ASTHMA – EPIDEMIOLOGY, RISK FACTORS AND PATHOPHYSIOLOGY

Alergijske bolesti i astma postale su najčešće kronične bolesti dječje dobi u razvijenim zemljama, sa stalnim porastom prevalencije u posljednjih nekoliko desetljeća. Astma kao kronična bolest uvelike ograničava fizički, emocionalni i socijalni aspekt bolesnikova života te utječe na obitelj, školovanje i karijeru. Kronična upala promjenjivog intenziteta u astmi je trajno prisutna i izaziva pojačanu reaktivnost dišnih putova, koja dovodi do ponavljajućih epizoda piskanja, zaduhe, napetosti u prsnom košu i kašlja. Akutna pogoršanja mogu nastati naglo, a prigodno mogu biti i opasna za život. Na pojavu i klinički tijek astme utječu brojni čimbenici vezani za bolesnika i okoliš. Kao posljedica neprepoznate ili neodgovarajuće liječene upale u astmi, dolazi do procesa remodeliranja dišnih putova i ireverzibilnog slabljenja plućne funkcije u većine bolesnika.Allergic diseases and asthma have become the most common chronic diseases of childhood in developed countries, with increasing prevalence in the last few decades. Asthma is a chronic illness with a strong impact on the patient’s physical, emotional and social aspects of life and it affects the child\u27s family, education and career. The chronic inflammation of the airways in asthma is variable but constant and causes increase in airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing. Acute exacerbations of asthma can be rapid in onset, severe and even life threatening in the absence of effective treatment. Risk factors involved in the development of asthma and the clinical expression of the disease may be classified as host factors and environmental factors. Unrecognised or inadequately treated chronic inflammation in asthma leads to airway wall remodelling and progressive irreversible loss of lung function in most patients

Allergen immunotherapy in the treatment of asthma

Alergenska imunoterapija (AIT) je jedino uzročno liječenje alergijskih bolesti čija je učinkovitost i sigurnost dokazana u liječenju alergijskog rinitisa i astme u djece i odraslih. Osim smanjenja simptoma bolesti i potrebe za farmakoterapijom, AIT može modificirati tijek bolesti i potaknuti razvoj alergen-specifične imunosne tolerancije. U liječenju alergijske astme AIT se primjenjuje subkutano i sublingvalno. Oba oblika primjene pokazala su sličan mehanizam indukcije tolerancije i podjednaku učinkovitost koja se zadržava još godinama nakon prekida liječenja. Sigurnosni profil je bolji kod sublingvalne AIT zbog manjeg rizika od teških alergijskih reakcija, a zbog jednostavne i bezbolne primjene sublingvalna AIT je metoda izbora za liječenje alergijskih respiratornih bolesti u djece. Randomizirane kliničke studije kao i studije iz stvarnog života pokazuju da AIT ima i preventivni učinak na smanjenje rizika za nastanak senzitizacija na nove alergene te smanjuje rizik za razvoj astme u bolesnika s alergijskim rinitisom. Usprkos brojnim dokazima koji podupiru važnost AIT u liječenju alergijskih bolesti, ovaj oblik liječenja još uvijek se nedovoljno koristi u kliničkoj praksi.Allergen immunotherapy (AIT) is to date the sole etiologic treatment of allergic diseases with proven efficacy and safety in allergic rhinitis and asthma. In addition to reducing the symptoms and the need for medication, AIT can influence the course of the disease and induce allergen-specific immune tolerance. In treatment of allergic asthma AIT is delivered either subcutaneously or sublingually. Both modes of delivery have similar clinical efficacy and capacity to modify the underlying allergic disease, which persist years after AIT discontinuation. Due to its superior safety profile and lower risk of severe allergic adverse reactions, along with simple and painless application, sublingual AIT is the treatment of choice in pediatric allergic respiratory diseases. Randomized clinical trials as well as real-life trials have shown that AIT can prevent new allergen sensitizations and reduce the risk of asthma in patients suffering from allergic rhinitis. Despite numerous clinical trials proving the importance of AIT in the treatment of allergic diseases, it still remains underused in clinical practice

Specific Features of Childhood Asthma

Astma u djece najčešće počinje u ranoj dobi i ima varijabilan tijek i različitu kliničku pojavnost. U djece se astma očituje različitim fenotipovima koji se mogu preklapati, ući u remisiju, ali i perzistirati do odrasle dobi. Razlikovanje astme od ponavljanog piskanja povezanog s drugim bolestima u prvim godinama života nije jednostavno. Astma u školske djece i adolescenata značajno je češće povezana s alergijom nego astma u odraslih. Klinička ekspresija bolesti, važnost alergije i nespecifičnih čimbenika u pokretanju simptoma i egzacerbacija astme, dijagnostika, praćenje upalnih zbivanja u bronhima, kao i liječenje, u djece se razlikuju od astme u odraslih. Na temelju ovih spoznaja formirane su internacionalne i nacionalne smjernice usredotočene samo na dječju astmu. U ovom tekstu iznesene su suvremene postavke o posebnostima astme dječje dobi.Asthma in children usually occurs at an early age and has a variable course and a diff erent clinical appearance. In children, asthma exhibits different phenotypes, which may overlap, enter into remission, but also persist into adulthood. It is not easy to diff erentiate asthma from recurrent wheezing associated with other diseases in the first years of life. Asthma in school children and adolescents is significantly more often associated with allergies than asthma in adults. Clinical expression of the disease, the importance of allergy and nonspecific triggers in the initiation of symptoms and asthma exacerbations, diagnostics, monitoring of bronchial inflammation, as well as the treatment itself in children are diff erent from those found in adults. Based on these findings, international and national guidelines have been established, focusing exclusively on paediatric asthma. This paper presents contemporary standpoints on the specific features of asthma in children

ORAL ALLERGY SYNDROME

Oralni alergijski sindrom (OAS) je alergijska reakcija posredovana IgE protutijelima koja se javlja nakon konzumacije svježeg voća i povrća u bolesnika s alergijom na peludi. Simptomi nastaju zbog unakrsne reaktivnosti između peludi i hrane biljnog podrijetla, a koristi se i naziv sindrom alergije na pelud i hranu. Bolesnici su senzibilizirani na alergene peludi i iskazuju alergijsku reakciju na hranu strukturne sličnosti s alergenima peludi. OAS se rijetko viđa u male djece, ali mu učestalost raste s dobi pa je najčešća manifestacija alergije na hranu u adolescenata i odraslih. Simptomi su najčešće lokalizirani u usnoj šupljini, ali se mogu javiti i trbušni simptomi na probavnom sustavu i anafilaksija. Bolesnici u pravilu toleriraju termički obrađenu hranu, iako u onih s atopijskim dermatitisom može doći do pogoršanja ekcema. U slučaju generaliziranih simptoma i anafilaksije savjetuje se strogo izbjegavanje i mjere prve pomoći, uključujući autoinjektor adrenalina.Oral allergy syndrome (OAS) is an IgE antibody-mediated allergic reaction that occurs after consumption of fresh fruits and vegetables in patients with allergy to pollen. Symptoms arise due to cross-reactivity between pollen and plant-derived food and another term used for this syndrome is pollen-food allergy syndrome. The patient is sensitized with pollen and exhibits an allergic reaction to food antigen with structural similarity to the pollen. OAS is rarely seen in young children, but the prevalence increases with age and OAS is the most common manifestation of food allergy in adolescents and adults. Symptoms are usually localized in the oral mucosa, but abdominal symptoms and anaphylaxis may occur as well. Patients generally tolerate thermally processed food, but in those with atopic dermatitis it may lead to worsening of eczema. In the case of generalized symptoms and anaphylaxis, strict avoidance and first aid measures including a self-injectable adrenaline are advised

The Distribution of HLA Alleles among Children with Atopic Asthma in Croatia

Allergic asthma is a multifactorial disease involving well known environmental factors and less identified genetic components. In several studies the HLA genes have been implicated in the development of asthma and atopy, but the importance of these associations remains unclear. The aim of the present study was to analyse the distribution of specificities at HLA class I loci (-A and -B) and HLA class II locus (-DRB1) in a group of 143 Croatian children with atopic asthma, regarding total serum IgE and specific IgE against common inhalant allergens, as well as their connection with different asthmatic phenotypes and to identify HLA genotype which increases the risk for atopy or asthma or which has a protective effect. As controls we used a group of 163 healthy unrelated individuals. HLA class I antigens were determined by serology, while DRB1 specificities were detected by polymerase-chain reaction amplification and hybridisation with sequence specific oligonucleotide probes method (PCR-SSOP). We found no significant correlation between any of the HLA-A antigens and asthma, atopy or associated atopic phenotypes. At HLA-B locus, HLA-B8 antigen was significantly increased among asthmatic patients (p=0.002), patients with high total serum IgE (p=0.002), as well as among patients sensitizated to Dermatophagoides pteronyssinus (Der p) (p=0.014) and among patients sensitizated to Der p + Dactylis glomerata (Dact g) or Ambrosia elatior (Amb a) (p=0.004). Among HLA-DRB1 specificities, HLA-DRB1*01 showed positive correlation with asthma and atopy (p=0.034), while HLA-DRB1*03 specificity was observed with significantly higher frequency among patients with total serum IgE 400 KU/L (p=0.048). HLA-DRB1*16 specificity was observed with significantly lower frequency among patients with asthma only in comparison to healthy controls (p=0.027) and to patients with asthma and allergic rhinitis (p=0.005). In conclusion, our data suggest that HLA specificities play a relevant role in predisposition to asthma, as well as in different clinical forms of atopic diseases. HLA-B8, HLA-DRB1*01 and HLA-DRB1*03 genotype increases the risk for atopic asthma and high serum IgE

The Distribution of HLA Alleles among Children with Atopic Asthma in Croatia

Allergic asthma is a multifactorial disease involving well known environmental factors and less identified genetic components. In several studies the HLA genes have been implicated in the development of asthma and atopy, but the importance of these associations remains unclear. The aim of the present study was to analyse the distribution of specificities at HLA class I loci (-A and -B) and HLA class II locus (-DRB1) in a group of 143 Croatian children with atopic asthma, regarding total serum IgE and specific IgE against common inhalant allergens, as well as their connection with different asthmatic phenotypes and to identify HLA genotype which increases the risk for atopy or asthma or which has a protective effect. As controls we used a group of 163 healthy unrelated individuals. HLA class I antigens were determined by serology, while DRB1 specificities were detected by polymerase-chain reaction amplification and hybridisation with sequence specific oligonucleotide probes method (PCR-SSOP). We found no significant correlation between any of the HLA-A antigens and asthma, atopy or associated atopic phenotypes. At HLA-B locus, HLA-B8 antigen was significantly increased among asthmatic patients (p=0.002), patients with high total serum IgE (p=0.002), as well as among patients sensitizated to Dermatophagoides pteronyssinus (Der p) (p=0.014) and among patients sensitizated to Der p + Dactylis glomerata (Dact g) or Ambrosia elatior (Amb a) (p=0.004). Among HLA-DRB1 specificities, HLA-DRB1*01 showed positive correlation with asthma and atopy (p=0.034), while HLA-DRB1*03 specificity was observed with significantly higher frequency among patients with total serum IgE 400 KU/L (p=0.048). HLA-DRB1*16 specificity was observed with significantly lower frequency among patients with asthma only in comparison to healthy controls (p=0.027) and to patients with asthma and allergic rhinitis (p=0.005). In conclusion, our data suggest that HLA specificities play a relevant role in predisposition to asthma, as well as in different clinical forms of atopic diseases. HLA-B8, HLA-DRB1*01 and HLA-DRB1*03 genotype increases the risk for atopic asthma and high serum IgE

A food-dependent and exercise induced anaphylaxis case report and practical considerations

Anafilaksija ovisna o hrani, potaknuta naporom (engl. food dependent exercise induced anaphylaxis, FDEIA) poseban je oblik preo- sjetljivosti na hranu posredovan IgE protutijelima, koji se javlja u bolesnika koji unutar nekoliko sati od konzumacije određene namir- nice budu izloženi tjelesnoj aktivnosti. U djece je posebice rijedak, a najčešće je uzrokovan pšeničnim brašnom, iako ga mogu uzro- kovati i druge žitarice, ribe, plodovi mora, orašasti plodovi, kikiriki, jaje, mlijeko i druga hrana. Dijagnoza se postavlja temeljem karakterističnih simptoma koji se pojavljuju tijekom ili nekoliko sati nakon tjelesne aktivnosti, kojoj prethodi ingestija određene hra- ne, in-vitro i in-vivo pretraga te provokacijski pokusi. Sama tjelesna aktivnost ili konzumacija hrane u odsustvu tjelesne aktivnosti, ne izaziva simptome. U ovom radu prikazujemo 17-godišnju bolesnicu koja je pokazala FDEIA-u nakon konzumacije proizvoda od pšeničnog brašna. Iako rijedak, ovaj je entitet potrebno poznavati kako bi se izbjegle životno ugrožavajuće alergijske reakcije, a temelj dijagnoze je detaljna anamneza.Food-dependent and exercise induced anaphylaxis (FDEIA) is a rare type of IgE-mediated food hypersensitivity precipitated by a combination of food and exercise. It is very rare in children, and most commonly caused by wheat, although it can also be caused by nuts, fish, eggs, milk and other foods. It is diagnosed based on clinical history, in-vitro and in-vivo diagnostic procedures and pro- vocative tests. We present a 17-year-old girl who suffered from several attacks of FDEIA after consuming wheat products. Although a rare disorder, healthcare professionals should be aware of FDEIA. A detailed history is the most important step in diagnosing FDEIA

Humani bokavirus u nazofaringealnom sekretu hospitalizirane djece s akutnom infekcijom dišnog sustava - Rezultati prve godine četverogodišnjeg prospektivnog istraživanja

Background. Human bocavirus (HBoV) is a recently discovered parvovirus that may cause respiratory disease. The aim of this study was to determine HBoV prevalence among hospitalized children with acute respiratory tract infection (ARI) in two Croatian hospitals, Children’s Hospital Zagreb and General Hospital Karlovac, and to compare it with prevalence of other respiratory viruses. Methods. From May 2017 to April 2018 nasopharyngeal and pharyngeal swabs from a total of 275 children with ARI of suspected viral etiology were obtained and tested by multiplex- PCR for the presence of 15 respiratory viruses, including HBoV. Results. Viral etiology was proved in 221/275 (80.4%) of the patients. HBoV was detected in 17 (6.2 %) samples. Two thirds of HBoV positive patients were between one and three years of age. HBoV was detected in older children when compared to the children infected with respiratory syncytial virus (P < 0.001), but younger when compared to those infected with influenza (P = 0.009). Seventy six percent of HBoV positive patients had upper and 24% lower respiratory tract infection. HBoV was more often detected in multiple virus infections compared to the other respiratory viruses (P < 0.001). HBoV is detected throughout the year except for the summer months. Conclusion. Human bocavirus, although often detected in combination with other respiratory viruses, is one of the possible causes of ARI in children. Continuous laboratory detection of HBoV in the respiratory secretion of children with ARI is required in order to complete our findings on clinical significance and epidemiology of this infection.Uvod. Humani bokavirus (HBoV) je nedavno otkriveni parvovirus koji može uzrokovati bolest dišnog sustava. Cilj ove studije je odrediti prevalenciju HBoV u djece primljene zbog akutne respiratorne infekcije (ARI) u dvije hrvatske bolnice, u Kliniku za dječje bolesti Zagreb i Opću bolnicu Karlovac te usporediti s prevalencijom drugih respiratornih virusa. Metode. Od svibnja 2017. do travnja 2018. testirano je ukupno 275 obrisaka nazofarinksa i ždrijela prikupljenih od djece s ARI sa sumnjom na virusnu etiologiju. Uzorci su testirani metodom multipleks-PCR na prisutnost 15 respiratornih virusa uključujući i HBoV. Rezultati. Virusna etiologija je dokazana u 221/275 (80,4%) bolesnika. HBoV je detektiran u 17 (6,2 %) kliničkih uzoraka. Većina djece s HBoV infekcijom (70,2 %) bila je u dobi između jedne i tri godine. Djeca u kojih je detektiran HBoV bila su starija od djece inficirane s respiratornim sincicijskim virusom (P < 0.001), ali mlađa od djece inficirane virusom influence (P= 0.009). Tri četvrtine HBoV inficirane djece imalo je dijagnozu infekcije gornjeg dišnog sustava (76%), dok je 24% djece imalo infekciju donjeg dišnog sustava. HBoV je značajno češće dokazan u koinfekciji s nekim od ostalih respiratornih virusa u odnosu na druge respiratorne viruse (P < 0.001). Virus je detektiran tijekom cijele godine, izuzev ljetnih mjeseci. Zaključak Humani bokavirus, iako često detektiran u kombinaciji s drugim respiratornim virusima, jedan je od mogućih uzročnika ARI u djece. Potrebna je kontinuirana laboratorijska detekcija ovog virusa u respiratornom sekretu djece s ARI kako bismo upotpunili saznanja o kliničkom značenju i epidemiologiji ove infekcije

Epidemiological characteristics of respiratory syncytial virus infections during 2009 and 2010 in Zagreb and Zagreb County

Cilj: Određivanje epidemioloških karakteristika infekcija respiratornim sincicijskim virusom (RSV) u djece na području grada Zagreba i Zagrebačkoj županiji tijekom 2009. i 2010. godine. Metode: U istraživanju je sudjelovalo 467 hospitaliziranih bolesnika, starosti od 0 do 10 godina, s akutnom respiratornom infekcijom uzrokovanom RSV-om. Studija je trajala od 1. siječnja 2009. do 31. prosinca 2010. godine. Od svakog bolesnika uzet je klinički materijal (nazofaringealni sekret), te je detekcija virusa rađena pomoću komercijalnih monoklonskih protutijela u izravnom imunofluorescentnom testu. Rezultati: Infekcija RSV-om dokazana je u 238 (50,96 %) dječaka, odnosno 229 djevojčica. Najveći broj oboljele djece bio je u dobi od 0 – 6 mjeseci (202, tj. 43,25 %). RSV je bio uzročnik bronhiolitisa u 141/467 (30,19 %) slučajeva, te pneumonije u 63/467 (13,49 %) slučajeva. Rasprava i zaključci: Početkom 2009. godine RSV je bio u silaznom kraku zimske epidemije koja se nastavila iz prosinca 2008. godine. Tijekom 2010. godine javila se manja RSV-epidemija, s vrhom u proljeće, te uzlazni krak veće zimske epidemije krajem iste godine. Navedeni rezultati u skladu su s našim prijašnjim zapažanjima koja govore o tome da se u Hrvatskoj epidemije RSV-om odvijaju u dvogodišnjim ciklusima.Aim: To establish the epidemiological characteristics of respiratory syncytial virus (RSV) infections in children in the territory of Zagreb and Zagreb County during the 2009 and 2010 years. Methods: The research included 467 inpatients, aged 0-10 years, with acute respiratory infection. Study period was from 1st January 2009 to 31st December 2010. Clinical materials (nasopharyngeal excretions) were taken from each patient and the virus was detected using commercial monoclonal antibodies in direct immunofluorescence assay. Results: RSV infection was diagnosed in 238 (50.96 %) boys and 229 girls. RSV infections were the most frequent among the infants aged 0-6 months (202; 43.25 %). RSV proved to be the causative agent of bronchiolitis in 141 out of 467 patients (30.19 %) and pneumonia in 63/467 cases (13.49 %). Discussion and conclusions: In the first months of 2009 the RSV has been on a downward arm of the winter epidemics that continued from December 2008. During the 2010 there was a smaller RSV epidemic peak in the spring and the upward arm of a larger epidemic in late winter of that year. These results are consistent with our previous observations that RSV epidemics occur in two-year cycles in Croatia

CROATIAN GUIDELINES FOR IN VITRO DIAGNOSIS OF IGE MEDIATED HYPERSENSITIVITY

In vitro dijagnostika alergijskih bolesti temelji se na određivanju koncentracije ukupnih i speciičnih IgE antitijela u serumu, koncentraciji IgG antitijela, plazmatske triptaze, eozinoilnog kationskog proteina te testu aktivacije bazoilnih leukocita. Upotreba in vitro dijagnostičkih testova mora biti temeljena na korelaciji anamneze, kliničke slike te in vivo provokativnih testova. Kliničko značenje povišene serumske koncentracije ukupnih IgE antitijela u dijagnostici alergijskih bolesti jest ograničena, budući da se ona susreće i u drugim nealergijskim bolestima. Povišene koncentracije speciičnih IgE protutijela, zajedno s pozitivnom anamnezom, indikativne su za klinički značajnu alergijsku bolest. Preporučena laboratorijska metoda za određivanje koncentracije IgE protutijela u serumu jest luoroenzimimunokemijska metoda. Povišene serumske koncentracije IgG protutijela nemaju dokazanu ulogu u dijagnostici alergije na hranu, a mogu poslužiti u procjeni uspješnosti speciične imunoterapije na alergene kukaca te procjeni rizika razvoja anailaksije uzrokovane ovom skupinom alergena. Povišena koncentracija serumske triptaze (podtip ), indikator je degranulacije mastocita uzrokovane speciičnim alergenom. Porast koncentracije eozinoilnog kationskog proteina (EKP) nastupa tijekom kasne faze alergijske reakcije te se može koristiti u praćenju alergijskih i drugih upalnih stanja u kojima eozinoili imaju glavnu ulogu. Test aktivacije bazoilnih (BAT) leukocita temelji se na određivanju staničnih razlikovnih obilježja, CD 63 i CD203c metodom protočne citometrije. BAT je koristan u dijagnostici alergija na alergene kukaca, nutritivnih te medikamentnih alergija. Alergološka dijagnostika temeljena na ekstraktima alergena može se koristiti u monosenzibiliziranih bolesnika s jasnom kliničkom slikom te u bolesnika kojima se planira prepisati samo simptomatska terapija. U suvremenoj su kliničkoj praksi razvijenih zemalja mnogo češći polisenzibilizirani bolesnici s kompleksnom simptomatologijom te sumnjom na križnu reaktivnost. Kod ovih se bolesnika preporuča koristiti molekularnu alergološku dijagnostiku.In vitro diagnostic procedure in allergology includes determination of serum levels of total and allergen speciic IgE antibodies, allergen speciic IgG antibodies, plasma tryptase, eosinophil cationic protein (ECP) and basophil activation test (BAT). In vitro tests should be used according to clinical history, physical examination, and in vivo methods for allergy testing. Clinical relevance of elevated total IgE in allergy diagnosis is modest, since it can be caused by other conditions. Elevated serum levels of allergen speciic IgE antibodies, together with positive medical history, are indicative of clinically relevant allergy. A recommendedlaboratory method for total and speciic IgE concentration measurement is the sandwich-type luoroimmunoassay ImmunoCAP, considered as an ideal immunoassay. Serum levels of allergen speciic IgG antibodies have no proved clinical relevance in food allergy diagnosis. They can be useful to monitor venom immunotherapy success, as well as to estimate the risk of venom induced anaphylaxis. Elevated plasma tryptase (subtype ) level is an indication of mast cell activation caused by speciic allergen. It should be obtained within 4 hours after an anaphylactic episode. Elevated level of ECP can be detected in patient blood during late phase of allergic reaction. It can be used to monitor patients with chronic allergenic and inlammatory conditions in which eosinophils play a central role. BAT includes measurement of CD 63 (cluster of differentiation) and CD 203 antigens of the molecular surface by low cytometry. It is useful in the diagnosis of venom, food and drug allergy, estimation of severity of allergic disease and natural tolerance to allergens. In vitro tests based on allergen extracts can be used for in vitro diagnosis in monosensitized patients with clear medical history and symptomatic treatment. Molecular allergy diagnosis should be performed in special clinical indications such as diagnosis of cross reactivity, prescription of speciic immunotherapy (especially in polysensitized patients with complex symptoms), diagnosis of idiopathic or cofactor induced anaphylaxis, latex allergy, and assessment of the risk of allergic reaction to speciic allergen