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Asthma is a chronic lung disease characterized by reversible bronchoconstriction and inflammation of the bronchi. Its increasing prevalence in childhood as well as different triggers make asthma a challenging disease in several ways: defining its phenotype/endotype, the diagnostic approach (especially in younger children), therapeutic options, and systematic follow-up. Considering these problems, this review approaches the current status and limitations of guidelines used for asthma management in children. It also emphasizes the key points which could lead to a better understanding and the direction to take in future studies.

Astma u dječjoj dobi jest heterogena kronična upalna bolest donjih dišnih puteva koja se očituje od rane životne dobi različitim fenotipovima i endotipovima, koji se mogu mijenjati tijekom djetinjstva. Promijenjena je paradigma liječenja astme u djece od koncepta „jedna veličina za sve“ prema konceptu personalizirane medicine. Liječenje astme je prema novim GINA (engl. global initiative for asthma) smjernicama personalizirano i prilagođeno svakom bolesniku u kontinuiranom ciklusu procjene bolesti, liječenja i redovitih kontrola. U kontroli i liječenju astme u djece personalizirani koncept temelji se na saznanjima o molekularnoj heterogenosti astme u dječjoj dobi, dostupnosti novih bioloških lijekova kao i inovativnih metoda praćenja adherencije na liječenje. Međutim, još uvijek značajan postotak djece s astmom ima nekontroliranu ili djelomično kontroliranu astmu, a personalizirani koncept se još uvijek rijetko primjenjuje u redovnoj kliničkoj praksi. Posebno se rijetko određuju biomarkeri i prepoznaju određeni fenotipovi/endotipovi, što se u praksi uglavnom provodi u rijetkim centrima, primarno za postavljanje indikacije za primjenu biološke terapije.

Akutni bronhiolitis infekcija je donjega dišnog sustava, zahvaća prvenstveno male dišne putove (bronhiole) te je čest uzrok bolesti i hospitalizacije dojenčadi i male djece. Po definiciji radi se o kliničkom sindromu respiratornog „distresa“, koji se javlja kod djece mlađe od dvije godine, a obilježavaju ga klinički znakovi infekcije gornjega dišnog sustava (npr. rinoreja) praćeni infekcijom donjega dišnog sustava. Obično se javlja s primarnom infekcijom ili reinfekcijom virusnim patogenom. Upala bronhiola nastaje kada virusi ulaze u terminalne bronhiolarne epitelne stanice te uzrokuju njihovo izravno oštećenje i upalu. Edem sluznice, prekomjerno stvaranje sluzi i propadanje epitelnih stanica dovode do začepljenja malih dišnih putova i stvaranja atelektaza. Bronhiolitis je najčešće uzrokovan virusnom infekcijom. Iako udio infekcije određenim virusima varira ovisno o godišnjem dobu, respiratorni sincicijski virus (RSV) je najčešći uzročnik, a potom rinovirus. Manje uobičajeni uzročnici jesu redom: virus parainfluence, humani metapneumovirus, virus influence, adenovirus, koronavirus i humani bocavirus. Molekularnom dijagnostikom virusna etiologija može se potvrditi u više od 95% slučajeva. Klinički se manifestira vrućicom, kašljem i poremećajem disanja (npr. tahipneja, retrakcije interkostalnih prostora i juguluma, piskanje, auskultacijski čujne krepitacije). Često mu prethode klinički znakovi infekcije gornjega dišnog sustava, koji traju jedan do tri dana. Postavljanje dijagnoze uglavnom se temelji na anamnezi i kliničkoj slici; laboratorijska i radiološka dijagnostika pomoćne su metode, a izolacija virusa daje nam konačnu potvrdu bolesti. Trajanje i tijek akutnog bronhiolitisa ovisi o dobi djeteta, težini bolesti, stanjima vezanim uz povećani rizik (npr. nedonoščad, kronična plućna bolest) i uzročniku bolesti. Liječenje je u većini slučajeva suportivno (adekvatna hidracija, toaleta nosa i održavanje prohodnosti dišnih putova, inhalacijska terapija), a kod težih kliničkih slika pribjegava se primjeni respiratorne potpore (neinvazivne i/ili invazivne). Unatoč svemu, bronhiolitis je ipak uglavnom samoograničavajuća bolest i većini djece nije potrebna hospitalizacija te se u potpunosti oporave do 28 dana od početka simptoma bolesti.

Kašalj predstavlja najčešći simptom zbog kojega bolesnici traže liječničku pomoć. Uzroci kašlja su mnogobrojni, a u djece je kašalj najčešće posljedica akutnih respiratornih infekcija koje su u 90% slučajeva virusne etiologije. Kako je akutni kašalj najčešće posljedica nekomplicirane i samolimitirajuće bolesti, u najvećem broju slučajeva ne zahtijeva nikakvo liječenje. S druge strane, kašalj i u tim slučajevima može značajno remetiti kvalitetu života te roditelji često očekuju neku vrstu liječenja za svoje dijete. Ipak, i akutni kašalj može biti kompliciran ili imati i životno ugrožavajući uzrok (aspiracija stranog tijela). Stoga je važno prepoznati tip i trajanje kašlja te posebice obratiti pažnju na posebna upozorenja koja ukazuju na potencijalnu opasnost za dijete. Vrlo mali broj lijekova za kašalj nalazi se na listi lijekova koje pokriva Hrvatski zavod za javno zdravstvo (HZZO), a gotovo da nema lijekova koji su odobreni za primjenu kod djece mlađe od dvije godine. Stoga postoje značajne nezadovoljene potrebe bolesnika vezano uz liječenje kašlja. Oko izbora lijekova postoje mnoge kontroverze i nerijetko se griješi pri njihovom odabiru. Zbog specifičnosti simptoma kašlja te posebnosti dječje populacije Ekspertna skupina za kašalj Hrvatskog društva za pedijatrijsku pulmologiju i Hrvatskog društva za otorinolaringologiju i kirurgiju glave i vrata Hrvatskoga liječničkog zbora izradila je smjernice za liječenje kašlja u djece. Ove smjernice imaju za cilj odgovoriti na glavna klinička pitanja koja se tiču empirijskog liječenja, praktičnih dijagnostičkih alata te dostupnih terapijskih opcija. Liječenje specifičnih stanja koja se manifestiraju i simptomom kašlja (primjerice astma ili refluks povezan s kašljem) nije obuhvaćeno ovim smjernicama. Smjernice nisu sufinancirane od strane farmaceutskih tvrtki, nego su izrađene u želji da se svim zainteresiranima i uključenima u liječenje djece omogući pregledni i smisleni pristup liječenju kašlja.

Alergenska imunoterapija (AIT) još uvijek je jedina dostupna terapija alergijskih bolesti koja djeluje na imunosnu disfunkciju u podlozi alergije te može modificirati tijek i napredovanje bolesti. Suvremeno načelo imunoterapije ne razlikuje se znatnije od ideje koju je imao Leonard Noon 1911. godine, kad je prvi puta AIT primijenjena za liječenje alergijskog rinitisa. AIT podrazumijeva ponavljanu primjenu rastućih doza alergena supkutanim injekcijama do doze održavanja koja se primjenjuje tijekom najmanje tri godine, čime se postiže specifična tolerancija na alergen s dugoročnom učinkovitošću i nakon prekida liječenja. U novije vrijeme sublingvalni put primjene, provediv i u kućnim uvjetima, pokazao se učinkovitom i sigurnom alternativom supkutanom putu. Oralna se imunoterapija sve više primjenjuje u liječenju IgE posredovane alergije na hranu i omogućava postizanje učinkovite ograničene desenzitizacije, ali ne i dugotrajne tolerancije. Imunosni mehanizmi pojave tolerancije uključuju povećano stvaranje interleukina 10 (IL-10) i transformirajućeg faktora rasta beta (TGF-β), smanjenje broja alergenski specifičnih T-pomoćničkih stanica tipa 2 (Th2), indukciju alergenski specifičnih regulacijskih limfocita T i B (Tregs i Bregs) i proizvodnju alergenski specifičnih IgG 4 i IgA blokirajućih protutijela. S obzirom na stalan porast prevalencije alergijskih bolesti, od velikog je interesa u liječenju alergija istražiti nove metode za postizanje imunotolerancije sa sigurnijim, učinkovitijim i dugotrajnijim učinkom; to uključuje alternativne putove primjene alergena za imunoterapiju, nove adjuvanse, rekombinantne alergene (uključujući hipoalergene varijante) i kombinaciju alergena s imunološkim modifikatorima ili monoklonskim protutijelima koji potiskuju Th2 stanični put.

Abstract Background Although it has been shown that allergen immunotherapy (AIT) is well‐tolerated in children, systematic and prospective surveillance of AIT safety in real life settings is needed. Methods The multinational Allergen Immunotherapy Adverse Events Registry (ADER) was designed to address AIT safety in real life clinical practice. Data on children ≤18 years old with respiratory allergies undergoing AIT were retrieved. Patient‐ and AIT‐related features were collected and analyzed. The characteristics of adverse events (AE) and risk factors were evaluated. Results A total of 851 patients, 11.3 ± 3.4 years old, with rhinitis only (47.6%); asthma and rhinitis (44.5%); asthma (7.9%), receiving 998 AIT courses were analyzed. Sublingual immunotherapy (SLIT) accounted for 51% of the courses. In 84.5% of patients only one AIT treatment was prescribed. Pollen was the most frequent sensitizer (57.1%), followed by mites (53.4%), molds (18.2%) and epithelia (16.7%). Local and systemic AEs were reported in 85 patients (9.9%). Most AEs (83.1%) were mild and occurred in

Allergic diseases are one of the most common chronic conditions and their prevalence is on the rise. Environmental exposure, primarily prenatal and early life influences, affect the risk for the development and specific phenotypes of allergic diseases via epigenetic mechanisms. Exposure to pollutants, microorganisms and parasites, tobacco smoke and certain aspects of diet are known to drive epigenetic changes that are essential for immune regulation (e.g., the shift toward T helper 2-Th2 cell polarization and decrease in regulatory T-cell (Treg) differentiation). DNA methylation and histone modifications can modify immune programming related to either pro-allergic interleukin 4 (IL-4), interleukin 13 (IL-13) or counter-regulatory interferon γ (IFN-γ) production. Differential expression of small non-coding RNAs has also been linked to the risk for allergic diseases and associated with air pollution. Certain exposures and associated epigenetic mechanisms play a role in the susceptibility to allergic conditions and specific clinical manifestations of the disease, while others are thought to have a protective role against the development of allergic diseases, such as maternal and early postnatal microbial diversity, maternal helminth infections and dietary supplementation with polyunsaturated fatty acids and vitamin D. Epigenetic mechanisms are also known to be involved in mediating the response to common treatment in allergic diseases, for example, changes in histone acetylation of proinflammatory genes and in the expression of certain microRNAs are associated with the response to inhaled corticosteroids in asthma. Gaining better insight into the epigenetic regulation of allergic diseases may ultimately lead to significant improvements in the management of these conditions, earlier and more precise diagnostics, optimization of current treatment regimes, and the implementation of novel therapeutic options and prevention strategies in the near future.

The prevalence of allergic diseases, including food allergy, is increasing, especially in developed countries. Implementation of an elimination diet is not a sufficient therapeutic strategy in patients with food allergy, whose quality of life is significantly impaired. In recent years, new effective therapeutic strategies have been developed, such as the application of oral, sublingual, and epicutaneous immunotherapy. Oral immunotherapy is the most often applied strategy because of its effectiveness and ease of application, with an acceptable safety profile. The effectiveness of oral immunotherapy in patients with egg, cow’s milk, and peanut allergy has been proven both in terms of raising of the threshold and the development of tolerance, and in some patients, the development of sustainable unresponsiveness. Although oral immunotherapy is an effective treatment for food allergy, several limitations, including a long duration and a significant rate of reported adverse events, reduces its success. Therefore, new therapeutic options, such as treatment with biologicals, either as combinations with food allergen immunotherapy or as monotherapy with the aim of improving the efficacy and safety of treatment, are being investigated.

The atopic march encompasses a sequence of allergic conditions, including atopic dermatitis, food allergy, allergic rhinitis, and asthma, that frequently develop in a sequential pattern within the same individual. It was introduced as a conceptual framework aimed at elucidating the developmental trajectory of allergic conditions during childhood. Following the introduction of this concept, it was initially believed that the atopic march represented the sole and definitive trajectory of the development of allergic diseases. However, this perspective evolved with the emergence of new longitudinal studies, which revealed that the evolution of allergic diseases is far more intricate. It involves numerous immunological pathological mechanisms and may not align entirely with the traditional concept of the atopic march. The objective of our review is to portray the atopic march alongside other patterns in the development of childhood allergic diseases, with a specific emphasis on the potential for a personalized approach to the prevention, diagnosis, and treatment of atopic conditions.

Nasal nitric oxide (nNO) is a gas synthesized by the inducible and constitutive NO synthase (NOS) enzyme in the airway cells of the nasal mucosa. Like lung nitric oxide, it is thought to be associated with airway inflammation in various respiratory diseases in children. The aim of our review was to investigate the current state of use of nNO measurement in children. A comprehensive search was conducted using the Web of Science and PubMed databases specifically targeting publications in the English language, with the following keywords: nasal NO, children, allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, primary ciliary dyskinesia (PCD), and cystic fibrosis (CF). We describe the use of nNO in pediatric allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, PCD, and CF based on the latest literature. nNO is a noninvasive, clinically applicable test for use in pediatric allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, PCD, and CF. It can be used as a complementary method in the diagnosis of these respiratory diseases and as a monitoring method for the treatment of allergic rhinitis and acute and chronic rhinosinusitis.

Community-acquired pneumonia is potentially serious infection in children. The diagnosis can be based on the history and clinical signs and symptoms. Additional diagnostic tests (laboratory, imaging, and microbiology) may be helpful when diagnosis is unclear. The most likely etiology depends on a number of factors such as seasonality, geographic location, the age of child, and the severity of disease. Treatment involves symptomatic measures, and in most children antibiotic therapy. This paper presents the clinical guidelines of the Croatian Society of Pediatric Pulmonology to standardize the procedures for the diagnosis and treatment of children with community-acquired pneumonia.

Children with food allergies are at higher risk for severe anaphylactic reactions and for key nutrient deficiency. In order to address these concerns, enable early detection, and improve the monitoring of children with food allergies, an innovative IT platform will be developed by IT experts (IN2 Ltd. Zagreb, Croatia, part of Constellation Software Inc. (Toronto, ON, Canada)) and Srebrnjak Children’s Hospital, Zagreb, Croatia (SCH) for the effective implementation of personalized balanced nutrition in preschool institutions in Croatia. Additionally, the data obtained through this research, including epidemiological data on allergic diseases, clinical data (diagnostic allergy tests and others), anthropometry, and physical activity status, will be used to create a national Allergy registry. Other than being a tool for personalized and balanced nutrition for children, especially those with special dietary requirements (including food allergy and intolerance), the IT platform developed in this study will enable the continuous monitoring of these children as a part of their clinical management plan and earlier detection of food allergies, intolerance, and other conditions, even outside of the healthcare system. This research also aims at optimizing current and developing novel personalized therapeutic regimes, detecting novel early biomarkers in children with food allergies and intolerances, and involving all key stakeholders (caregivers, preschool institutions, etc.) in the shared-care approach in the management of food allergies in children.

Abstract Despite widely and regularly used therapy asthma in children is not fully controlled. Recognizing the complexity of asthma phenotypes and endotypes imposed the concept of precision medicine in asthma treatment. By applying machine learning algorithms assessed with respect to their accuracy in predicting treatment outcome, we have successfully identified 4 distinct clusters in a pediatric asthma cohort with specific treatment outcome patterns according to changes in lung function (FEV1 and MEF50), airway inflammation (FENO) and disease control likely affected by discrete phenotypes at initial disease presentation, differing in the type and level of inflammation, age of onset, comorbidities, certain genetic and other physiologic traits. The smallest and the largest of the 4 clusters- 1 (N = 58) and 3 (N = 138) had better treatment outcomes compared to clusters 2 and 4 and were characterized by more prominent atopic markers and a predominant allelic (A allele) effect for rs37973 in the GLCCI1 gene previously associated with positive treatment outcomes in asthmatics. These patients also had a relatively later onset of disease (6 + yrs). Clusters 2 (N = 87) and 4 (N = 64) had poorer treatment success, but varied in the type of inflammation (predominantly neutrophilic for cluster 4 and likely mixed-type for cluster 2), comorbidities (obesity for cluster 2), level of systemic inflammation (highest hsCRP for cluster 2) and platelet count (lowest for cluster 4). The results of this study emphasize the issues in asthma management due to the overgeneralized approach to the disease, not taking into account specific disease phenotypes.

Background: Respiratory syncytial virus (RSV) stimulates the production of specific immunoglobulin (Ig) E and IgG4 antibodies as a hallmark of the Th2 immune response. In this paper, we evaluated the occurrence of atopic diseases in 10-year-old children who were positive for RSV-specific IgG antibodies during infancy. Methods: The prospective follow-up of 72 children included a physical examination, an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and the determination of RSV-specific antibodies and total and allergen-specific IgE. Results: Children with asthma had their first wheezing episode at a younger age (χ2 8.097, df = 1, p = 0.004). RSV-specific IgG4 levels at year one were positively correlated with atopic dermatitis (AD) (tau_b = 0.211, p = 0.049) and current AD (tau_b = 0.269, p = 0.012); and RSV-specific IgE levels were positively correlated with allergic rhinitis (AR) (tau_b = 0.290, p = 0.012) and current AR (tau_b = 0.260, p = 0.025). Positive RSV-specific IgE at the age of one increased the chances of asthma occurrence by 5.94 (OR = 5.94, 95% CI = 1.05–33.64; p = 0.044) and the chances of AR by more than 15 times (OR = 15.03, 95% CI = 2.08–108.72; p = 0.007). A positive family history of atopy increased the chances of asthma occurrence by 5.49 times (OR = 5.49, 95% CI = 1.01–30.07; p = 0.049), and a longer duration of exclusive breastfeeding lowered that chance (OR = 0.63, 95% CI = 0.45–0.89; p = 0.008). Prenatal smoking increased the chances of AR occurrence by 7.63 times (OR = 7.63, 95% CI = 1.59–36.53; p = 0.011). Conclusion: RSV-specific IgE and RSV-specific IgG4 antibodies could be risk markers for the development of atopic diseases in children.

Introduction Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. Methods Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. Results We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. Conclusion Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.

Asthma in children is a heterogeneous disease manifested by various phenotypes and endotypes. The level of disease control, as well as the effectiveness of anti-inflammatory treatment, is variable and inadequate in a significant portion of patients. By applying machine learning algorithms, we aimed to predict the treatment success in a pediatric asthma cohort and to identify the key variables for understanding the underlying mechanisms. We predicted the treatment outcomes in children with mild to severe asthma (N = 365), according to changes in asthma control, lung function (FEV1 and MEF50) and FENO values after 6 months of controller medication use, using Random Forest and AdaBoost classifiers. The highest prediction power is achieved for control- and, to a lower extent, for FENO-related treatment outcomes, especially in younger children. The most predictive variables for asthma control are related to asthma severity and the total IgE, which were also predictive for FENO-based outcomes. MEF50-related treatment outcomes were better predicted than the FEV1-based response, and one of the best predictive variables for this response was hsCRP, emphasizing the involvement of the distal airways in childhood asthma. Our results suggest that asthma control- and FENO-based outcomes can be more accurately predicted using machine learning than the outcomes according to FEV1 and MEF50. This supports the symptom control-based asthma management approach and its complementary FENO-guided tool in children. T2-high asthma seemed to respond best to the anti-inflammatory treatment. The results of this study in predicting the treatment success will help to enable treatment optimization and to implement the concept of precision medicine in pediatric asthma treatment.