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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

The aim of this article is to critically review the managing of vaccination over the course of the present COVID-19 pandemic against the knowledge that had already been at hand and the scientific data that had yet to be learned. In the period before vaccines for COVID-19 became available, the startling similarity in epidemiologic behavior between COVID-19 and the Spanish flu could be observed. The development of vaccines against COVID-19 has evolved at an unprecedented speed resulting in highly immunogenic vaccines with incredible protective characteristics covering a relatively short follow-up time in clinical trials. The rollout in the general population turned out to take significantly longer time than the duration of immunity conferred by a 2-dose vaccination schedule (about 3-4 months). Therefore, the SARS-CoV-2 was left with the opportunity for random mutations with each replication cycle, resulting in immune evasion, shortened incubation, shortened serial interval, and increased transmissibility. The short incubation period of COVID-19 requires a steady protective antibody titer to be maintained to avert infection, achieve herd immunity, and terminate the pandemic spread. The protective neutralization titer needed to avert symptomatic infection and infection altogether is about 3% and 20%, respectively, of the mean convalescent titer. The latter corresponds to an absolute titer of 1:10–1:30. The intensity and duration of protective vaccinal and hybrid humoral immunity are explored. From the present perspective, it was naive to believe that a 2-dose vaccination would suffice to counter COVID-19 primarily due to its short incubation and a roll-out that was not catching up with the waning protective vaccinal antibody levels. Besides, the spacing of doses and boosters with respect to previous infection or vaccination, and differences in natural immunity and vaccine-induced immunity (adenovirus-vectored and mRNA) are discussed. The issue of vaccination and multisystem inflammatory syndrome in children is briefly presented. Finally, ethical points are discussed as some vaccine production platforms and neutralization tests use human cell lines derived from aborted fetuses.Conclusion – If the COVID-19 vaccines had been licensed as 3-dose vaccines, with more generous spacing, e.g. 0-2-6 months, providing for quantitatively larger and temporally more durable humoral immunity, that would have enabled attaining a steadier herd immunity and probably a paradoxical earlier effect on stopping the transmission.

The aim of this article is to review the allergic reactions to infectious disease vaccines in children and offer guidance on how to practically approach the question of a possible allergic reaction to a vaccine. Allergies to vaccines occur at an estimated rate of 1-2 in 1,000,000 vaccine doses. For the most part concerns over possible allergies to vaccines are usually not supported by the appropriate scientific facts and are exaggerated by ignorance, fear and irrational beliefs. If an allergic reaction to a vaccine is believed to have occurred, the first step is to link the clinical symptoms to the vaccine administration. Urticaria, angioedema, wheezing and hypotension occuring within 30 minutes after vaccine administration point to a probable severe IgE-mediated reaction. Most vaccine constituents may cause the immediate type allergic reaction: stabilizers (gelatin, dextran), remnants of culture media (ovalbumin, yeast), latex from vial stoppers, antimicrobial agents added to maintain sterility, the least common being microbial antigens and preservatives. Prick and intradermal testing with whole vaccine and with specific constituents should be performed within 3-12 weeks following the reaction. In vitro tests (specific IgE) should be done if available. Positive in vivo or in vitro tests do not necesssarily preclude further vaccination, especially if it is considered vital or outweighing the potential risks. However, decision should be made on a case by case basis by a qualified allergist. Fractionated or graded dose protocols are available for implementation in day care or hospital settings. Conclusion – Systemic IgE mediated allergy to vaccines is rare in children. If it occurs a full list of vaccine constituents should be considered and appropriate allergological testing performed.

Patients with successful autologous or allogeneic hematopoietic stem-cell therapy should get booster courses of previous vaccinations Additionally, the patient should get inactivated Inf, PCV and Men vaccine Inactivated vaccines can generally be started at 6 months post HSCT, provided the child has no immunosuppression for the past 3 months, a lymphocyte count >1200/μL, and endogenous IgG > 500 mg/dL Live vaccines are strictly contraindicated. Only MMR and Var can be considered in select well engrafted cases, no sooner than 24 months after HSCT. Requirement is CD4+ count >700/mL, endogenous IgG >500 mg/dL, and adequate serological response to inactivated vaccines, no immunosuppression and no GVHD Passive immunoglobulin prophylaxis is established for measles by IVIG and for chickenpox by VZIG Chemoprophylaxis with valacyclovir is available for chickenpox, in intramuscular and subcutaneous forms The 16% HNIG concentrate can provide passive protection for measles, and to some extent hepatitis A and chickenpox

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).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.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.

Temporal association of an adverse event to immunization should not automatically be considered to constitute a causal relation If the events are not causally related, the continuation of immunization is advised Atopy and autoimmunity are not associated with history of immunization Comorbid disorders like multiple sclerosis, Guillain-Barre syndrome and thrombocytopenia may constitute relative or absolute contraindications to specific vaccines

Anaphylaxis to vaccines is rare; approximately once in one million doses Anaphylaxis usually occurs within the first 30 min after exposure, but sometimes it can take up to 4 h or longer Symptoms of anaphylaxis are polymorphic, but well systematized and should be readily recognized and carefully appreciated Anaphylaxis should be acutely treated with adrenaline, systemic corticosteroids, volume replacement, and antihistamines Twenty-four-hour hospital observation is indicated because a biphasic course is possible in anaphylaxis Diagnosis relies on skin testing with the culprit vaccine and its components, and where available, in vitro tests for the specific IgE to vaccine additives Anaphylaxis contraindicates further immunization with the culprit vaccine; in exceptional vital situations, a desensitization-immunization graded dose protocol may be attempted in an intensive care setting

Tick-borne encephalitis (TBE) is a viral neurological zoonotic disease transmitted to humans by ticks or by consumption of unpasteurized dairy products from infected cows, goats, or sheep. TBE is highly endemic in areas of Central and Eastern Europe and Russia where it is a major public health concern. However, it is difficult to diagnose TBE as clinical manifestations tend to be relatively nonspecific and a standardized case definition does not exist across the region. TBE is becoming more important in Europe due to the appearance of new endemic areas. Few Central European Vaccination Awareness Group (CEVAG) member countries have implemented universal vaccination programmes against TBE and vaccination coverage is not considered sufficient to control the disease. When implemented, immunization strategies only apply to risk groups under certain conditions, with no harmonized recommendations available to date across the region. Effective vaccination programmes are essential in preventing the burden of TBE. This review examines the current situation of TBE in CEVAG countries and contains recommendations for the vaccination of children and high-risk groups. For countries at very high risk of TBE infections, CEVAG strongly recommends the introduction of universal TBE vaccination in children > 1 y of age onwards. For countries with a very low risk of TBE, recommendations should only apply to those traveling to endemic areas. Overall, it is generally accepted that each country should be free to make its own decision based on regional epidemiological data and the vaccination calendar, although recommendations should be made, especially for those living in endemic areas.

WOS: 000398771800023, PubMed ID: 27697500, 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., Jeffrey Modell Foundation; National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease [U54 AI 082973, R13AI094943], Supported by a grant from Jeffrey Modell Foundation (to M.d.l.M.). The Primary Immune Deficiency Treatment Consortium (PIDTC) is supported by the National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease grants U54 AI 082973 and R13AI094943.

Konverzivni poremećaj u adolescenata može imati dramatičnu kliničku prezentaciju te ga je u prvi mah teško razlikovati od organskih ili od drugih psihijatrijskih bolesti. Prikazujemo tri bolesnice u dobi od 11 do 13 godina koje su dovedene u hitnu pedijatrijsku ambulantu pod slikom neepileptičkih psihogenih napadaja. Zbog dramatične kliničke prezentacije, odsutnosti kontakta i sličnosti s pravim epileptičkim napadajima, primijenjene su reanimacijske mjere te antikonvulzivna terapija. Tek naknadno, detaljnom dijagnostičkom obradom, isključeno je organsko podrijetlo simptoma. Psihološkim testiranjem te pregledom dječjeg i adolescentnog psihijatra postavljena je dijagnoza konverzivnog poremećaja, a liječenje i praćenje nastavljeno je na dječjoj i adolescentnoj psihijatriji. Kako bi se izbjegle nedoumice te primjena rizičnih i nepotrebnih terapijskih postupaka, u svakodnevnoj hitnoj pedijatrijskoj praksi potrebno je misliti i na moguće neepileptičke psihogene napadaje., Conversion disorders in adolescents can have dramatic clinical presentation which may be diffi cult to distinguish from organic or other psychiatric disorders. We describe three female adolescents aged 11 to 13 years, brought to the pediatric emergency room with psychogenic nonepileptic fi ts. Due to the dramatic clinical presentation, unresponsiveness and similarity to true epileptic seizures, they were initially thought to need resuscitation and anticonvulsant therapy, and were hospitalized. The work-up could not disclose any organic origin of their symptoms. Psychological testing and consultation with the child and adolescent psychiatrist led to the diagnosis of conversion disorder and further treatment and follow up was scheduled at the child and adolescent psychiatry department. In order to avoid confusion and unnecessary and potentially risky therapeutic interventions, it is crucial to consider the possibility of psychogenic nonepileptic seizures in everyday pediatric emergency practice.

Streszczenie Wraz z postepującym starzeniem sie populacji europejskiej prawdopodobnie bedzie nastepowal staly wzrost zachorowalności i zwiekszenie nakladow finansowych na leczenie w populacji osob doroslych. Tendencje te czynią zasadne przeprowadzenie przeglądu i rewizji mozliwych strategii profilaktycznych, jakimi są szczepienia. Z uwagi na niedobor skoordynowanych programow szczepien u doroslych istotny problem stanowi wdrazanie tej formy immunizacji w populacji doroslych. W krajach Europy Zachodniej zaczeto uwzgledniac koniecznośc rozszerzenia szczepien w tej grupie demograficznej. Problem ten w Europie Środkowej pozostaje slabo poznany i wciąz niedostatecznie opisany. W niniejszym artykule podsumowano dostepne dane, ktorych analiza wskazuje na koniecznośc rozszerzenia kalendarza szczepien doroslych w grupie krajow Europy Środkowej, nalezących do Stowarzyszenia Świadomej Postawy wobec Szczepien CEVAG ( Central European Vaccination Awareness Group ) (Bulgaria, Chorwacja, Czechy, Estonia, Wegry, Łotwa, Litwa, Rumunia, Slowacja, Slowenia i Turcja). Grupa CEVAG zaleca wdrozenie kalendarza szczepien doroslych, ktory powinien obejmowac szczepienia przeciwko chorobom o najwiekszej śmiertelności i zachorowalności w tej populacji. Kalendarz ten powinien byc indywidualizowany w stosunku do indywidualnych potrzeb i priorytetow krajowych.

The 2009 influenza A(H1N1) pandemic is markedly different from seasonal influenza with the disease affecting the younger population and a larger than expected number of severe or fatal cases has been seen in pregnant women, obese people and in people who were otherwise healthy. In Europe, influenza activity caused by the 2009 influenza A(H1N1) virus has passed the winter peak with nearly all countries now reporting lower influenza activity. However, although the rate of 2009 pandemic influenza A(H1N1) is declining, fatal cases continue to be reported and the future is hard to predict. The most effective protection against influenza is vaccination and increasing vaccine coverage is the only way to eliminate uncertainties regarding possible future waves of 2009 pandemic influenza A(H1N1). Recommendations have been developed for several central European countries but there is no clear or uniform definition with respect to priority groups or age groups who should receive vaccination. This paper contains the Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for the vaccination of adults and children against 2009 pandemic influenza A(H1N1). CEVAG recommends vaccination of all health-care workers, pregnant women, childrenor = 6 months and2 years of age and people with chronic medical conditions as a first priority.

Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells. and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain: no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe. (C) 2009 Elsevier Ltd. All rights reserved.

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) 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-12Rβ1 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-12Rβ1 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.

Mycotoxicoses are acute and chronic poisonings caused by mould toxins called mycotoxins. Although acute mycotoxicoses, caused by high mycotoxin levels in food are rare nowadays, they need to be described in order to inform physicians and other health care workers about their symptoms. Children are more sensitive to mycotoxins because of their lower body mass, higher metabolic rate, and underdeveloped organ functions and detoxication mechanisms. Some mycotoxicoses appear only in children, and some are more pronounced in children than in adults. Acute mycotoxicoses in children are reported poorly, mostly because they occur in the tropical regions with poor healthcare coverage. In developed countries healthcare authorities are more concerned about child exposure to low levels of mycotoxins with immunotoxic, genotoxic or carcinogenic properties

Over the last decade, childhood immunization has substantially reduced morbidity and mortality from vaccine-preventable diseases. However, particular paediatric risk groups, such as those with comorbidities, may not be adequately vaccinated despite being more susceptible to complications and death from certain infectious diseases. This may be due to lack of immunization recommendations, lack of awareness, or incomplete adherence to existing guidelines. Furthermore, recommendations for immunization can be inconsistent across Europe. An expanded initiative from the Central European Vaccination Awareness Group aims to raise awareness of the different high-risk paediatric groups, differentiate them according to their specific risk, and formalise a guidance statement for the immunization of each population.

Mycotoxicoses are acute and chronic poisonings caused by mould toxins called mycotoxins. Although acute mycotoxicoses, caused by high mycotoxin levels in food are rare nowadays, they need to be described in order to inform physicians and other health care workers about their symptoms. Children are more sensitive to mycotoxins because of their lower body mass, higher metabolic rate, and underdeveloped organ functions and detoxication mechanisms. Some mycotoxicoses appear only in children, and some are more pronounced in children than in adults. Acute mycotoxicoses in children are reported poorly, mostly because they occur in the tropical regions with poor healthcare coverage. In developed countries healthcare authorities are more concerned about child exposure to low levels of mycotoxins with immunotoxic, genotoxic or carcinogenic properties., Mikotoksikoze su akutna i kronična trovanja toksinima plijesni koji se nazivaju mikotoksini. Odrasle osobe i djeca stalno su izloženi niskim koncentracijama mješavine mikotoksina, većinom putem kontaminirane hrane. Akutne toksikoze koje uzrokuje izloženost velikim količinama mikotoksina danas su rijetke te su opisane kako bi se liječnici i drugo zdravstveno osoblje informirali o njihovim simptomima koji mogu oponašati druge bolesti. Djeca su osjetljivija na toksični učinak mikotoksina zbog toga što je njihova tjelesna masa manja, a neki sustavi za detoksikaciju nisu u potpunosti razvijeni. Neke se mikotoksikoze javljaju samo u djece ili su u djece simptomi jače izraženi. Podrobnih podataka o epidemiologiji mikotoksikoza u dječjoj dobi nema jer one pogađaju prvenstveno najsiromašnije, uglavnom u zemljama tropskoga pojasa gdje je zdravstvena služba nedostatna, a potrebe stanovništva za liječenjem velike. U tim se zemljama češće javljaju i kronične mikotoksikoze, no ima ih i u zemljama s umjerenom klimom. U razvijenim su zemljama zdravstvene vlasti više zabrinute zbog izloženosti djece niskim koncentracijama mikotoksina koji imaju imunotoksična, genotoksična i kancerogena svojstva.

Hearing loss in patients with X-linked agammaglobulinemia is often attributed to recurrent infections. However, recent genetic studies suggest a different etiology in some patients. We present three unrelated patients, 6, 9, and 14 years of age, with large deletions of the terminal portion of the Bruton tyrosine kinase (Btk) gene extending 4.2-19 kb beyond the 3' end of the gene. The DNA immediately downstream of the 3' end of Btk contains the deafness-dystonia protein gene (DDP). Mutations in this gene have recently been shown to underlie the Mohr-Tranebjaerg syndrome, which is characterized by sensorineural deafness, dystonia, and mental deficiency. Besides the immunodeficiency, our patients exhibited progressive sensorineural deafness. The clue to an associated hearing problem was delayed development of speech in one patient and post-lingual deafness noticed between the age of 3-4 years in the other two. These patients have not yet exhibited significant associated neurologic deficits.

Summary In order to build a common data pool and estimate the disease burden of primary immunodeficiencies (PID) in Europe, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Since its start in 2004, 13 708 patients from 41 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity with 2880 patients or 21% of all entries, followed by selective immunoglobulin A (sIgA) deficiency (1424 patients, 10·4%). The total documented prevalence of PID is highest in France, with five patients per 100 000 inhabitants. The highest documented prevalence for a single disease is 1·3 per 100 000 inhabitants for sIgA deficiency in Hungary. The highest reported incidence of PID per 100 000 live births was 16·2 for the period 1999–2002 in France. The highest reported incidence rate for a single disease was 6·7 for sIgA deficiency in Spain for the period 1999–2002. The genetic cause was known in 36·2% of all registered patients. Consanguinity was reported in 8·8%, and 18·5% of patients were reported to be familial cases; 27·9% of patients were diagnosed after the age of 16. We did not observe a significant decrease in the diagnostic delay for most diseases between 1987 and 2010. The most frequently reported long-term medication is immunoglobulin replacement.

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.

As Europe's population ages, disease morbidity and treatment costs in the adult population are likely to rise substantially, making this a pertinent time to review and revise preventive strategies such as vaccination. Vaccine uptake remains a problem for adults and there is a lack of coordinated programmes for vaccination of adults. Countries in Western Europe have begun to identify the need to increase adult vaccination, but the situation in Central European countries remains poorly identified and inadequately described. This paper summarises the evidence to support the development of an adult vaccination calendar in the Central European Vaccination Awareness Group (CEVAG) member countries (Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Romania, Slovakia, Slovenia and Turkey). CEVAG recommends the introduction of an adult vaccination calendar, which should include vaccination against diseases that represent a large burden in adults in terms of mortality and morbidity. This calendar could be modified to meet the priorities of individual countries.

Rubella is a contagious viral disease with few complications except when contracted by pregnant women. Rubella infection in pregnancy can result in miscarriage, stillbirth or an infant born with congenital rubella syndrome (CRS) which comprises deafness, heart disease, cataracts and other permanent congenital manifestations. Clinical diagnosis of rubella is difficult due to overlapping symptoms with many other diseases and confirmation of rubella is not possible without laboratory testing. Effective vaccination programmes are critical to the elimination of rubella and prevention of CRS. Such programmes have been successful in several countries in Europe and around the world. However, rubella outbreaks still occur due to suboptimal vaccine coverage and in the past 10 years rubella has been reported in Central European countries such as Romania and Poland. Over the past decade the elimination of rubella and prevention of congenital rubella infection in Europe has been a high priority for the WHO European Regional Office. In 2010 the WHO regional committee for Europe renewed its commitment to the elimination of rubella and prevention of CRS with a new target of 2015. This paper examines the current situation for rubella and CRS in Central Europe and describes the different rubella vaccination programmes in the region. The Central European Vaccination Advisory Group (CEVAG) recommends that two doses of measles, mumps and rubella vaccine, MMR, should be given to all children. The first dose should be given between 12 and 15 months of age. The second dose can be given between the ages of 21 months and 13 years with the exact age of administration of the second dose depending on the situation specific to each country. All suspected rubella cases should be laboratory-confirmed and monitoring systems to detect and investigate cases of CRS should be strengthened.

Alergijski rinitis najčešći je oblik kroničkog rinitisa u dječjoj dobi. Pokreće ga alergijska upala i obično je udružen s drugim atopijskim bolestima: astmom i atopijskim ekcemom. Glavni su alergeni aeroalergeni: grinja iz kućne prašine, te peludi stabala, trava i korova. Međutim, nije sasvim rijetko da se simptomi alergijskog rinokonjunktivitisa pojave u svezi s nutritivnom alergijom i oralnim alergijskim sindromom, osobito u dojenčadi i male djece. Alergijski je rinitis često udružen s alergijskom astmom, bilo da joj prethodi, ili da nastane naknadno, a u svakom slučaju otežava njezino liječenje. Oslonac liječenja je ekspozicijska profilaksa, antihistaminici, antagonisti leukotriena i intranazalni kortikosteroidi. Alergijski je rinokonjunktivitis jedna od glavnih indikacija za specifičnu alergensku imunoterapiju koja može imati i preventivni učinak na razvoj astme. Alergijski rinitis udružen s povremenom ili blagom trajnom astmom može biti dobrom indikacijom, ne samo za imunoterapiju, već i za kombinirano liječenje antihistaminikom i antagonistom leukotriena. Kod težih oblika ne treba prezati od intranazalnih kortikosteroida. Kod kratkoročne primjene (do 3 mjeseca) za sada nisu ustanovljene znatnije lokalne niti sistemne nuspojave., 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.

Streptococcus pneumoniae causes considerable global paediatric morbidity and mortality, despite the availability of safe and effective pneumococcal conjugate vaccines (PCVs). To justify the introduction of PCVs, accurate information on the burden of disease is required. Here, we present an appraisal of the pneumococcal epidemiological situation in 11 Central European countries. The data are based on study findings presented at the 12th Central European Vaccine Advisory Group (CEVAG) meeting, held on 21-22 May 2010 in Sofia, Bulgaria, and a literature review of the PubMed database using the search terms 'pneumococcal' or 'Streptococcus pneumoniae', in combination with 'otitis media', 'pneumonia', 'meningitis' or 'bacteraemia/sepsis', and '[Central European country name]'. The incidence of pneumococcal disease appears to be lower in Central Europe than previously reported for Europe as a whole, with the highest risk in infants aged 0-2 years. The fatality rates in the under fives from invasive infections are up to 40%. A paucity of comprehensive country-specific data on pneumococcal disease burden arises from the lack of homogenous surveillance programmes. Standardised, active surveillance systems are required for the accurate evaluation of the pneumococcal disease burden in the region. Only then can the need for vaccination be addressed.

WOS: 000283840300002, PubMed ID: 21057261, Interleukin-12 receptor beta 1 (IL-12R beta 1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guerin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years +/- 9.8 years (range, 0.5-46.4 yr). IL-12R beta 1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought., Rockefeller University Center for Clinical and Translational Science [5UL1RR024143-03]; Rockefeller University; ANRFrench National Research Agency (ANR); PHRC; EUEuropean Union (EU) [LHSP-CT-2005-018736]; BNP Paribas Foundation; Dana Foundation; March of DimesMarch of Dimes; Fondation pour la Recherche MedicaleFondation pour la Recherche Medicale; Howard Hughes Medical InstituteHoward Hughes Medical Institute, The St. Giles Laboratory of Human Genetics of Infectious Diseases is supported by grants from The Rockefeller University Center for Clinical and Translational Science grant number 5UL1RR024143-03, and The Rockefeller University, ANR, PHRC, EU (LHSP-CT-2005-018736), BNP Paribas Foundation, the Dana Foundation, and the March of Dimes. LDB is supported by the Fondation pour la Recherche Medicale as part of the PhD program of Pierre et Marie Curie University (Paris, France). JLC was an International Scholar of the Howard Hughes Medical Institute.

Cijepljenje je najveće postignuće u medicini 20. stoljeća koje je spasilo više života od ikoje druge medicinske intervecije. U radu se raspravlja o kontraindikacijama za cijepljenje djece s neurološkim poremećajima / bolestima prije i poslije cijepljenja. Opće kontraindikacije u ovim skupinama djece ne razlikuju se od onih koje se primjenjuju za opću pedijatrijsku populaciju. Posebne zapreke mogu se odnositi na pojedina cjepiva. Neprogresivne encefalopatije nastale zbog ranog perinatalnog oštećenja mozga (cerebralna paraliza), dobro kontrolirane epilepsije, kongenitalne neuromuskularne i većina bolesti metabolizma u ranoj dječjoj dobi, kao i razvojni pervazivni poremećaji, akutni demijelinizirajući encefalomijelitis, transverzni mijelitis, multipla skleroza i Guillain–Barreov sindrom npr. u kasnijem djetinjstvu – nisu kontraindikacija za cijepljenje. U svakodnevnom kliničkom radu svjedoci smo primjene neformalnih – „(pseudo)kontraindikacija“ (blaga bolest sa subfebrilitetom, primanje antibiotika, nedonošenost, „mala“ težina, nedavna izloženost zarazi ,alergija na penicilin i mnoge druge). Blage do umjerene lokalne i opće reakcije na prethodno cjepivo nisu zapreka za nastavak cijepljenja. Osobno iskustvo pokazuje da se postvakcinalne promjene u primarnom ciklusu cijepljenja protiv difterije – tetanusa - hripavca (DTP) mogu značajno umanjiti primjenom nestaničnog cjepiva (DTaP) koje je odnedavno u primjeni i u našoj zemlji. Progresivne akutne i subakutne infekcijske, metaboličke i imunološke encefalopatije ili encefalomijelopatije, koma, druga trajna stanja poremećene svijesti s promjenama u likvoru i EEG-u, infantilni spazmi i Reyov sindrom apsolutne su kontraindikacije za primjenu cjepiva protiv hripavca. Isto se odnosi i na encefalopatiju u vremenskoj povezanosti sa cijepljenjem te anafilaksija na cjepivo s DTP-om. Aseptički meningitis nakon cijepljenja protiv ospica, zaušnjaka i crljenke ( MPR) nije kontraindikacija za revakcinaciju. U skupini od 43-je perinatalno neurorizične dojenčadi, koja je bila upućena na neuropedijatrijski pregled do dobi tri mjeseca radi mišljenja o započinjanju cijepljenja DTP-om, preporuka neuropedijatra uzimala se u obzir i primjenjivala se u 24/43 (56%) slučajeva (djeca su bila cijepljena u razdoblju od mjesec dana nakon pregleda)., Vaccination is the most important medical success of the 20th century, having resulted in saving more lives than any other medical intervention. The contraindications for vaccination are discussed in children with neurological disorders and diseases which were present before or occurred after vaccination. General contraindications for vaccination in these children do not differ from contraindications in the general pediatric population. Special contraindications refer to particular vaccines. Non-progressive encephalopathies caused by early perinatal brain damage (cerebral palsy), well controlled epilepsies, congenital neuromuscular diseases and the majority of metabolic diseases as well as developmental pervasive disorders, acute encephalomyelitis and transverse myelitis, multiple sclerosis and Guillian Bareov syndrome in later childhood – are not contraindications for vaccination. Vaccination is often hampered by „pseudo-contraindications“ such as mild febrile illness, antibiotic therapy, prematurity, „low“ weight, recent exposure to infection or allergy to penicillin. These informal contraindications should be avoided in the best interests of the child. Mild and moderate local or general reactions after previous vaccination are not contraindications for further vaccination. Our experience showed that side effects after acellular vaccine against Diphtheria- Tetanus – Pertussis (DTaP), which is now used in our country too, are less frequent. Progressive acute and subacute infectious, metabolic or immunological encephalo-pathies or encephalomyelopathies, coma, prolonged unconscious state with EEG and cerebro-spinal fluid changes, infantile spasms and Rey's syndrome are absolute contraindications for vaccination against Pertussis. The children with encephalopathy temporarily related to vaccination against Pertussis as well as children with anaphylactic reaction after vaccination should not be vaccinated against Pertussis. The children who developed aseptic meningitis after MPR vaccination (against Morbilli, Mumps and Rubeolla) should be revaccinated. In the group of 43 children who had perinatal neurological difficulties and were sent to the neuropediatrician in the first three months of life, 56 % of them were vaccinated during the following month after consultation.

Cilj: Prikazati elektroforetsku sliku izoenzima ALP u serumu dojenčadi i djece koja su u tijeku akutne respiracijske bolesti imala povećanu ukupnu katalitičku aktivnost ALP. Ispitanici i metode: Prikazani su rezultati u 21 djeteta (od toga 17 dojenčadi), 8 djevojčica i 13 dječaka, u dobi od 2 mjeseca do 8 godina, hospitaliziranih zbog respiracijskih bolesti. U serumu djece određena je ukupna katalitička aktivnost ALP i provedeno elektroforetsko razdvajanje izoenzima ALP. Rezultati: Osmoro djece (38,1%) je u tijeku hospitalizacije imalo povećanu ukupnu katalitičku aktivnost ALP (raspon od 528 do 5622 U/L). Tipičnu sliku benigne prolazne hiperfosfatazemije, koja podrazumijeva pojavu brze anodne frakcije (brža od jetrene frakcije) i tzv. katodne frakcije (brža od koštane frakcije), imalo je petero djece. Izoenzim nalik placentalnom izoenzimu izdvojio se u dvoje djece. Izraženu koštanu frakciju, ali i frakciju nalik placentalnoj imalo je dijete s rahitisom. Predjetreni oblik ALP otkriven je kod dvoje djece, a jetreni izoenzim u jednog djeteta. Zaključak: Akutna respiracijska bolest u dojenčadi i djece može imati za posljedicu prolazno povećanje katalitičke aktivnosti ALP odnosno pojavu različitih izoenzimskih vrpca, primjerice brze anodne i tzv. katodne frakcije (kod prolazne hiperfosfatazemije), predjetrene frakcije i frakcije koja odgovara placentalnom izoenzimu. Prolazna hiperfosfatazemija se dokazuje nakon što se ukupna aktivnost ALP značajno smanji odnosno vrati u referentne raspone unutar 3-4 mjeseca. U tom slučaju daljnje analize nisu potrebne., Aim: To present the electrophoretic pattern of alkaline phosphatase (ALP) isoenzymes in serum of infants and children exhibiting increased total ALP catalytic activity in the course of acute respiratory disease. Subjects and methods: Results obtained in 21 children (17 of them infants), including 13 male and eight female children aged 2 months to 8 years, hospitalized for respiratory diseases are presented. Total ALP catalytic activity was determined and electrophoretic separation of ALP isoenzymes was performed in children's sera. Results: Increased total ALP catalytic activity (range, 528-5622 U/L) during hospital stay was recorded in eight (38.1%) children. A typical picture of be-nign transient hyperphosphatasemia (TH), which implies the occurrence of fast anodal fraction (faster than hepatic fraction) and near-cathode fraction (faster than bone fraction), was recorded in five children. The placental-like isoenzyme was detected in two children. Expression of bone fraction and placental-like fraction was recorded in a rachitic child. Prehepatic ALP was expressed in two children, and hepatic ALP isoenzyme in one child. Conclusion: Acute respiratory disease in infants and children may entail transient increase in the ALP catalytic activity with the occurrence of various isoenzyme bands such as fast anodal and near-cathode fraction (in TH), prehepatic fraction and placental-like fraction. TH is verified when total ALP activity has decreased and returned to reference intervals. In this case, no additional testing is required.

Background: The aim of this study was to determine cut-off values for total serum immunoglobulin E (IgE) between non-atopic and atopic children with respiratory symptoms. Children of 0-16 years of age were evaluated for respiratory symptoms of >4-week duration. Methods: Children were divided into two groups: non-atopic children (n=3355) who were non-IgE-sensitized with undetectable allergen-specific IgE (/=1 allergens (specific IgE >/=0.35 kIU(A)/L). Upper and lower centiles were determined and cut-off values calculated using receiver operating characteristic (ROC) analysis. Results: Serum total IgE increased with age in both groups, although at a variable level and rate, and reached a plateau at 9 and 10 years in non-atopic and atopic children, respectively. Atopic children had on average 14-fold higher serum total IgE compared to non-atopic children. In both groups, the median was lower than the corresponding mean and the distribution skewness was always positive (group I, 0.87 ; group II, 0.91). In almost all age groups, the 95th percentile for non-atopic children corresponded to the calculated cut-off values, whereas the 10th percentile for atopic children corresponded to the respective cut-off values only until the age of 8 years, after which greater differences between the cut-off values and the 10th percentile were recorded. Cut-off values for total serum IgE in children up to 16 years were determined with diagnostic sensitivity, specificity and area under the ROC curve of 96%, 91% and 0.950, respectively. Conclusions: The 95th percentile for total IgE in non-atopic children and the 10th percentile in atopic children could be taken as cut-off values in children up to 8 years of age, after which significant percentile discrepancies between non-atopic and atopic children were recorded. Since atopic subjects show a more irregular centile distribution, cut-off values are best determined by ROC analysis.

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 adolescents12 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.

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 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., Opisani su farmakologija, djelotvornost, doziranje, nuspojave i ekonomičnost primjene anti IgE antitijela – omalizumab. Omalizumab je generičko ime za ljudsko / mišje kimerično (rekombinantno humanizirano) monoklonalno IgG antitijelo. Anti-IgE sprječava vezanje IgE na efektorske stanice i sprječava upalni odgovor posredovan s IgE. Nakon subkutane primjene sporo se apsorbira te dostiže vršnu koncentraciju u serumu nakon 7 do 8 dana. Uz preporučene doze koncentracija slobodnog IgE u serumu smanjuje se unutar jednog sata. Doziranje se podešava prema tjelesnoj masi i koncentraciji IgE-a u serumu. Omalizumab je djelotvoran kao dopunska terapija u pacijenata (starijih od 12 godina) sa slabo kontroliranom umjerenom do teškom alergijskom astmom odnosno s alergijskim rinitisom. Smanjuje potrebu za inhalacijskim kortikosteroidima te pogoršanje astme. Dobro se podnosi, ali sigurnost primjene, kako u odraslih tako i u djece, treba još ispitati.

The aim of the study was to compare physician/patient differences in the perception of asthma. The data were obtained by questionnaires from 156 physicians and 148 asthmatics in four urban regions in Croatia. On a »bad day«, 62% of physicians and 16% of patients perceived respiratory symptoms with statistically significant difference. The patients described asthma impact in terms of reduced daily activities and experienced emotional problems. Asthma was estimated as controlled in 28% of adults and 49% of children, nevertheless, 45% of adults and 22% of children reported respiratory symptoms. The patients seem to be satisfied with asthma control that does not correspond to suppression of symptoms, whereas physicians neglect patients’ emotional problems and asthma impact on everyday life. The differences in the perception of asthma may reflect differences in beliefs about health. Physicians see health as an absence of symptoms, whereas patients regard being healthy as »being able«.

Mutations in Bruton's tyrosine kinase (Btk) result in the immunodeficiency X-linked agammaglobulinemia (XLA). In a previous study of 101 patients with presumed XLA, we identified seven patients with large genomic alterations in Btk. The recent completion of 100 kb of contiguous DNA sequence at the Btk locus has allowed us to characterize these mutations in detail and to identify four different types of alterations. These alterations included a 253-bp retroposon insertion at position +5 within intron 9, an inversion of greater than 48 kb that disrupted Btk between exons 4 and 5, a 12.9-kb duplication including Btk exons 2 to 5, and four deletions ranging from 2.8 to 38 kb in size. The duplication and three of the deletions resulted from unequal crossovers of Alu repeats. Further, three of the deletions terminated within a repeat-rich cluster spanning 30 kb of sequence 3' of Btk exon 19, suggesting that this region was more susceptible to unequal crossovers than the rest of the Btk gene. These studies describe the first reports of an insertion, an inversion, and a duplication in Btk and demonstrate the utility of large-scale sequencing in the elucidation of disease-causing mutations.

Presentation of un unusual periurethral localization pheochromocytoma into a child.