High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy.

BACKGROUND: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT. METHODS: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. RESULTS: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01). CONCLUSIONS: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Attitudes of Croatian pulmonologists concerning obstacles to earlier, more appropriate use of biologics in severe asthma: Survey results.

AIMS: Biologics have been proven efficacious for patients with severe asthma (SA). It is essential to diagnose such individuals correctly. This study was designed to survey pulmonologists to identify barriers to early diagnosis and subsequent appropriate use of biologics for SA in Croatia. METHODS: A pulmonologist group with expertise in SA developed the initial list of questions, with the final questionnaire created according to a 2-round Delphi method. The resulting survey consisted of 23 items consequently divided into 4 domains: 1) Pulmonologists' demographics and professional experiences; 2) Concerns about asthma management; 3) Attitudes toward SA diagnosis; and 4) Beliefs and attitudes regarding the use of biologics in managing SA. The given answers represented the respondents' estimates. RESULTS: Eighty-four surveys were analyzed, with pulmonologists observing that general practitioners often inaccurately diagnose asthma and treat acute exacerbations. Although specialist centers are capably and correctly equipped, the time to diagnose patients with SA is approximately 3.5 months, with initial use of biologics delayed an additional 2 months. The primary indications for prescribing biologics are conventional therapy with oral glucocorticoids (91.7%) and frequent acute exacerbations (82.1%). In addition to improper diagnosis (64.3%), many patients with SA do not receive the indicated biologics owing to strict administrative directives for reimbursement (70.2%) or limited hospital resources (57.1%). LIMITATIONS: The limitations of this survey include the subjective nature of the collected data, the relatively small sample size, and the lack of the biologic efficacy evaluation. CONCLUSIONS: Croatian pulmonologists observed that a significant number of patients with SA who are eligible for biologics are not prescribed them, largely because of an inaccurate and/or delayed diagnosis, a delayed referral to a specialist center, highly restrictive criteria for reimbursement, and/or institutional budgetary limitations.

Limitations of the results from randomized clinical trials involving intravenous and nebulised magnesium sulphate in adults with severe acute asthma.

The role of intravenous (IV) or nebulised magnesium sulphate (MgSO4) in the treatment of severe acute asthma in adults is unclear. A controversy exists regarding its efficacy. In children MgSO4 has a more evident clinical effect, but the child population has not been considered in this work. The applicability of the results from randomized clinical trials (RCTs) involving MgSO4 in adult population is questioned in the optimal treatment of asthma exacerbations. According to the newest guidelines from the Global Initiative for Asthma (GINA), optimal treatment in the emergency department (ED) is based on short-acting beta2-agonists (SABA), oral or IV corticosteroids (CS), short acting muscarinic antagonists (SAMA) and the controlled oxygen therapy. Further improvements with IV or nebulised MgSO4 were assessed in a recent large multicentre, double-blind, placebo-controlled randomized 3 Mg trial, which failed to demonstrate clinical benefit. Several other RCTs found some benefit with MgSO4, although the majority lacked some treatment options that are used in the optimal treatment of asthma exacerbations. Therefore, we reviewed the limitations of RCTs of IV or nebulised MgSO4 in adults with acute asthma, with the aim to answer in which subpopulation MgSO4 could be beneficial.

Mood disorders in adult asthma phenotypes.

OBJECTIVE: Studies show high comorbidity of mood disorders in asthma. As asthma is a highly heterogeneous disease with different phenotypes it can be expected that there is a difference in this association with different asthma phenotypes. The aim of our cross-sectional study was to assess the association of specific asthma phenotypes with anxiety and/or depression and their impact on asthma control. METHODS: A cross-sectional study in 201 consecutive adult outpatients with asthma (≥18 years of age) was conducted. Each patient underwent physical examination, detailed medical history, Hospital Anxiety and Depression Scale, Asthma Control Questionnaire, Asthma Control Test, together with measurements of lung function and fraction of exhaled nitric oxide. Phenotypes were assessed using cluster analysis, and a multivariate analysis was used to identify associations of mood disorders with different phenotypes. RESULTS: Five asthma phenotypes were identified: allergic (AA, 43.8%), aspirin-exacerbated respiratory disease (AERD, 21.9%), late-onset (LOA, 18.9%), obesity-associated (OAA, 10.0%), and respiratory infections associated asthma (RIAA, 5.5%). A multivariate analysis showed a significant association of anxiety with LOA and comorbid hypertension (LOA, odds ratio (OR) = 2.12; hypertension, OR = 2.37, p = 0.012), and depression with AA, RIAA, hypertension, and ACQ score (AA, OR = 6.07; RIAA, OR = 4.73; hypertension, OR = 5.67; ACQ, OR = 1.87; p < 0.001). Comorbid anxiety/depression was associated with AA, LOA, RIAA, hypertension, and ACQ score (AA, OR = 10.15; LOA, OR = 2.98; RIAA, OR = 6.29; hypertension, OR = 5.15; ACQ, OR = 1.90; p < 0.001. CONCLUSION: Mood disorders were significantly associated with AA, LOA, and infection-associated asthma, together with comorbid hypertension and the level of asthma control.

Changing pattern of sensitization in Croatia to aeroallergens in adult population referring to allergy clinic during a period of 15 years.

Published data indicate that during the last decades there is a possible change in the pattern of sensitization to different aeroallergens in adult population with atopy. The aim of this investigation was based on the hypothesis that during last 15 years there has been a change in the structure of prevalence of sensitization to different aeroallergens in adult population of Zagreb and its surroundings with atopy. Medical records from outpatient allergy clinic were screened for the period 1991-2004. We included 794 patients during years 1991-1994, 814 patients during years 1995-1999, and 969 patients during years 2000-2004. Following data were analyzed: age, gender, education level, residence, referral diagnosis, dominant symptoms, results of skin-prick test (SPT), total and specific serum immunoglobulin E. As risk factors for allergic sensitization we determined the decade of birth (p < 0.0001), male gender (p < 0.008), level of education (p < 0.0001), and place of residence (p < 0.05). Proportion of sensitized individuals to pollen significantly increased from the period 1991-1994 towards 2000-2004 (p < 0.001 for the trend) with a significant increase in the proportion of sensitized individuals to weed pollen (p = 0.002 for the trend) while the proportion of sensitized to other two groups of pollen (grasses and trees) was not significantly different. A significant increase in the proportion of sensitized individuals was determined for sensitization to ragweed pollen (p = 0.004 for the trend), and to mugwort (p = 0.005 for the trend). Despite all its limitations primarily based on the selection bias the results of this study are conclusive about the significant change in the proportion of sensitization to different aeroallergens and different pollen groups and individual pollen species during the investigated 15-year time interval.

[Infections due to nontuberculous mycobacteria]. / Infekcije izazvane netuberkuloznim mikobakterijama.

The best known members of genus Mycobacterium belong to M. tuberculosis complex. Other mycobacteria are known as nontuberculous mycobacteria (NTM). NTM less commonly cause a disease (mycobacteriosis), more often colonising respiratory tract. The presence of NTM is more common in immunocompromised patients and in those with a previous lung disease. The decrease in the incidence of tuberculosis is followed by increased incidence of NTM. Since tuberculosis has been declining in Croatia over the last 50 years, increasing incidence of NTM is expected. Growing incidence of chronic obstructive pulmonary disease (COPB) is contributing to this increase. NTM are ubiquitous and inhaling of aerosol particles constitutes the dominant route of infection. They are not transmitted via interhuman contact. In addition to pulmonary and skin infections, disseminated infections are also described. The treatment of mycobacteriosis is difficult and long. Besides using antituberculotic drugs such as rifampin and ethambutol, the therapies use fluoroquinolones; the introduction of macrolides has significantly improved the outcome of treatment.