Coeliac disease and HLA-conferred susceptibility to autoimmunity are associated with IgE sensitization in young children.

Non peer reviewe

Early childhood infections and the use of antibiotics and antipyretic-analgesics in Finland, Estonia and Russian Karelia.

Aim Infections in early childhood are common reasons to seek medical attention. This study compares the prevalence of infections, and the use of antibiotics and antipyretic-analgesics, in children from Finland, Estonia and Russian Karelia. Methods Children with a genetically increased risk for type 1 diabetes (N = 797) were observed from birth up to 3 years of age. Illnesses and medications were reported by parents continuously. All reported infections, antibiotics and antipyretic-analgesics were compared between Finland and Estonia, and to a lesser extent with Russian Karelia, due to poor study compliance. Results Compared with Estonians, Finns reported more infections during the first and second years of life. During the follow-up, Finnish children had 10 infections while Estonians only had 8 (p <0.001). Finns also used more antibiotics and antipyretic-analgesics in each year during the follow-up. Russian Karelians reported the lowest frequency of infections and the most infrequent use of antibiotics and antipyretic-analgesics in the first two years of life. Conclusion Infections and the use of antibiotics and antipyretic-analgesics in early childhood were most frequent in Finland, where socio-economic conditions are the most developed and microbial encounters are sparse. This may reflect on the hygiene hypothesis, a less effective immune system that allows normally harmless microbes to attack and cause clinical infections.Peer reviewe

Rhinoviruses in infancy and risk of immunoglobulin E sensitization

Previous data about the role of viruses in the development of allergic immunoglobulin E (IgE) sensitization are contradictory. The aim of this study was to determine the possible associations between exposure to different viruses (rhinovirus, enterovirus, norovirus, and parechovirus) during the first year of life and IgE sensitization. Viruses were analyzed from stool samples collected monthly from infants participating in a prospective birth cohort study. From that study, 244 IgE sensitized case children and 244 nonsensitized control children were identified based on their allergen-specific IgE antibody levels at the age of 6, 18, and 36 months. Stool samples (n = 4576) from the case and control children were screened for the presence of rhinovirus, enterovirus, norovirus, and parechovirus RNA by reverse transcription quantitative polymerase chain reaction. The study showed that rhinovirus was the most prevalent virus detected, present in 921 (20%) samples. None of the viruses were associated with IgE sensitization in the full cohort but after stratifying by sex, the number of rhinovirus positive samples was inversely associated with IgE sensitization in boys (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.69-0.94; P = 0.006). There was also a temporal relation between rhinoviruses and IgE sensitization, as rhinovirus exposure during the first 6 months of life was associated with a reduced risk of subsequent IgE sensitization in boys (OR: 0.76; 95% CI: 0.6-0.94; P = 0.016). In conclusion, early exposure to rhinoviruses was inversely associated with IgE sensitization but this protective association was restricted to boys.Peer reviewe

Lapsuudenajan infektiot ja niiden yhteys allergisiin- ja immuunisairauksiin Suomessa, Virossa ja Venäjän Karjalassa

Background: The incidence of immune-mediated diseases, such as type 1 diabetes (T1D), celiac disease (CD), and allergic diseases, has been increasing since the 1950s. This trend has been particularly conspicuous in affluent Westernized countries. Etiologies behind these diseases are still poorly understood, but socioeconomic circumstances and environmental factors may play a crucial role in their pathomechanisms. The hygiene hypothesis aims to explain the rising trend in immune-mediated diseases by suggesting that children’s developing immune systems are vulnerable to malfunction in environments that provide inadequate microbial exposure early in life. Aims: This thesis aims to explore how early clinical infections, their medications, and allergic sensitization associate with the development of T1D, CD, and allergies in three geographically close areas in Finland, Estonia, and Russian Karelia. These neighboring countries have shown clear contrasts in the frequencies of immune-mediated diseases, standards of hygiene, and socioeconomic circumstances. Methods: As part of the DIABIMMUNE study, over 4500 children from Finland, Estonia, and Russian Karelia were prospectively followed either from birth to 3 years of age or from 3 to 5 years of age. Children attended regular clinical visits that comprised physical examinations and the collection of biological samples for the assessment of immune-mediated outcomes. Children’s parents prospectively reported all participating children’s illnesses, infections, medications, and allergic symptoms that appeared during the follow-up. Results: Regarding infectious illnesses, respiratory infections were most frequently reported, followed by gastrointestinal infections, unlocalized febrile episodes, and other localized infections. Compared to Russian Karelian and Estonian children, Finnish children experienced more infections and used more medications. Finnish children also had the highest frequency of T1D, CD, and allergic sensitization. In all, progression to T1D was associated with a higher number of infections, and progression to CD with a higher number of febrile infections. Of systemic antibiotics and antipyretic analgesics, penicillin and acetaminophen, respectively, were the most common. Children who progressed to T1D or CD and their unaffected peers used medications similarly. Children with and without allergic sensitization had similar frequencies of infectious diseases and their medications. Children carrying genetic risk for autoimmunity developed immunoglobulin E (IgE) sensitization more often than their general-population peers. Early IgE sensitization associated with an increased risk for the development of clinical allergy symptoms and CD, but not for T1D. The predictive value of the sensitization for clinical allergies was age-dependent, and in all, sensitization predicted allergy-related symptoms quite poorly. Sensitization tests predicted allergic symptoms caused by aeroallergens better than those caused by dietary allergens, and the results for aeroallergen sensitization were more consistent between serum and skin testing methods. Conclusions: Immune-mediated diseases, early-life infections, and the use of various medications were more common in Finland than in the neighboring areas of Estonia and Russian Karelia. The co-occurrence of allergic and autoimmune diseases may suggest that, to a certain extent, these diseases share some common pathomechanisms. Keywords: aeroallergen, allergy, antibiotic, antipyretic analgesic, atopy, autoimmunity, celiac disease, childhood infection, dietary allergen, Estonia, Finland, human leukocyte antigen, hygiene hypothesis, IgE sensitization, islet autoimmunity, Russian Karelia, skin prick test, type 1 diabetes.  Tausta: Immuunivälitteisten sairauksien, kuten tyypin 1 diabeteksen, keliakian ja allergioiden, esiintyvyys on viimeisten 50 vuoden ajan lisääntynyt erityisesti länsimaissa. Näiden sairauksien etiologiaa ei vielä täysin varmuudella tunneta, mutta sosioekonomisten olosuhteiden ja ympäristötekijöiden epäillään vaikuttavan sairauksien patofysiologiaan. Hygieniahypoteesi pyrkii selittämään immuunivälitteisten sairauksien yleistymistä sillä, että kypsymisvaiheessa olevan immuunijärjestelmän tulee altistua mikrobeille riittävissä määrin, jotta se kykenee erottamaan kehon omat rakenteet haitallisista taudinaiheuttajista. Jos kypsymisvaiheessa mikrobialtistuksia ei ole riittävästi, immuunijärjestelmä voi käynnistää virheellisiä puolustusvasteita harmittomia ympäristötekijöitä sekä kehon omia rakenteita vastaan. Tavoite: Väitöskirjan tavoite on tutkia, miten lapsuudenajan infektiot, niiden lääkitykset sekä allerginen herkistyminen ennustavat tyypin 1 diabeteksen, keliakian ja allergiaoireiden kehittymistä. Tutkimus toteutettiin Suomessa, Virossa ja Venäjän Karjalassa, missä erot sosioekonomisissa olosuhteissa ja hygieniatasossa sekä autoimmuuni- ja allergiasairauksien esiintyvyyksissä ovat olleet merkittävät. Menetelmät: Osana DIABIMMUNE-tutkimusta yli 4500 lasta Suomesta, Virosta ja Venäjän Karjalasta seurattiin joko syntymästä kolmeen ikävuoteen tai kolmesta viiteen ikävuoteen asti. Lapset tutkittiin säännöllisesti vastaanotolla, heiltä otettiin useita veri- ja muita biologisia näytteitä sekä heiltä kerättiin tietoja sairastumisista, lääkkeiden käytöstä ja allergiaoireista. Tulokset: Tavallisimmat infektiot lapsilla olivat hengitystieinfektiot, jonka jälkeen seurasivat järjestyksessä suolistoperäiset, sijainniltaan määrittämättömät sekä muut infektiot. Verrattuna Viron ja Venäjän Karjalan lapsiin suomalaisilla lapsilla oli eniten infektioita ja niihin liittyvää lääkkeiden käyttöä. Suomalaisilla oli myös korkeimmat diabeteksen, keliakian ja allergisen herkistymisen esiintyvyydet. Kaiken kaikkiaan diabetekseen sairastuneilla lapsilla oli varhaislapsuudessa enemmän infektioita ja keliakiaan sairastuneilla enemmän kuumeisia infektioita verrattuna terveisiin lapsiin. Antibiooteista eniten käytettiin penisilliiniä ja kuumetta alentavista lääkkeistä parasetamolia. Lääkkeiden käytössä ei löytynyt eroja diabetekseen ja/tai keliakiaan sairastuneiden ja terveiden välillä. Vastaavanlaisia eroja infektioesiintyvyydessä tai lääkkeiden käytössä ei löytynyt allergisesti herkistyneiden ja herkistymättömien välillä. Verrattuna normaaliväestöön allerginen herkistyminen oli tavallisempaa lapsilla, joilla on perinnöllinen alttius autoimmuunisairauksiin. Varhainen herkistyminen allergeeneille lisäsi riskiä kehittää allergiaoireita ja keliakiaa, mutta ei riskiä sairastua tyypin 1 diabetekseen. Kliinisten allergiaoireiden ennustaminen allergeeneille herkistymisen avulla oli kuitenkin ikäriippuvaista eikä ennustaminen ollut kovin luotettavaa. Ilmatieallergeenien aiheuttamat allergiaoireet olivat paremmin ennustettavissa herkistymistesteillä verrattuna ruoka-allergeenien aiheuttamiin oireisiin. Ilmatieallergeenien osalta seerumin ja ihon herkistymistestit olivat myös useimmiten yhteneväiset. Johtopäätökset: Aikaiset infektiot ja lääkkeidenkäyttö sekä immuunivälitteiset sairaudet ovat tavallisimpia Suomessa verrattuna naapurimaihimme. Allergisten ja autoimmuunisairauksien esiintyvyyksien toisiinsa liittyminen saattaa viitata näiden sairauksien osittain jaettuihin ja samantapaisiin patofysiologisiin mekanismeihin.Bakgrund: Incidensen för immunmedierade sjukdomar, såsom typ 1-diabetes, celiaki och allergiska sjukdomar, har under de senaste 50 åren ökat speciellt i västvärlden. Etiologin bakom dessa sjukdomar och bakom den stigande incidensen är oklar, men socioekonomiska förhållanden och miljöbetingade faktorer tros vara av betydelse i sjukdomarnas patofysiologi. Hygienhypotesen utgår från att immunsystemets utveckling och mognad kräver exponering för olika mikrober tidigt i livet för att lära sig att känna igen och skydda kroppen för patogener samt för att utveckla tolerans mot ofarliga strukturer, såsom kroppens egna celler. Om mikrobexponeringen är otillräcklig, förblir immunsystemet benäget för rubbningar, och kan börja attackera kroppens egna strukturer eller allergener. Detta är något som potentiellt kunde förklara de stigande incidenserna för immunmedierade sjukdomar. Mål: Den här avhandlingen strävar efter att utreda hur barndomens tidiga infektioner, läkemedelsanvändning och testning för allergisk sensibilisering förutspår utvecklingen av typ 1-diabetes, celiaki och allergirelaterade symptom. Studien genomfördes i Finland, Estland och Ryska Karelen, där skillnader i socioekonomiska förhållanden och hygiennivån samt i incidenserna för autoimmuna och allergirelaterade sjukdomar har varit iögonfallande stora. Metoder: Som en del av DIABIMMUNE-studien följdes mer än 4500 barn endera från födseln till 3 eller från 3 till 5 års ålder upp. Barnen undersöktes regelbundet på mottagningen, testades på blod- och andra biologiska prov relaterade till immunmedierade utfall samt uppföljdes för insjuknande i infektioner och andra sjukdomar, användning av läkemedel och förekommande av allergirelaterade symptom. Resultat: Respiratoriska infektioner förekom mest, varefter följde gastrointestinala, lägesmässigt ospecificerade och andra infektioner. Jämfört med ester och kareler, insjuknade finländska barn i infektioner och använde läkemedel mest frekvent. Finländare insjuknade även i diabetes, celiaki och utvecklade allergisk sensibilisering oftare än barn från de två andra länderna. Barn som insjuknade i diabetes hade flera infektioner och barn som utvecklade celiaki flera febrila infektioner, jämfört med friska barn. Bland antibiotika och febernedsättande mediciner användes penicillin respektive paracetamol mest. Inga märkbara skillnader mellan barn som insjuknade i diabetes och/eller celiaki och friska barn sågs i läkemedelsanvändningen. Liknande skillnader i infektionsprevalensen eller läkemedelsanvändningen observerades inte mellan barn med eller utan allergisk sensibilisering. Jämfört med barn i den allmänna populationen var sensibilisering vanligare hos barn som bar på ärftlig benägenhet för autoimmuna sjukdomar. Sensibilisering i tidiga barndomen ökade risken att få allergirelaterade symptom och celiaki, men inte risken att insjukna i typ 1-diabetes. Däremot var förutspående av kliniska allergier med hjälp av sensibilisering relativt opålitbart och beroende av ålder. Allergirelaterade symptom orsakade av inhalerande allergener var bättre förutspådda av sensibiliseringstest än symptom orsakade av dietära allergener. Sensibilisering för inhalerbara allergener var även i högre grad konsistenta mellan serum och pricktestmetoder. Slutsats: Immunmedierade sjukdomar samt insjuknande i infektioner och läkemedelsanvändning var vanligast bland finländska barn, jämfört med barnen i de två grannländerna. Kopplingarna mellan prevalensen av autoimmuna och allergiska sjukdomar kunde indikera gemensamma patofysiologiska mekanismer

Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk

Background: The etiology of type 1 diabetes (T1D) is largely unknown. Infections and microbial exposures are believed to play a role in the pathogenesis and in the development of islet autoimmunity in genetically susceptible individuals. Objective: To assess the relationships between early childhood infections, islet autoimmunity, and progression to T1D in genetically predisposed children. Methods: Children with HLA-conferred disease susceptibility (N=790; 51.5% males) from Finland (n=386), Estonia (n=322), and Russian Karelia (n=82) were observed from birth up to the age of 3 years. Children attended clinical visits at the age of 3, 6, 12, 18, 24, and 36 months. Serum samples for analyzing T1D-associated autoimmune markers were collected and health data recorded during the visits. Results: Children developing islet autoimmunity (n=46, 5.8%) had more infections during the first year of life (3.0 vs. 3.0, mean rank 439.1 vs. 336.2; p=0.001) and their first infection occurred earlier (3.6 vs. 5.0 months; p=0.005) than children with no islet autoimmunity. By May 2016, seven children (0.9%) had developed T1D (progressors). Compared to non-diabetic children, T1D progressors were younger at first infection (2.2 vs. 4.9 months; p=0.004) and had more infections during the first 2 years of life (during each year 6.0 vs. 3.0; p=0.001 and p=0.027, respectively). By 3 years of age, the T1D progressors had twice as many infections as the other children (17.5 vs. 9.0; p=0.006). Conclusions: Early childhood infections may play an important role in the pathogenesis of T1D. Current findings may reflect either differences in microbial exposures or early immunological aberrations making diabetes-prone children more susceptible to infections

Rhinoviruses in infancy and risk of immunoglobulin E sensitization

Previous data about the role of viruses in the development of allergic immunoglobulin E (IgE) sensitization are contradictory. The aim of this study was to determine the possible associations between exposure to different viruses (rhinovirus, enterovirus, norovirus, and parechovirus) during the first year of life and IgE sensitization. Viruses were analyzed from stool samples collected monthly from infants participating in a prospective birth cohort study. From that study, 244 IgE sensitized case children and 244 nonsensitized control children were identified based on their allergen-specific IgE antibody levels at the age of 6, 18, and 36 months. Stool samples (n = 4576) from the case and control children were screened for the presence of rhinovirus, enterovirus, norovirus, and parechovirus RNA by reverse transcription quantitative polymerase chain reaction. The study showed that rhinovirus was the most prevalent virus detected, present in 921 (20%) samples. None of the viruses were associated with IgE sensitization in the full cohort but after stratifying by sex, the number of rhinovirus positive samples was inversely associated with IgE sensitization in boys (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.69-0.94; P = 0.006). There was also a temporal relation between rhinoviruses and IgE sensitization, as rhinovirus exposure during the first 6 months of life was associated with a reduced risk of subsequent IgE sensitization in boys (OR: 0.76; 95% CI: 0.6-0.94; P = 0.016). In conclusion, early exposure to rhinoviruses was inversely associated with IgE sensitization but this protective association was restricted to boys