Jennifer W. Leiding

Warts and all: human papillomavirus in primary immunodeficiencies.

Infection with human papillomavirus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and dedicator of cytokinesis 8 (DOCK8) are typically associated with extensive HPV infections, whereas several other primary immune defects result in severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them.

Reviews and feature articleWarts and all: Human papillomavirus in primary immunodeficiencies

Infection with human papillomavirus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and dedicator of cytokinesis 8 (DOCK8) are typically associated with extensive HPV infections, whereas several other primary immune defects result in severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them.

Corticosteroid Therapy for Liver Abscess in Chronic Granulomatous Disease

Liver abscesses in chronic granulomatous disease (CGD) are typically difficult to treat and often require surgery. We describe 9 X-linked CGD patients with staphylococcal liver abscesses refractory to conventional therapy successfully treated with corticosteroids and antibiotics. Corticosteroids may have a role in treatment of Staphylococcus aureus liver abscesses in CGD.

Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations

Background: Gain‐of‐function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life‐threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. Objective: We sought to aggregate the worldwide experience of HSCT in patients with GOF‐STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft‐versus‐host disease, and transplant‐related complications. Methods: Data were collected from an international cohort of 15 patients with GOF‐STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. Results: Primary donor engraftment in this cohort of 15 patients with GOF‐STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event‐free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. Conclusion: Our data indicate that HSCT for patients with GOF‐STAT1 mutations is curative but has significant risk of secondary graft failure and death.

Pathologic Findings in NEMO Deficiency: A Surgical and Autopsy Survey.

Hypomorphic mutations in nuclear factor κB (NF-κB) essential modulator (NEMO), encoded by IKBKG, lead to a variable combined immunodeficiency, which puts patients at risk of early death from infectious complications. The spectrum of clinical manifestations includes inflammatory disorders, especially colitis. Because of the multiple complications of NEMO deficiency, a variety of biopsy, excisional, and autopsy materials from these patients may be subject to pathologic examination. Therefore, using samples from a cohort of patients with this disorder, we aimed to survey the pathologic spectrum of NEMO deficiency and search for correlations between specific genotypes and phenotypes. Clinical and laboratory data, mutation analysis, and pathology from 13 patients were examined, including 6 autopsies. No specific genotype-pathology correlation was identified. However, we confirmed an association between ectodermal dysplasia and inflammatory conditions. We found no characteristic pathology to identify patients with NEMO deficiency; therefore, history, physical examination, and specific infections must remain the clues to suggest the diagnosis. Variability among patients and by infection makes the pathologic recognition of NEMO deficiency challenging.

STAT3 regulates cytotoxicity of human CD57+ CD4+ T cells in blood and lymphoid follicles

A subset of human follicular helper T cells (TFH) cells expresses CD57 for which no distinct function has been identified. We show that CD57+ TFH cells are universally PD-1hi, but compared to their CD57− PD-1hi counterparts, express little IL-21 or IL-10 among others. Instead, CD57 expression on TFH cells marks cytotoxicity transcriptional signatures that translate into only a weak cytotoxic phenotype. Similarly, circulating PD-1+ CD57+ CD4+ T cells make less cytokine than their CD57− PD-1+ counterparts, but have a prominent cytotoxic phenotype. By analysis of responses to STAT3-dependent cytokines and cells from patients with gain- or loss-of-function STAT3 mutations, we show that CD4+ T cell cytotoxicity is STAT3-dependent. TFH formation also requires STAT3, but paradoxically, once formed, PD-1hi cells become unresponsive to STAT3. These findings suggest that changes in blood and germinal center cytotoxicity might be affected by changes in STAT3 signaling, or modulation of PD-1 by therapy.

Neutrophil Evolution and Their Diseases in Humans

Granulocytes have been preserved and have evolved across species, developing into cells that provide one of the first lines of host defense against pathogens. In humans, neutrophils are involved in early recognition and killing of infectious pathogens. Disruption in neutrophil production, emigration, chemotaxis, and function cause a spectrum of primary immune defects characterized by host susceptibility to invasive infections.

Auditory and vestibular phenotypes associated with GATA3 mutation

Objective To report the auditory and vestibular phenotypes of patients with GATA3 mutation. Study Design Case series of 6 patients. Setting Tertiary referral center. Patients All patients had the classic triad of GATA3 deficiency: hypoparathyroidism, hearing loss, and renal dysplasia. Patients (29–60 yr old; mean age, 42.5 yr; 3 male and 3 female subjects) were confirmed to have heterozygous mutations involving GATA3 by Sanger sequencing. Interventions Behavioral audiometry, distortion product otoacoustic emissions (DPOAEs), and auditory brainstem responses (ABRs) were used to assess hearing. Rotational vestibular testing was used to assess vestibular function. Results All patients with GATA3 mutation presented with hearing loss during childhood. The mean 3-frequency (0.5/1/2 kHz) pure tone average was 67 dB HL (range, 50–83 dB HL; SD, 9.3). The average speech discrimination score was 73% (range, 36%–100%; SD, 15.9). DPOAEs were absent in all patients. ABRs were remarkably robust and provided no evidence of retrocochlear dysfunction. Some patients complained of dizziness, but rotary chair testing was normal across participants for whom testing occurred. Conclusion Patients with GATA3 mutation present with early-onset sensorineural hearing loss (SNHL). DPOAEs were absent, supporting outer hair cell dysfunction, whereas ABRs were present and robust. Rotational vestibular testing revealed no evidence of abnormal horizontal semicircular canal function.

Thoracic Duct Injury Resulting in Abnormal Newborn Screen

Measurement of T-cell receptor excision circles (TREC) in neonates has allowed for population-based screening of severe combined immunodeficiency and other disorders associated with T-cell lymphopenia. In addition to primary T-cell lymphopenic disorders, secondary causes of T-cell lymphopenia can be diagnosed with TREC analysis. We discuss the diagnostic evaluation of a patient with normal TREC analysis at birth that became abnormal after cardiac surgery. TREC analysis was performed by the Florida State Laboratory. Diagnostic evaluation and treatment were performed at All Childrens Hospital, St Petersburg, Florida. We identified a 38-day-old female patient with thoracic duct injury, which caused chylothorax and chylous ascites diagnosed after an abnormal newborn screen. Chylothorax was secondary to thoracic duct injury after cardiac surgery and led to severe lymphopenia and hypogammaglobulinemia. Thoracic duct ligation led to improved lymphocyte counts and normalization of immunoglobulin levels. Secondary causes of lymphopenia are detected with TREC assay that lead to abnormal newborn screen results. Many secondary causes of lymphopenia can be acquired with normal initial newborn screens that become abnormal over time.

Psychrobacter immobilis septicemia in a boy with X-linked chronic granulomatous disease and fulminant hepatic failure.

A 16-year old boy with chronic granulomatous disease (CGD) developed Psychrobacter immobilis septicemia during a course of fulminant hepatic failure. The patient died despite aggressive management with antimicrobials and corticosteroids. While Psychrobacter immobilis rarely affects humans, it should be considered an organism that can cause sepsis in patients with CGD.