Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Cervicitis in adolescents: do clinicians understand diagnosis and treatment?

BACKGROUND: Cervicitis is widespread, but no studies have examined cervicitis in accordance with established guidelines for diagnosis and treatment. Study objectives were to describe adherence to Centers for Disease Control and Prevention guidelines for diagnosis and treatment of cervicitis within an adolescent population and to compare factors associated with adherence to guidelines in a primary care setting and the Emergency Department. METHODS: Data were collected as part of a retrospective chart review of evaluation, diagnosis, and treatment of STI in adolescent women in an outpatient setting. Participant charts were eligible for review if they were 12-21 years of age and were given an ICD-9 and chart diagnosis of cervicitis. Two primary outcome variables: meeting cervicitis guidelines and correct treatment among those meeting cervicitis guidelines (no/yes) were utilized; the study controlled for age, race, venue, past infection with chlamydia or gonorrhea. RESULTS: Subjects (n = 365) were examined for the primary outcome variables and 75.1% (274/365) met at least one criterion for cervicitis. Of these, 166 (60.9%: 166/274) subjects were found to meet criteria for cervicitis alone, versus subjects meeting criteria for both cervicitis and pelvic inflammatory disease (PID) (39.4%: 108/274). The majority, 89.3%, (326/365) were treated for both chlamydia and gonorrhea, but only 64.7% (211/326) were treated correctly for both infections. CONCLUSIONS: Our findings suggest that knowledge deficits exist in diagnosis and treatment of cervicitis in adolescent patients and in differentiating between cervicitis and PID. Educational tools, simulated patient exercises, and order sets may be warranted for quality improvement to allow for improved care of this at risk sexually active population.

Interleukin-17 contributes to generation of Th1 immunity and neutrophil recruitment during Chlamydia muridarum genital tract infection but is not required for macrophage influx or normal resolution of infection.

Interleukin 17 (IL-17) contributes to development of Th1 immunity and neutrophil influx during Chlamydia muridarum pulmonary infection, but its role during C. muridarum genital tract infection has not been described. We detected similar numbers of Chlamydia-specific Th17 and Th1 cells in iliac nodes of wild-type mice early during genital C. muridarum infection, while Th1 cells predominated later. il17ra(-/-) mice exhibited a reduced chlamydia-specific Th1 response in draining iliac nodes and decreased local IFN-γ production. Neutrophil influx into the genital tract was also decreased. However, il17ra(-/-) mice resolved infection normally, and no difference in pathology was observed compared to the wild type. Macrophage influx and tumor necrosis factor alpha (TNF-α) production were increased in il17ra(-/-) mice, providing a compensatory mechanism to effectively control chlamydial genital tract infection despite a reduced Th1 response. In ifnγ(-/-) mice, a marked increase in cellular infiltrates and chronic pathology was associated with an increased Th17 response. Although neutralization of IL-17 in ifnγ(-/-) mice decreased neutrophil influx, macrophage infiltration remained intact and the bacterial burden was not increased. Collectively, these results indicate that IL-17 contributes to the generation of Th1 immunity and neutrophil recruitment but is not required for macrophage influx or normal resolution of C. muridarum genital infection. These data highlight the redundant immune mechanisms operative at this mucosal site and the importance of examining site-specific responses to mucosal pathogens.

Antibiotic hypersensitivity in CF: drug-induced life-threatening hemolytic anemia in a pediatric patient.

Adverse reactions to antibiotics in patients with cystic fibrosis (CF) are a growing concern. We report the case of a pediatric patient with CF with multiple comorbidities and a history of drug reactions, who developed life-threatening piperacillin-induced immune hemolytic anemia. We review drug-induced hemolytic anemia (DIIHA) in particular, and antibiotic hypersensitivity in CF in general, including the frequency, pathogenesis, and risk factors. Finally, we discuss the treatment options and propose an algorithm for the management of drug-induced hypersensitivity reactions in patients with CF.