care process measures and outcomes were evaluated using repeated measures mixed modeling. The results were reported as incident rate ratio (IRR) for each additional month with 95% confidence interval (CI). A comprehensive program that included education on evidence-based practices for optimal care of mechanically ventilated patients with real-time benchmarking of daily care process measures to drive improvement in forty-two ICUs from 26 hospitals in Saudi Arabia (>27,000 days of observation). Compliance with subglottic suctioning, SAT and SBT increased monthly during the project by 3.5%, 2.1% and 1.9%, respectively (IRR 1.035, 95%CI 1.007-1.064, p = 0.0148; 1.021, 95% CI 1.010-1.032, p = 0.0003; and 1.019, 95%CI 1.009-1.029, p = 0.0001, respectively). The use of neuromuscular blockers decreased monthly by 2.5% (IRR 0.975, 95%CI 0.953-0.998, p = 0.0341). The compliance with head of bed elevation was high at baseline and did not change over time. Based on data for 83153 ventilator days, VAE rate was 15.2/1000 ventilator day (95%CI 12.6-18.1) at baseline and did not change during the project (IRR 1.019, 95%CI 0.985-1.053, p = 0.2812). Based on data for 8523 patients; the mortality was 30.4% (95%CI 27.4-33.6) at baseline, and decreased monthly during the project by 1.6% (IRR 0.984, 95%CI 0.973-0.996, p = 0.0067). A national quality improvement collaborative was associated with improvements in daily care processes. These changes were associated with a reduction in mortality but not VAEs. Registration The study is registered in clinicaltrials.gov (NCT03790150).

Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation.

BACKGROUND: Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC). Permissive factors that lead to immune deficiencies can underlie persistent or recurring candidiasis, called chronic mucocutaneous candidiasis (CMC). Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy). Inborn errors of the immune system (primary immune deficiencies) can present with isolated CMC known as CMC disease (CMCD), which is most often found in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)/APECED or in patients with an underlying gain-of-function STAT1 mutation (GOF-STAT1). OBJECTIVE: To describe a new form of inherited/familial CMC with a high risk for developing squamous cell carcinoma of the oesophagus, due to a gain-of-function mutation in the STAT1 gene. METHODS AND RESULTS: This report describes a family of patients with CMC with confirmed GOF-STAT1 mutation. These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC. This case series describes six patients in three generations of the same family, two of whom developed and died of SCC. We recommend regular endoscopic surveillance to detect early oesophageal neoplasia in patients with CMCD as well as urgent endoscopy in symptomatic patients. CONCLUSION: CMC is not a well-recognised condition in gastroenterology practice and clinicians need to be aware of the genetics of the condition as well as the risk for oesophageal cancer so that they can counsel their patients and arrange surveillance appropriately.