Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti–IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren’s-like syndrome, uncommon entities in European APECED cohorts, affected 40%–80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4+ T cells and CD21loCD38lo B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.

Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9 -/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9 -/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans.

Background and Aims Autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED‐associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. Approach and Results Forty‐five consecutive patients with APECED were evaluated (2013‐2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients’ stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L‐amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability‐increasing fold‐containing B1, tryptophan hydroxlase, and 21‐hydroxylase (21‐OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH‐like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. Conclusions APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment‐responsive disease. Several APECED‐associated autoantibodies, but not standard AIH‐associated biomarkers, correlate with APAH.

BackgroundThe clinical importance of an elevated platelet count is often overlooked, particularly as a diagnostic clue to the presence of an underlying infection. We sought to better describe the relationship between thrombocytosis and inflammatory conditions, with a focus on infectious causes.MethodsWe retrospectively reviewed 801 sequential cases of thrombocytosis (platelet count > 500 × 109/L) at a tertiary care hospital.ResultsEssential thrombocythemia was the most common cause of primary thrombocytosis, and these patients were more likely to have extreme (> 800 × 109/L) and prolonged (> 1 month) thrombocytosis. Secondary thrombocytosis was more common than primary, with infectious causes accounting for nearly half the cases. Demographic factors associated with an infectious etiology included inpatient status, quadriplegia/paraplegia, an indwelling prosthesis, dementia and diabetes. Clinical and laboratory characteristics associated with an infectious cause of thrombocytosis included fever, tachycardia, weight loss, hypoalbuminemia, neutrophilia, leukocytosis and anemia. Patients with thrombocytosis secondary to infection had a more rapid normalization of platelet count, but higher risk of dying, than those with secondary, non-infectious causes.ConclusionsInfection is a common cause of thrombocytosis and should be considered in patients with comorbidities that increase risk of infection and when clinical and/or laboratory data support an infectious etiology. Thrombocytosis may have prognostic implications as a clinical parameter.

SUMMARY Objectives To investigate the utility of beta-D-glucan (BDG) testing in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive fungal infection (IFI), as compared to BAL galactomannan (GM). Methods We retrospectively reviewed medical records of 132 consecutive patients at the National Institutes of Health (NIH) in whom BAL BDG testing was performed for diagnosis of pneumonia. Using the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines, we determined which patients had proven or probable IFI, and assessed the diagnostic performance of BAL BDG testing, relative to BAL GM. We also determined the reproducibility of the BDG assay in BAL via repeat testing of patient samples. Results Ten patients had Pneumocystis pneumonia, and 34 patients had proven/probable IFI, including 14 with invasive aspergillosis (IA). BAL BDG was 100% sensitive for Pneumocystis. Although BAL BDG had similar sensitivity to BAL GM for the diagnosis of IA and IFI, it exhibited inferior specificity. Repeat testing demonstrated poor reproducibility of the BDG assay in BAL but not in serum. Conclusions BDG testing exhibits poor specificity and reproducibility in BAL. Identification of the BAL-specific factors that may interfere with the performance of the assay could improve the clinical usefulness of BAL BDG testing.

A 67 year-old Caucasian male from Arizona presented with indolent symptoms of intestinal obstruction and hydronephrosis, found at surgery to be caused by a mass involving the terminal ileum and cecum, extending into the posterior abdominal wall and obstructing the right ureter. Histopathology was diagnostic of basidiobolomycosis. PCR of tissue and sequencing identified the fungus as, Basidiobolus ranarum. During one year of posaconazole treatment, the residual mass shrank, hydronephrosis was relieved and peripheral eosinophilia resolved.

Objectives Fluoroquinolones are routinely overprescribed for uncomplicated urinary tract infection (uUTI), acute sinusitis, and acute bronchitis. In 2016, the United States (US) Food and Drug Administration (FDA) updated the boxed warning on fluoroquinolones, recommending against their use as first‐line agents for the routine pharmacologic management of uUTI, acute sinusitis, and acute bronchitis in patients who have other treatment options. The primary objective of this study was to determine if the 2016 expanded boxed warning was associated with decreased fluoroquinolone prescription rates for these three diagnoses. Methods We retrospectively reviewed antibiotics prescribed at a single, large, academic outpatient center for these three diagnoses between January 2013 and May 2018. Interrupted time series analysis was used to compare the rate of fluoroquinolone prescriptions before and after the May 2016 FDA boxed warning. Results A total of 10 087 antibiotic prescriptions for these three diagnoses were examined. There was no significant change in fluoroquinolone prescription rates after the FDA boxed warning. The majority of inappropriate fluoroquinolone prescriptions were given for the management of uUTI. Conclusion The 2016 US FDA boxed warning against fluoroquinolone use for uUTI, acute sinusitis, and acute bronchitis was not associated with a statistically significant reduction in the rate of fluoroquinolone prescriptions for these diagnoses. Additional research is needed to define how US FDA boxed warnings may be incorporated into broader antibiotic stewardship programs to decrease overuse of fluoroquinolones and avoid adverse effects of the drug class, including Clostridioides difficile infections and emergence of resistant organisms.

This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key posttranslational regulatory modification of STAT1 and identify a novel mechanism for gain-of-function STAT1 disease in human subjects.