Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Rotavirus vaccination in central Europe.

Each year, rotavirus (RV) infection is the leading cause of acute gastroenteritis requiring hospitalisation and of nosocomially transmitted diseases in children younger than 5 years across Central European Vaccination Awareness Group (CEVAG) countries; however, inadequate surveillance systems and lack of routine RV testing still exist in most CEVAG countries, making it difficult to accurately assess the present burden of acute RV gastroenteritis in the younger population. Furthermore, routine immunisation of infants with RV vaccines has not been implemented, and no official and uniform recommendations exist in most of the countries in these territories. The present study provides CEVAG country-specific estimates of the disease burden of RV gastroenteritis among the youngest population and presents evidence-based advice on the use of RV vaccines in the region, while providing a framework for vaccination at the national level.

Inflammatory markers in childhood asthma.

The major characteristic of asthma is persistent airway inflammation that fails to resolve spontaneously. Dysregulation of pro- and anti-inflammatory mechanisms is responsible for the development of chronic inflammation. The inflammatory reaction is mediated by numerous cells and their mediators. Detection and quantification of airway inflammation in children are subject to many requirements, e.g., use of biologic samples obtained in a non-invasive way; use of standardized analytical methods to determine biomarkers that can identify inflammation processes (inflammation itself, oxidative stress, apoptosis and remodelling); determining the role of systemic inflammation; assessment of correlation of various biomarkers of inflammation with clinical parameters and their diagnostic efficacy; providing a tool(s) to monitor diseases, and to evaluate adequacy of therapy; and predicting the clinical course of inflammation and prognosis of asthma. Using standardized analyses, it is now possible to determine direct markers of local inflammation, i.e., fractional nitric oxide (marker of oxidative stress) in exhaled breath, pH (marker of acid stress) in breath condensate, and indirect markers in blood/serum, i.e., eosinophil granulocytes (indicating migration), eosinophil cationic protein (marker of activated eosinophil granulocytes) and C-reactive protein (marker of systemic inflammation). However, none of these biomarkers are specific for asthma. Further standardization of the known pulmonary biomarkers of local inflammation and identification of new ones will allow for longitudinal follow-up of inflammation in children with asthma.

[Allergic rhinitis in children]. / Osobitosti alergijskog rinitisa u djece.

Allergic rhinitis is the most prevalent form of chronic rhinitis in children. It is driven by allergic inflammation and is commonly associated with other atopic diseases such as asthma and atopic eczema. The main allergens are primarily aeroallergens: house dust mite, and tree, grass and weed pollen. It is, however, not exceptional to experience symptoms of allergic rhinoconjunctivitis in conjunction with food allergy and oral food allergy syndrome, especially in infants and toddlers. Allergic rhinitis is often associated with allergic asthma, either preceding it, or developing later and making it more difficult to treat. The mainstay of treatment is exposure prophylaxis, antihistamines, leukotriene antagonists and intranasal corticosteroids. Allergic rhinitis is one of the prime indications for specific allergen immunotherapy, which may have a preventive effect on the development of asthma. Allergic rhinitis associated with intermittent or mild persistent asthma may be a good indication for concomitant combination treatment with antihistamines and leukotriene antagonists. Intranasal corticosteroids should not be withheld in more severe forms. Shortterm (up to 3 months) use of intranasal corticosteroids has not been associated with any significant local or systemic side effects.

Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications.

The clinical phenotype of interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rbeta1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rbeta1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.

Burden of varicella in Central and Eastern Europe: findings from a systematic literature review.

INTRODUCTION: Vaccination against varicella rapidly reduces disease incidence, resulting in reductions in both individual burden and societal costs. Despite these benefits, there is no standardization of varicella immunization policies in Europe, including countries in Central and Eastern Europe (CEE). AREAS COVERED: This systematic literature review identified publications on the epidemiology of varicella, its associated health and economic burden, and vaccination strategies within the CEE region, defined as Albania, Bosnia-Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, Slovakia, and Slovenia. Twenty-six studies were identified from a search of PubMed, Embase®, and MEDLINE® biomedical literature databases, supplemented by gray literature and country-specific/global websites. EXPERT COMMENTARY: Limited information exists in published studies on the burden of varicella in CEE. The wide variability in incidence rates between countries is likely explained by a lack of consistency in reporting systems. Funded universal varicella vaccination (UVV) in CEE is currently available only in Latvia as a one-dose schedule, but Hungary together with Latvia are introducing a two-dose strategy in 2019. For countries that do not provide UVV, introduction of vaccination is predicted to provide substantial reductions in cases and rates of associated complications, with important economic benefits.

Chronic autoimmune urticaria in children.

Results of determination of circulating histamine releasing autoantibodies using histamine release urticaria test in 12 children (aged 3 to 18 years, mean age 8.5 years; 7 female and 5 male) with chronic urticaria are presented. Standard work-up including detailed history, allergy testing and routine laboratory findings did not disclose any plausible cause of chronic/recurrent urticarial eruption in these children. All children underwent serum-induced basophil histamine release urticaria test. At serum dilution of 12.5%, the mean percent of histamine liberation was 40.8% (range 18%-77%; normal <16.5%), which indicated the presence of autoantibodies to Fc epsilon RI and/or to the IgE-Fc epsilon RI complex. The percent of histamine release did not correlate with patient age or duration and severity of symptoms. Thus the autoimmune basis of chronic urticaria was established. Associated antithyroid autoantibodies were found in two patients. Complete or partial remission was obtained with treatment that included antihistamines, low salicylate-low preservative diet in all, and high dose intravenous immunoglobulin in 3 children.

Anti-IgE therapy with omalizumab in asthma and allergic rhinitis.

The pharmacology, efficacy, dosage, adverse effects, and economics of anti IgE (omalizumab) are discussed. Omalizumab is the generic name for the human/murine chimeric (recombinant humanized) monoclonal IgG antibody. Anti-IgE prevents IgE from attaching to effector cells, and thereby blunts IgE-mediated inflammatory responses. After subcutaneous administration its absorption is slow, reaching peak concentration in serum after an average of 7-8 days. At recommended doses, serum free IgE levels decrease within 1 hour following the first dose and are maintained between doses. Dose and dosing frequency are adjusted according to body mass and serum total IgE concentration before the start of treatment. Omalizumab administered subcutaneously is an effective treatment for add-on therapy in patients with poorly controlled, moderate-to-severe allergic asthma and allergic rhinitis (adults and adolescents > 12 years). It reduces the requirement for inhaled corticosteroids while protecting against disease exacerbation. Omalizumab is well tolerated, but the safety profile requires long-term assessment in adults as well as in children.

Chest radiography findings in primary pulmonary tuberculosis in children.

Plain chest radiography plays a major role in the diagnosis and follow-up of pulmonary tuberculosis in childhood. The aim of our study was to investigate the distribution of characteristic chest radiographic findings at diagnosis in children with pulmonary tuberculosis. The age of the patients and the type and localization of radiographic changes at admission were retrospectively analyzed. We reviewed chest radiographs in 204 children admitted from January 1, 1991 until June 30, 1994 for newly diagnosed pulmonary tuberculosis. Mean age +/- SD was 6.4 +/- 4.2 years (range 0-14). The most common lesion was lymphadenopathy (found in 172 children, 84.3%). It was significantly more common in the youngest age group (0-4 years) and was more significantly present in the right hilo-mediastinal region. Parenchymal changes were found in 125 children (61.3%). They were also significantly more common in the young age group and in the right lung. Other less common lesions included pleuritis, atelectasis, destructive-cavitary lesions and miliary dissemination. In conclusion, the leading radiographic finding in pulmonary tuberculosis in childhood remains hilar lymphadenopathy, but parenchymal changes are clearly strongly present, and should be sought and appreciated in the diagnostic work-up for pulmonary tuberculosis in childhood.