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.

House dust mite-specific immunotherapy alters the basal expression of T regulatory and FcεRI pathway genes.

BACKGROUND: Regulatory T (Treg) cells and IgE-mediated signaling pathways could play important roles in the induction of allergen tolerance during house dust mite-specific subcutaneous immunotherapy (HDM-SCIT). Our aim was to compare the basal expression levels of Treg, T helper 1 (Th1) and Th2 transcription factors and components involved in IgE-mediated signaling in healthy subjects with those in HDM-allergic patients both untreated and successfully treated with HDM-SCIT. METHODS: Thirty-nine HDM-allergic patients who completed a 3- to 5-year course of mite extract SCIT, 20 mite-allergic controls and 25 healthy controls participated in this study. The efficacy of SCIT was monitored using skin-prick tests (SPTs), total immunoglobulin E (tIgE), specific IgE (sIgE), sIgG(4), nasal challenge and visual analog scale (VAS) scores at several time points. The mRNA levels of forkhead box protein 3 (FOXP3), T-BET, GATA-3, FcεRI, spleen tyrosine kinase (Syk), phosphatidylinositol 3 kinase (PI3K) and SH2 domain-containing inositol phosphatase (SHIP) were quantified by real-time RT-PCR using nonstimulated whole blood samples. RESULTS: Decreased wheal sizes and VAS scores, negative challenges and increased sIgG(4) levels indicated that SCIT was effective in the treated patients. Basal expression levels of FOXP3 and GATA-3 decreased and T-BET levels increased in both treated patients and in healthy controls compared to untreated patients. The IgE-mediated pathway kinases Syk and PI3K exhibited reduced expression, whereas SHIP phosphatase levels were elevated in both treated patients and healthy controls relative to untreated patients. The expression levels of FcεRI were not significantly altered. CONCLUSIONS: Immunotherapy using HDM extracts results in a modification of the basal expression levels of several IgE-related signaling factors and induces a highly significant upregulation of Th1-response and downregulation of Th2-response transcription factors. Interestingly, this therapy also appears to reduce the basal expression of FOXP3.

[House dust mite allergy--living with the invisible roommates]. / Alergija na grinje kucne prasine--zivot s nevidljivim sustanarima.

House dust mites are the most common sources of allergic sensitization, primarily responsible for the occurrence of various clinical forms of respiratory and skin allergies, but also of certain forms of food allergy. There are many various mite species, of which only a small number are constantly or occasionally found in house dust samples. Mites from Pyroglyphidae family, Dermatophagoides pteronyssinus and Dermatophagoides farinae are most frequently responsible for sensitization of susceptible persons. Other less commonly found species may represent individual primary sources of sensitization, or may cause disease symptoms due to cross-reactivity. The exposure to various mite species within different geographical regions accounts for the generation of various sensitization profiles. Knowing these profiles is important for planning rational specific immunotherapy, which greatly determines its efficacy. The aims of this paper are to review the environment conditions that influence mite incidence and the ways their changes can control allergen amounts in patient homes, to review the allergenic content and the significance of cross-reactivity among mite allergens, and finally, to explain the factors that enable the generation of various sensitization profiles.

[House dust mite allergy--how to win?]. / Alergija na grinje kucne prasine--kako pobijediti?

Manifestations of house dust mite allergy include perennial allergic rhinitis often accompanied by ocular symptoms, allergic asthma, and somewhat rarer atopic dermatitis. Sensitization to mite tropomyosin may lead to hypersensitivity to certain foodstuffs. Allergic sensitization and development of the disease are connected to the level of allergen exposure, indicating that the patients' home exposure to mite allergens is a useful indicator of their risk. Since the possibility of allergen avoidance is limited, and available pharmacological treatments have just symptomatic effects, the only causative treatment for mite allergy is specific immunotherapy. Its well-documented clinical effects include reduction of symptoms, prevention of the disease severity progression, and prevention of sensitization to new allergens. Immunological parameters show characteristic dynamics during treatment, which is also reflected in gradual reduction of the skin reactivity towards the allergen. Despite ample evidence and a hundred-year use in clinical practice, the efficacy of specific immunotherapy is sometimes still questioned. The aim of this paper is to show that, when properly indicated with due consideration of the person's sensitization profile, it is a very successful treatment method.

[Pathophysiological mechanisms of allergic disease occurrence and treatment]. / Patofizioloski mehanizmi u nastanku i lijecenju alergijskih bolesti.

Why the exposure to the harmless and ubiquitous environmental substances causes inappropriately strong reactions of the immune system clinically manifested as allergies in some people, and how repeated exposures to the same substances during the specific immunotherapy divert immunologic reactivity, are so far only partially answered questions. The events that occur during the allergic inflammatory response are relatively well-known, as are the major operative mechanisms through which the specific immunotherapy, the only causative treatment method, changes that response. Nevertheless, everyday new findings are completing the puzzle and our understanding of these complex processes. The aim of this paper was to review the up-to-date known mechanisms of allergic disease occurrence and treatment, with regard to the key role of T cells in these processes.

[The high-affinity IgE-receptor signaling pathway in the treatment of allergies]. / Signalni put visokoafinitetnog IgE-receptora u lijecenju alergijskih bolesti.

The rise in a prevalence of allergic diseases observed in industrialized countries over many years, and generally a rising number of the patients, require constant searching for newer and better ways of treatment. The central event in the formation of the allergic inflammation, the activation of mast cells and basophils, is mediated by signaling through the high-affinity IgE receptor, FcepsilonRI. The signaling starts by cross-linking of receptor-bound IgE with an allergen. This initiates a cascade of signaling events that activates the cell and ultimately causes the release of mediators responsible for allergic responses. The major flaw of medications traditionally used for the treatment of allergies is their orientation to single mediators, and not to the whole sequence of complex events leading to the onset of early and late symptoms. The aim of this paper was to review a complex sequence of events from the allergen binding to the onset of symptoms, highlighting the importance of the IgE-receptor signaling pathway in searching for new therapeutic modalities.

Second-line treatment for Helicobacter pylori infection based on moxifloxacin triple therapy: a randomized controlled trial.

BACKGROUND: In eradication of Helicobacter pylori infection, standard quadruple second-line therapy consisting of proton pump inhibitor (PPI), bismuth, metronidazole and tetracycline often fails and shows poor patient compliance. The aim of our study was to evaluate the efficacy and tolerability of moxifloxacin-based triple therapy as an alternative second-line protocol. METHODS: A total of 160 patients, in whom the initial standard PPI triple therapy had failed to eradicate H. pylori infection, were included in the study. The initial H. pylori status was assessed using the (13)C-urea breath test. Patients were randomized to one of the following 7-day treatment regimens: (1) OMM: omeprazole 20 mg twice a day, moxifloxacin 400 mg/day, metronidazole 500 mg three times a day; and (2) OBMT: omeprazole 20 mg twice a day, colloidal bismuth subcitrate 120 mg four times a day, metronidazole 500 mg three times a day, tetracycline 500 mg four times a day. Patient compliance and adverse events were evaluated one week after completion of therapy. H. pylori status was re-assessed with the (13)C-urea breath test six weeks after the end of therapy. RESULTS: The eradication rates were 73.2% (60/82) and 78.9% (60/76) with moxifloxacin-based triple therapy, and 53.8% (42/78) and 64.6% (42/65) with bismuth-based quadruple therapy, by intention-to-treat (p = 0.018) and per-protocol (p = 0.088) analyses, respectively. Adverse events/intolerability were described in 12/82 patients in the OMM group and 18/78 patients in the OBMT group. Compliance with treatment was 92.7% in the OMM group and 83.3% in the OBMT group. CONCLUSION: Moxifloxacin-based triple therapy is a highly effective second-line eradication treatment in H. pylori infection. Because of its high levels of safety and tolerability, this protocol represents an adequate alternative to the standard bismuth-based quadruple therapy.

[Plant food allergy: apple as a model]. / Alergija na hranu biljnog podrijetla: jabuka kao model.

Allergic reactions to plant foodstuffs comprise a whole spectrum of clinical manifestations, from very mild ones, localized to oral mucosa, to the most severe including life-threatening anaphylactic shock. The reason is the presence of a few structurally and functionally different allergens in each foodstuff. On the other hand, the similarity between particular allergens in different foodstuffs and the presence of their homologues in other sources (pollens, insect venoms) give a lot of possibilities for cross-reactions during allergic sensitization. Apple has a significant place in human nutrition. However, it is also a fruit that most frequently causes allergic reactions. Apple allergens are well known and appropriately characterized, and their homologues are present in other vegetable foodstuffs. Thus, apple represents a good model of plant food hypersensitivity. The aim of this paper is to review the mechanisms of allergic sensitization, the types of clinical manifestations, the influence of allergen content variability, and the diagnostic and therapeutic issues connected with plant food allergy, using apple as a model.

[Prevalence of symptoms of asthma, allergic rhinitis, conjunctivitis and atopic eczema: ISAAC (International Study of Asthma and Allergies in Childhood) in a population of schoolchildren in Zagreb]. / Prevalencija simptoma astme, alergijskog rinitisa i konjunktivitisa te atopijskog ekcema: ISAAC u populaciji skolske djece u Zagrebu.

OBJECTIVE: Numerous studies of the population prevalence of asthma, allergic rhinitis, and atopic eczema revealed some international differences. However, the International Study of Asthma and Allergies in Childhood (ISAAC) was the first one using a standardized methodology to evaluate the prevalence of these diseases, and to make comparisons within and between countries. The results showed marked variations in 12-month prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema symptoms with 20-fold (range 1.6-36.8%), 30-fold (range 1.4-39.7%), and 60-fold (range 0.3-20.5%) differences between the centres with the highest and the lowest prevalence, respectively. AIM: Our aim was to gain the insight into the prevalence of allergic diseases in Zagreb, Croatia by the methods of internationally standardized protocol, proposed by the ISAAC Steering Committee. METHODS: Original questionnaires, translated from English into Croatian, consisting of questions about the child's demographic characteristics, core modules on wheezing, rhinitis and eczema, and supplementary modules, were completed by parents of 10-year-old children (4th grade) attending 18 elementary schools in a city of Zagreb. Total of 1047 questionnaires were returned and analysed after the inconsistent responses were eliminated by phone calling. DISCUSSION: Phase one of the ISAAC study has shown a wide variation in the prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema symptoms throughout the world, with differing international patterns for the different disorders. Four prevalence ranges have been established for better illustration of the geographic distribution of asthma prevalence: (I) < 5%; (II) 5 to < 10%; (III) 10 to < 20%; (IV) > or = 20%. The highest 12-month prevalences of asthma symptoms were found in developed countries (UK, Australia, New Zealand, Republic of Ireland, and most centres in North, Central, and South America), being in prevalence range IV. The lowest prevalences (range I) were found in several Eastern European countries, Indonesia, Greece, China, Taiwan, Uzbekistan, India, and Ethiopia. According to the results of our study, a continental part of Croatia with a 12-month prevalence of wheezing of 6.02% corresponds to range II. Prevalence of asthma symptoms was greater in males, which is consistent with the results of the younger age group previously analysed. For allergic rhinoconjunctivitis and atopic eczema symptoms grouping of centres with a high prevalences into specific regions was less well defined than for asthma. Centres with the highest prevalences were scattered across the world. In contrast, centres with the lowest prevalences were similar to those for asthma symptoms. Our results of the 12-month prevalence of allergic rhinoconjunctivitis (12.13%), and atopic eczema (7.83%) symptoms were somewhere between the two extremes. As with asthma symptoms, the prevalence of rhinoconjunctivitis symptoms was greater in males. Contrary, the difference in prevalence of atopic eczema symptoms between the sex groups has not been found. The worldwide variations in prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema symptoms suggest that environmental factors may be critical to the development of these disorders in childhood. Furthermore, different patterns of geographical distribution of particular disorders suggest that major risk factors for them may be different or may involve different latency periods and time trends. Therefore, studies that include objective clinical assessment are required. CONCLUSION: According to our results, Zagreb is a city with relatively low prevalence of allergic diseases symptoms. Larger sample size of at least 3000 subjects is required to provide sufficient precision for estimates of symptom severity, and to generate adequate number of subjects with particular disorders for further analyses. Therefore, we recently increased our sample size to more than 3000 subjects, and started ISAAC Phase two (clinical examination, measures of bronchial hyperresponsiveness, measures of atopy, measures of environmental exposure to aeroallergens, and genetic analyses) in Zagreb, Croatia.

[Lymphangioleiomyomatosis]. / Limfangiolejomiomatoza.

Lymphangioleiomyomatosis (LAM) is a progressive and usually fatal interstitial lung disease characterized by an abnormal smooth-muscle proliferation in the lung and axial lymphatics. It affects almost exclusively young women of childbearing age. The presenting features most commonly include dyspnea, symptoms of pneumothorax and cough. Less commonly patients can present with chest pain, pleural or pericardial effusion and lymphedema. Our patient, a 41-year-old woman, complained mainly of fatigue that had lasted for 2 months and finally became febrile and dispneic, especially when lying down. Pulmonary diagnostic procedures revealed several multicystic destruction of lung parenchyma. There was also respiratory insufficiency with O2 saturation of 87% and lung diffusion capacity reduced to 48%. The retroperitoneum was filled with neoplastic mass as shown on an abdominal CT scan. Pathohistologic analysis of retroperitoneal mass together with the radiologic finding of the lungs correlated with the diagnosis of LAM. The patient was prescribed corticosteroid therapy, which led to rapid clinical improvement. After making a definite diagnosis, the patient was recommended further treatment with medroxyprogesterone. This case shows that LAM, although rare, can present a diagnostic problem to clinicians and should always be considered as one of the diagnostic possibilities in young women with nonspecific pulmonary symptoms.

Allergic diseases in relationship with environmental factors in a population of school children in Zagreb, Croatia.

Most scientists believe that increasing number of people with allergic diseases may be connected with some aspects of the "Western lifestyle". This paper discusses data obtained from questionnaires originally designed by the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee concerning exposure to different environmental factors. The study included 1047 children. Allergic and non-allergic groups showed statistically significant differences in the attendance of kindergarten, vaccination against pertussis, pertussis infection, and parasite infestation. Exposure to tobacco smoke during pregnancy and exposure to dampness and moulds also entailed a risk for allergy. We speculate that changing some conditions, such as use of carpets and use of feather pillows, were connected with the expression of allergic diseases. Some correlations were consistent with earlier observations of other authors, while others differed and need further confirmation on a larger sample.