Childhood asthma and allergy: the role of vaccinations and other early life events

Atopic disorders have become increasingly prevalent in the western world during the last decades of the 20th century. Research concerning the cause(s) of this increase has so far suggested a complex interplay between genetic and environmental factors. These studies have also indicated that priming starts at a very young age, even before birth. Therefore most studies on this subject have been in children. No clear causes of the increase of these disorders have come up so far, although there are indications that the increased hygienic living-conditions could play a role. Knowledge of causal factors would open opportunities for prevention. The aim of this thesis was to contribute a small piece to the immense endeavour of building foundations for prevention strategies. It also aimed at yielding objective information on implications of childhood vaccinations as a tool for workers in the field of preventive health care and for the general public. The study population described in the chapters 2 and 4 were 8-12 year old children of the Orthodox Reformed (Protestant) population, living in an area in the Netherlands which stretches from the south-west to the east (study population I). Chapters 3, 5 and 6 apply to retrospectively collected health report data of a cohort of 700 families with index children born in 1988-1990 (study population II). These files contained reports of health check-ups of children living in Zwijndrecht, a town south of Rotterdam, at the age of 6 years. Chapter 1 gives an introduction and discusses the background of the thesis: the prevalence of atopic disorders has increased dramatically in the western world over the last decades of the past century and much effort has been put into finding the cause(s) of this increase. The hygiene hypothesis assumes that this increase is caused by a too hygienic environment where children are not enough exposed to pathogens. This exposure is said to be necessary for a healthy development of their immune system. Extensive research has been conducted to test the hygiene hypothesis, and, although much of the evidence is conflicting, there is some evidence that some aspects of hygiene are related to the development of atopic disorders. In this thesis we focused on two aspects of “hygiene”: vaccinations and family size. Chapter 2 presents a study of the relationship between the diphtheria-tetanus-pertussis-poliomyelitis vaccination (DTPPo) in the first year of life and reported atopic disorders at age 8-12 years. We conducted this study in children of Orthodox Reformed (Protestant) families in the Netherlands (study population I). A part of these families refuse vaccinations for religious reasons, and therefore we could compare vaccinated and unvaccinated children in a rather homogenous population. We included children via Orthodox Reformed schools, sent in total almost 4500 questionnaires of which 1875 (42%) were returned. The conclusion of this study is, that vaccinated and unvaccinated children have an equal risk of atopy. In Chapter 3 we addressed the same research question as in chapter 2. However, this study was conducted in children of 700 families with index children born in 1988-1990 (study population II) and the outcome of interest was atopy at age 6 years. Data were collected from reports of routinely conducted health examinations at the age of 6 years. Although we focussed on the pertussis vaccination at first, it became evident that there was almost 100% overlap with the DTPPo vaccination. The conclusion of this study is, that unvaccinated children had a higher risk of atopy at age 6 years. However, the number of unvaccinated children in this study was small and therefore the result is not reliable on its own. Chapter 4 describes a study on the relationship between the Haemophilus influenzae type b vaccination (Hib) and reported atopic disorders at age 8-12 years. This study was conducted in the DTPPo vaccinated part of study population I. The Hib vaccination was introduced in the Netherlands in 1993, implying that a part of these DTPPo vaccinated children did not regularly get the Hib vaccination in the first year of life. This study concluded that there was no indication for a different risk of atopy due to the Hib vaccination. In Chapter 5 we investigated the so-called “sibling effect” (the phenomenon first described in 1986 that children from larger families have a smaller risk of atopic disorders than children from small families). This study was conducted in study population II. Because we studied the sibling effect within families, we were able to disentangle the independent effects of sibship size and birth order. In an ordinary cohort of children these variables are usually strongly correlated and it is consequently not possible to disentangle their effects From this study it became evident, that a higher birth order (or a higher number of older siblings) is associated with a lower risk of allergy, independent of the size of the sibship. In chapter 6 we studied the associations of atopy at age 6 years with perinatal characteristics (gestational age, birth weight and neonatal head circumference) and obstetric complications. These associations were studied in population II. We concluded, confirming earlier findings, that premature children have a higher risk of asthma at age 6 years. Other findings were that children with a high ratio of head circumference to birth weight, children delivered with vacuum extraction, and children delivered after induced labour had a higher risk of allergy. Chapter 7 discusses the findings in this thesis, also in relation to what was already known on the etiology of atopic disorders. The finding that the DTPPo vaccination and the Hib vaccination are not related to atopic disorders is reassuring for those parents who are hesitating about the health effects of vaccinations and could, if communicated well, contribute to stop the, in some countries (like the UK and the Netherlands), steady decrease of the vaccination coverage. The findings on birth order and perinatal risk factors are mere links in a chain of hypotheses on the mechanisms underlying atopic disorders and could thus contribute to preventive strategies in the future. We finally speculate on possible mechanisms on the basis of our findings and results of studies conducted on other topics and make recommendations for daily practice and future research.Atopische aandoeningen komen steeds vaker voor. Deze stijging heeft in de laatste decennia van de vorige eeuw plaatsgevonden. Onderzoek naar de oorzaken van deze stijging heeft een ingewikkeld samenspel tussen aanleg en omgevingsfactoren laten zien. Uit dit onderzoek is ook gebleken, dat de aandoening al op heel vroege leeftijd begint, zelfs al voor de geboorte. Daarom wordt er veel onderzoek in kinderen gedaan. Tot nu toe heeft men niet echt duidelijke oorzaken voor het meer vóórkomen kunnen vinden. Er zijn wel aanwijzingen dat misschien de toegenomen hygiëne een rol speelt. Als we precies zouden weten wat de oorzaken zijn, zouden we een preventieprogramma kunnen opzetten. Het doel van deze studies was een klein stukje bij te dragen aan de grote klus om een goede fundering voor zo’n preventieprogramma te leggen. Een ander doel was objectieve informatie te vergaren over de impact van kindervaccinaties op het krijgen van atopie. Deze informatie is bedoeld voor mensen die werken in de preventieve gezondheidszorg en voor de hele bevolking. De studiepopulatie die wordt beschreven in hoofdstuk 2 en 4 (studie­populatie I) waren 8-12 jaar oude kinderen uit de Reformatorische groep die woont in een strook die zich uitstrekt van het zuid-westen naar het oosten an Nederland (ook wel de “Bible Belt” genoemd). Hoofdstuk 3, 5 en 6 hebben betrekking op gegevens uit rapporten van schoolartsbezoeken van een cohort van 700 gezinnen met index-kinderen, die tussen begin 1988 en eind 1990 zijn geboren (studie-populatie II). Deze kinderen woonden ten tijde van hun bezoek aan de schoolarts (op 6-jarige leeftijd) in Zwijndrecht. Hoofdstuk 1 is een inleiding en bespreekt de achtergronden van de studies in dit proefschrift: atopische aandoeningen komen steeds vaker voor in de westerse wereld. De echte toename heeft gedurende de laatste decennia van de vorige eeuw plaatsgevonden. Er is veel onderzoek gedaan naar de oorzaken van deze toename. Volgens de hygiënehypothese is de oorzaak een te hygiënische leefomgeving, waarin kinderen niet genoeg aan ziekteverwekkers worden blootgesteld. Men neemt aan, dat deze blootstelling nodig is voor een gezonde ontwikkeling van het immuunsysteem. Er zijn veel studies gedaan met als doel de hygiënehypothese te testen. Hoewel veel resultaten elkaar tegenspreken, lijkt het er toch op, dat sommige aspecten van hygiëne gerelateerd zijn aan het risico op atopische aandoeningen. In dit proefschrift worden twee aspecten van hygiëne bestudeerd: vaccinaties en gezinsgrootte. Hoofdstuk 2 beschrijft een studie naar de relatie tussen de difterie-tetanus-kinkhoest-polio vaccinatie (DKTP) in het eerste levensjaar en gerapporteerde atopische aandoeningen op de leeftijd van 8-12 jaar. Deze studie werd uitgevoerd in een groep reformatorische kinderen in Nederland (studiepopulatie I). Een deel van de ouders van deze kinderen wijst vaccinaties af uit godsdienstige overwegingen. Daarom was het mogelijk binnen een redelijk homogene groep gavccineerde en ongevaccineerde kinderen met elkaar te vergelijken. We includeerden kinderen via reformatorische scholen en verzonden bijna 4500 vragenlijsten, waarvan er 1875 (42%) ingevuld werden teruggestuurd. De conclusie van deze studie is, dat gevaccineerde en ongevaccineerde kinderen een even grote kans hebben op een atopische aandoening. In hoofdstuk 3 onderzochten wij dezelfde relatie als in hoofdstuk 2, maar nu in de kinderen van 700 gezinnen in Zwijndrecht met index-kinderen geboren in 1988-1990 (studie-populatie II). In deze studie werd gekeken naar atopische aandoeningen op de leeftijd van 6 jaar. Data werd verzameld uit verslagen van schoolartsonderzoeken op de leeftijd van 6 jaar. Onze hypothese betrof eigenlijk de kinkhoest vaccinatie, maar het bleek dat als een kind niet gevaccineerd was tegen kinkhoest, hij/zij bijna altijd ook niet gevaccineerd was met de DKTP­cocktail. De conclusie van deze studie is, dat ongevaccineerde kinderen een grotere kans hebben op een atopische aandoening op de leeftijd van 6 jaar. Echter, het aantal ongevaccineerde kinderen in deze studie was klein en daarom is dit resultaat alleen niet echt een sterk bewijs. In hoofdstuk 4 beschrijven wij een studie naar de relatie tussen de Haemophilus influenzae type b vaccinatie (Hib) en gerapporteerde atopische aandoeningen op de leeftijd van 8-12 jaar. De onderzoeksvraag werd onderzocht in het DKTP gevaccineerde deel van studiepopulatie I. De Hib vaccinatie werd in Nederland in 1993 aan het Rijks Vaccinatie Programma toegevoegd. Studiepopulatie I werd deels vóór, deels na 1993 geboren. Daardoor heeft een deel van deze DKTP gevaccineerde kinderen de Hib in het eerste levensjaar niet ontvangen. De conclusie is, dat er geen aanwijzing is voor een veranderd risico op atopische aandoeningen ten gevolge van de Hib vaccinatie. In hoofdstuk 5 onderzochten wij het zogenoemde “sibling effect”. Deze term staat voor het verschijnsel (voor het eerst beschreven in 1986), dat kinderen met veel broers en zussen minder kans op een atopische aandoening hebben dan kinderen met minder broers en zussen. We voerden deze studie uit in studiepopulatie II. Omdat de onderzoekseenheden in deze studiepopulatie gezinnen zijn, waren we in staat de variabele “gezinsgrootte” te onderscheiden van de variabele “plaats in de kinderrij”. In een “gewoon” cohort van kinderen zijn deze twee variabelen n.l. sterk gecorreleerd, en zijn de effecten niet goed te onderscheiden. Uit deze studie bleek, dat hoe hoger de plaats in de kinderrij binnen een gezin (of: hoe meer oudere broers en zussen) des te kleiner de kans op een atopische aandoening, onafhankelijk van de gezinsgrootte. Hoofdstuk 6 beschrijft de relaties van atopische aandoeningen op de leeftijd van 6 jaar met geboortegegevens (zwangerschapsduur, geboortegewicht, schedelomtrek en complicaties bij de geboorte, zoals een keizersnede, vacuumverlossing, tangverlossing of een ingeleide bevalling). Deze studie werd gedaan in studiepopulatie II. We vonden, dat te vroeg geboren kinderen een grotere kans hebben op astma op zesjarige leeftijd dan kinderen die à terme geboren zijn. Een andere bevinding was, dat kinderen met een relatief grote schedelomtrek (ten opzichte van hun gewicht), kinderen die met vacuum extractie waren geboren en kinderen bij wie de weeën waren opgewekt een grotere kans hadden om allergisch te zijn op zesjarige leeftijd. Hoofdstuk 7 bespreekt de bevindingen van dit proefschrift, ook in het licht van wat al bekend was over de etiologie van atopische aandoeningen. De conclusie dat vaccineren niet uitmaakt voor het krijgen van atopische aandoeningen is geruststellend voor ouders die twijfels hebben over de effecten van vaccinaties op de gezondheid van hun kinderen. Als dit resultaat bredere bekendheid krijgt, kan het ertoe bijdragen dat de (in sommige landen zoals Engeland en Nederland) dalende vaccinatiegraad wordt omgebogen. De resultaten over plaats in de kinderrij en perinatale risicofactoren zijn bijdragen aan de vorming van hypothesen over de mechanismen in het ontstaan van atopische aandoeningen. Zij kunnen aldus bijdragen aan de ontwikkeling van toekomstige preventieprogramma’s. Verder speculeren we op grond van onze bevindingen en andere onderzoeksresultaten over mogelijke mechanismen en we doen aanbevelingen voor de dagelijkse praktijk en toekomstig onderzoek

Lower risk of atopic disorders in whole cell pertussis-vaccinated children

This study addressed whether whole cell pertussis-vaccinated children have a different risk of atopic disorders compared with children who did not receive this vaccination. Data on vaccination status, atopic disorders and child and family characteristics of the children of 700 families were collected in this retrospective study. A minority of these 700 families refused vaccinations for religious reasons. The relation between pertussis-vaccination status and atopic disorders was analysed by means of adjusted logistic regression for repeated measurements in order to account for the correlation between sibship members. The 700 families included 1,961 children. Data on vaccination status and atopic disorders were available for 1,724 children. Vaccinated children had a reduced risk of atopic disorders. Whole cell pertussis vaccination is associated with a lower risk of atopic disorders, though other vaccine components (diphtheria, tetanus, poliomyelitis) or other vaccinations may also be involved

Randomised placebo-controlled trial of inhaled sodium cromoglycate in 1-4-year-old children with moderate asthma

BACKGROUND: Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children. The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children. We studied the feasibility and effects of this therapy compared with placebo in children aged 1-4 years. METHODS: 218 children aged 1-4 years with moderate asthma were recruited through 151 general practitioners between March, 1995, and March, 1996. They were randomly assigned sodium cromoglycate (10 mg three times daily) or placebo, given by inhaler with spacer device and face-mask for 5 months. Rescue medication (ipratropium plus fenoterol aerosol) was available during the baseline period of 1 month and the intervention period. Parents completed a daily symptom-score list. The primary outcome measure was the proportion of symptom-free days in months 2 to 5. Analysis was by both intention to treat and on treatment. FINDINGS: 167 (77%) children completed the trial. 131 (78%) of these children used at least 80% of the recommended dose. Of the 51 children who stopped prematurely, 23 had difficulties with inhaled treatment. The mean proportion of symptom-free days for both groups was greater for the treatment period than for the baseline period (95% CI for mean difference 5.1 to 17.5 cromoglycate, 11.9 to 23.3 placebo). However there were no differences between the sodium cromoglycate and placebo groups in the proportion of symptom-free days (mean 65.7 [SD 25.3] vs 64.3 [24.5]%; 95% CI for difference -8.46 to 5.70) or in any other outcome measure. INTERPRETATION: Our study in a general practice setting shows that inhalation therapy with a spacer device and face-mask is feasible in a majority of children below the age of 4 years. However, long-term prophylactic therapy with inhaled sodium cromoglycate is not more effective than placebo in this age-group

Fusidic acid cream in the treatment of impetigo in general practice: double blind randomised placebo controlled trial

OBJECTIVE: To test the hypothesis that fusidic acid would not increase the treatment effect of disinfecting with povidone-iodine alone in children with impetigo. DESIGN: Randomised placebo controlled trial. SETTING: General practices in Greater Rotterdam. PARTICIPANTS: 184 children aged 0-12 years with impetigo. MAIN OUTCOME MEASURES: Clinical cure and bacterial cure after one week. RESULTS: After one week of treatment 55% of the patients in the fusidic acid group were clinically cured compared with 13% in the placebo group (odds ratio 12.6, 95% confidence interval 5.0 to 31.5, number needed to treat 2.3). After two weeks and four weeks the differences in cure rates between the two groups had become smaller. More children in the placebo group were non-compliant (12 v 5) and received extra antibiotic treatment (11 v 3), and more children in the placebo group reported adverse effects (19 v 7). Staphylococcus aureus was found in 96% of the positive cultures; no strains were resistant to fusidic acid. CONCLUSIONS: Fusidic acid is much more effective than placebo (when both are given in combination with povidone-iodine shampoo) in the treatment of impetigo. Because of the low rate of cure and high rate of adverse events in the placebo group, the value of povidone-iodine in impetigo can be questioned

Equal performance of aspiration and stent retriever thrombectomy in daily stroke treatment

BACKGROUND: Mechanical thrombectomy with stent retrievers has proved to be safe and effective in endovascular treatment of acute ischemic stroke. Direct aspiration has shown revascularization rates comparable to those of stent retrievers in the recent ASTER and COMPASS trials. However, the efficacy of aspiration in routine clinical practice has not yet been shown. OBJECTIVE: To show that aspiration has clinical and technical outcomes equal to those of stent retriever thrombectomy in daily clinical practice. METHODS: We analysed data of patients with a large vessel occlusion of the anterior circulation registered in the Dutch MR CLEAN Registry between March 2014 and June 2016. Primary outcome was functional outcome measured with the modified Rankin Scale (mRS) score. Secondary outcomes were reperfusion grade, periprocedural complication rate, and procedure duration. Association of treatment technique with functional outcome was estimated with univariable and multivariable ordinal logistic regression analysis and expressed as a common OR (cOR) for a shift towards better outcome on the mRS. RESULTS: As first-line treatment, 207 of 1175 patients (17.6%) were treated with direct aspiration, and 968 (82.4%) by a stent retriever. We observed no differences in functional outcome (adjusted cOR=1.020 (95% CI 0.68 to 1.52)) and periprocedural complications. Successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b) was similar. Duration of the procedure was shorter with aspiration (57 min (IQR 35-73) vs 70 min (IQR 47-95), p<0.0001). CONCLUSION: Direct aspiration shows clinical outcomes equal to those of stent retriever thrombectomy in our large multicenter real-life cohort. We found no difference in complication rates and shorter procedure times for aspiration

Importance of Occlusion Site for Thrombectomy Technique in Stroke:Comparison Between Aspiration and Stent Retriever

BACKGROUND AND PURPOSE: Thrombectomy with stent retriever and direct aspiration are equally effective in the endovascular treatment of anterior circulation acute ischemic stroke. We report efficacy and safety of initial treatment technique per occlusion segment.METHODS: For this study, we analyzed data from the MR CLEAN Registry, a prospective, observational study in all centers that perform endovascular therapy in the Netherlands. We used ordinal logistic regression analysis to compare clinical and technical results of first line direct aspiration treatment with that of stent retriever thrombectomy stratified for occlusion segment. Primary outcome measure was functional outcome at 3 months. Secondary outcome measures included reperfusion grade expressed as the extended Thrombolysis in Cerebral Infarction score, periprocedural complication risk, time to reperfusion, and mortality.RESULTS: Of the 2282 included patients, 1658 (73%) were initially treated with stent retriever and 624 (27%) with aspiration. Four hundred sixty-two patients had an occlusion of the intracranial part of the carotid artery, 1349 of the proximal middle cerebral artery, and 471 of the distal parts of the middle cerebral artery. There was no difference in functional outcome between aspiration and stent retriever thrombectomy (odds ratio, 1.0 [95% CI, 0.9-1.2]) in any of the occlusion segments (P value for interaction=0.2). Reperfusion rate was higher in the aspiration group (odds ratio, 1.4 [95% CI, 1.1-1.6]) and did not differ between occlusion segments (P value for interaction=0.6). Procedure times were shorter in the aspiration group (minutes 50 versus 65 minutes; P&lt;0.0001). There was no difference in periprocedural complications or mortality.CONCLUSIONS: In unselected patients with anterior circulation infarcts, we observed equal functional outcome of aspiration and stent retriever thrombectomy in all occlusion segments. When aspiration was the first line treatment modality, reperfusion rates were higher and procedure times shorter in all occlusion segments.</p