Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Seronegative Mediastinal Coccidioidomycosis as a Novel Presentation of CTPS1 Combined Immunodeficiency.

Inborn errors of immunity may present with susceptibility to coccidioidomycosis. This is especially so in disorders impairing the interferon-γ and interleukin 12 signaling axis. We describe the first case of cytidine nucleotide triphosphate synthetase 1 (CTPS1) deficiency, a combined immunodeficiency impairing lymphocyte proliferation, presenting with coccidioidomycosis.

Infant Exposure to Acid Suppressant Medications Increases Risk of Recurrent Wheeze and Asthma in Childhood.

BACKGROUND: Acid suppressant medications (ASMs) are commonly prescribed in infancy. Little is known about the relationship between ASM exposure and risk of childhood asthma and atopic conditions. OBJECTIVE: We sought to examine the association between infant ASM exposure and risk for developing recurrent wheeze, allergen sensitization, and asthma in early childhood. METHODS: We used data from a diverse, multicenter, prospective cohort study of 921 infants with a history of bronchiolitis. ASM exposure (histamine-2 receptor antagonists and/or proton pump inhibitors) during infancy (age: <12 months) was ascertained by parent report and medical record review. The outcomes were recurrent wheeze by age 3 years, early childhood allergen sensitization (serum specific IgE), and asthma by age 6 years. We constructed multivariable Cox proportional hazards models and multivariable logistic regression models adjusting for multiple confounders. RESULTS: Of the 921 children in the cohort, 202 (22%) were exposed to ASMs during infancy. Compared with unexposed children, those exposed to ASM were more likely to develop recurrent wheeze by age 3 years (adjusted hazard ratio: 1.58, 95% confidence interval [CI]: 1.20-2.08, P = .001) and asthma by age 6 years (adjusted odds ratio: 1.66, 95% CI: 1.22-2.27, P = .001). ASM exposure during infancy was not significantly associated with the development of early childhood allergen sensitization (adjusted odds ratio: 1.00, 95% CI: 0.70-1.44, P = .99). CONCLUSIONS: Although exposure to ASMs during infancy does not increase the risk of allergen sensitization in early childhood, ASM exposure during infancy increases the risk of recurrent wheeze and asthma during early childhood.

Severe Combined Immunodeficiency (SCID) Screening in Arizona: Lessons Learned from the First 2 Years.

PURPOSE: The incidence of severe combined immunodeficiency (SCID) in the USA was reported as 1 in 58,000 live births. In Arizona, it was anticipated that newborn screening would identify two to four cases of SCID per year. This estimate did not consider ethnic nuances in Arizona, with higher percentages of Native American and Hispanic populations compared to national percentages. The true incidence of SCID and non-SCID T cell lymphopenia has not previously been reported in Arizona. METHODS: A retrospective chart review was performed on all abnormal SCID newborn screening (NBS) tests in Arizona from January 1, 2018, to December 31, 2019, using data from the Arizona Department of Health Services and the Phoenix Children's Hospital's electronic medical record [IRB# 20-025]. RESULTS: Seven infants were diagnosed with SCID, yielding an incidence of 1 in 22,819 live births. Four of these infants had Artemis-type SCID. Thirteen infants were identified with an abnormal initial NBS which ultimately did not lead to a diagnosis of SCID. Four of these infants were diagnosed with congenital syndromes associated with T cell lymphopenia. Infants of Hispanic ethnicity were over-represented in this cohort. CONCLUSION: Over 2 years, NBS in Arizona confirmed an incidence more than 2.5 times that reported nationally. This increased incidence is likely reflective of Arizona's unique population profile, with a higher percentage of Native American population. The findings in our non-SCID cohort are in alignment with previously published data, except for an increased percentage of infants of Hispanic/Latino ethnicity, possibly reflecting Arizona's increased percentage of Hispanic/Latino population compared to the general US population.

Serum periostin among infants with severe bronchiolitis and risk of developing asthma: A prospective multicenter cohort study.

BACKGROUND: Infants hospitalized for bronchiolitis (severe bronchiolitis) are at high risk for developing childhood asthma. However, the pathobiological link between these conditions remains unclear. We examined the longitudinal relationship of periostin (an extracellular matrix protein upregulated in response to type 2 inflammation) during bronchiolitis with the subsequent development of asthma. METHODS: In a 17-center prospective cohort study of infants (aged <1 year) with severe bronchiolitis, we measured the serum periostin level at hospitalization and grouped infants into 3 groups: low, intermediate, and high levels. We examined their association with asthma development by age 6 years and investigated effect modification by allergic predisposition (eg, infant's IgE sensitization). RESULTS: The analytic cohort consists of 847 infants with severe bronchiolitis (median age, 3 months). Overall, 28% developed asthma by age 6 years. In the multivariable model adjusting for nine patient-level factors, compared to the low periostin group, the asthma risk was significantly higher among infants in the intermediate group (23% vs. 32%, OR 1.68, 95%CI 1.12-2.51, p = .01) and non-significantly higher in the high-level group (28%, OR 1.29, 95%CI 0.86-1.95, p = .22). In the stratified analysis, infants with IgE sensitization had a significantly higher risk for developing asthma (intermediate group, OR 4.76, 95%CI 1.70-13.3, p = .002; high group, OR 3.19, 95%CI 1.08-9.36, p = .04). By contrast, infants without IgE sensitization did not have a significantly higher risk (p > .15). CONCLUSIONS: In infants with severe bronchiolitis, serum periostin level at bronchiolitis hospitalization was associated with asthma risk by age 6 years, particularly among infants with an allergic predisposition.

Diagnosis of Pediatric Non-Esophageal Eosinophilic Gastrointestinal Disorders by Eosinophil Peroxidase Immunohistochemistry.

BACKGROUND: Diagnosis of non-esophageal eosinophilic gastrointestinal disorders requires quantification of tissue eosinophils. Our objective was to evaluate eosinophil peroxidase (EPX) immunohistochemistry (IHC) as a method for histologic diagnosis of eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD). METHODS: We performed a retrospective analysis of biopsies from pediatric EG/EoD cases and controls. Subjects with EG or EoD had ≥30 eosinophils per high power field (eos/hpf) in ≥5 hpf in the stomach and/or ≥3 hpf in the duodenum, respectively. Controls had no histopathologic diagnosis recorded. Tissue eosinophil counts were assessed by hematoxylin & eosin stains. EPX stains were assessed using a unique histopathologic scoring system. Slides were digitized and EPX+ staining area/mm2 was quantified by image analysis. RESULTS: Twenty-six EG/EoD cases and 40 controls were analyzed. EPX scores and EPX/mm2 levels were markedly elevated in EG/EoD (p ≤ 0.0001). Eosinophil density (eos/mm2) correlated strongly with EPX scores and EPX/mm2 levels in the stomach (r ≥ 0.77) and moderately with EPX scores and EPX/mm2 levels in the duodenum (r ≥ 0.52); (p < 0.0001). EPX quantification identified EG/EoD subjects with high diagnostic accuracy (EPX score: AUC = 1 for EG and EoD; EPX/mm2: AUC = 0.98 (95%CI 0.96-1) for EG, AUC = 0.91 (95%CI 0.81-1) for EoD). CONCLUSION: EPX-based assessment of eosinophilic inflammation may facilitate automated histologic diagnosis.

Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.

Association of Rhinovirus C Bronchiolitis and Immunoglobulin E Sensitization During Infancy With Development of Recurrent Wheeze.

Importance: Rhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities. Objective: To examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze. Design, Setting, and Participants: This multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014). Exposures: Major causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C). Main Outcomes and Measures: Development of recurrent wheeze (as defined in national asthma guidelines) by age 3 years. Results: This analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction < .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1). Conclusions and Relevance: This multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.

Heterogeneity in presentation and treatment of catamenial anaphylaxis.

BACKGROUND: Few reports have documented the uncommon association of the female menstrual cycle with anaphylaxis, an entity known as cyclic or catamenial anaphylaxis. OBJECTIVE: To examine cases of perimenstrual anaphylaxis, focusing on differences in presentation and response to treatment, in the hopes of enriching the description of this rare entity. METHODS: A cohort of 8 women with catamenial anaphylaxis were identified and retrospectively compared with regard to age at onset, organ involvement, diagnostic studies, and response to therapy. RESULTS: The median age at onset was 34 years (range, 14-40 years), and the median number of perimenstrual anaphylactic episodes at presentation was 10 per patient (range, 4-24 per patient). Most had cutaneous and gastrointestinal symptoms. The results of extensive investigations for anaphylactic triggers were negative, and masquerading conditions, such as carcinoid syndrome, pheochromocytoma, and systemic mastocytosis, were ruled out in all patients. Skin test results for progesterone were negative in all but 1 of 4 patients tested. None had elevated total serum IgE levels. Response to suppressive treatments regimens varied considerably, but none treated with high-dose systemic steroids had improvement. Similarly, ketotifen, celecoxib, rofecoxib, and oral contraceptives failed to control the anaphylactic reactions. Although antihistamines failed in 7 patients, 1 had improvement. Others responded to leuprolide, medroxyprogesterone, or salpingo-oophorectomy. CONCLUSION: Whether the mechanism causing cyclical anaphylaxis may involve hypersensitivity to progesterone or prostaglandins, the variable response to suppressive medications in these cases suggests that catamenial anaphylaxis is a heterogeneous disorder in which a number of mechanisms and mediators may play a role. It is an emergent and probably underrecognized entity in the medical literature.

Methylene blue for the treatment of refractory anaphylaxis without hypotension.

Anaphylaxis is a life-threatening reaction treated primarily with epinephrine. Methylene blue, a competitive inhibitor of guanylate cyclase, interferes with the vasodilatory actions of nitric oxide. It has recently been proposed by the Joint Taskforce on Practice Parameters as an alternative treatment for anaphylaxis with hypotension that is not responsive to classical therapy. Little evidence supports its use in normotensive patients with refractory anaphylaxis. We present the case of a 43-year-old woman with severe anaphylaxis unresponsive to epinephrine. Physical examination revealed marked respiratory distress, raised oral lesions, and altered mental status but lacked hypotension. After infusion of methylene blue, symptom resolution occurred almost immediately, and intubation was spared. Side effects were minimal. We propose methylene blue as a safe treatment option for refractory anaphylaxis, whether with or without hypotension.

Common RAPD pattern of Pseudomonas aeruginosa from patients and tap water in a medical intensive care unit.

The epidemiology of Pseudomonas aeruginosa infections and colonizations was studied prospectively on a 12-bed medical intensive care unit. Patients were monitored for P. aeruginosa colonization by performing throat swabs or tracheal aspirates on admission and weekly thereafter over a period of 6 months. Cultures of possibly infected sites were taken as clinically indicated. Water samples from all patient care-related tap water outlets were collected in 2-weekly intervals and examined for the presence of P. aeruginosa. Strains isolated from patients and water samples were analysed by serotyping and random amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) typing. During the 6-month period, 60 of 143 (42%) water samples contained P. aeruginosa at various levels ranging from 1 to >100 colony-forming units per 100ml sample. Genotypically, water samples contained 8 different clonotypes. Nine patients had infections due to P. aeruginosa and 7 patients were colonized. Isolates from patients showed a similar distribution of genotypes as did tap water isolates, and strains of identical genotype as patient strains had been isolated previously from tap water outlets in 8 out of 16 (50%) infection or colonization episodes. However, patients also harboured strains not previously isolated from tap water. Thus, in addition to tap water, other environmental or unknown reservoirs appeared to play a role for the epidemiology of P. aeruginosa infections on this ward. However, because tap water played a significant role for strain transmissions, we conclude that intensified water site care is justified.