Wilfried Karmaus

Does a higher number of siblings protect against the development of allergy and asthma? A review

Study objective: To review the “protective” effects of having a higher number of siblings for the risk of atopic eczema, asthma wheezing, hay fever, and allergic sensitisation. Method: Review of the literature (Medline since 1965 and references). Main results: 53 different studies were identified. For eczema, 9 of 11 studies reported an inverse relation with number of siblings; for asthma and wheezing, 21 of 31 reported the inverse association; for hay fever, all 17 studies showed the effect; for allergic sensitisation or immunoglobulin E reactivity 14 of 16 studies supported the “protective” effect of a higher number of siblings. The studies emphasise a “theory” that is based exclusively on epidemiological associations. Conclusions: Research has not yet answered the question of which causal factors explain the sibling effect. Causal factors must meet two criteria; they must vary with sibship size and they must protect against atopic manifestations. The prevailing “hygiene hypothesis” failed to explain the findings adequately. Alternative explanations include in utero programming or endocrine explanatory models. The epidemiology research into siblings and atopic disorders has entered an intellectually challenging phase. Possessing sufficient knowledge about the causal factors might prevent at least 30% of all cases of asthma, eczema, and hay fever.

Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control.

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) and low-level lead exposure are high-prevalence conditions among children, and studies of large populations have suggested that these conditions are related. We examine this relationship in children from a community sample exposed to average background levels of lead who have a diagnosis of ADHD that is established by clinical criteria. METHODS One hundred fifty children ages 8-17 years participated (mean age = 14 years; 53 control subjects, 47 ADHD Predominantly Inattentive type, 50 ADHD-Combined type). Diagnosis was formally established with a semi-structured clinical interview and parent and teacher ratings. Children completed intelligence quotient (IQ) measures and the stop task (a neuropsychological measure). Lead was assayed from whole blood with inductively coupled plasma mass spectrometry. RESULTS Blood lead levels in this sample closely matched US population exposure averages, with a maximum level of 3.4 mug/dL. Blood lead levels were statistically significantly higher in ADHD-combined type than in non-ADHD control (p < .05) children. Blood lead was associated with symptoms of hyperactivity-impulsivity but not inattention-disorganization, after control of covariates. Blood lead levels were linked with a lower IQ (p < .05), but IQ did not account for effects on hyperactivity. Instead, hyperactivity mediated effects of lead on IQ. Effects of blood lead on hyperactivity-impulsivity were mediated by poor performance on the stop task. This mediation effect was independent of effects of lead on IQ. CONCLUSIONS Low-level lead exposure might be an important contributor to ADHD. Its effects seem to be mediated by less effective cognitive control, consistent with a route of influence via striatal-frontal neural circuits.

Polybrominated biphenyls, polychlorinated biphenyls, body weight, and incidence of adult-onset diabetes mellitus.

Background: Prior studies have reported an increased risk of diabetes related to polychlorinated biphenyl (PCB) exposure. No study has yet investigated whether polybrominated biphenyls (PBBs), which are similar in chemical structure, increase the incidence of diabetes. Methods: The Michigan PBB cohort was established in 1976 and surveyed again in 1991–1993 and in 2001. PBB and PCB serum levels were measured from blood collected at enrollment. To determine the incidence of adult-onset diabetes, we analyzed cohort members without diabetes at enrollment, ages 20 years and older, with known PBB and PCB levels, who participated in at least 1 follow-up survey (n = 1384). Using Poisson regression, we determined the incidence density ratio (IDR) of diabetes for different serum levels of PBB and PCB, controlling for age, body mass index, smoking, and alcohol consumption at enrollment. Results: Analyzing 25 years of follow-up data, we did not find that higher PBB serum levels were a risk factor for the incidence of diabetes mellitus. However, in women, but not in men, higher PCB serum levels were associated with increased incidence of diabetes (IDR = 2.33; 95% confidence interval = 1.25–4.34 in the highest PCB group compared with the lowest). In both men and women, overweight and obesity increased the diabetes incidence. Conclusions: We found no association between PBB serum levels and diabetes incidence. In women, there was a positive linear association of diabetes incidence with PCB serum levels at enrollment. This finding is in agreement with 2 prior studies indicating a higher relative risk of diabetes in PCB-exposed women.

Does the Sibling Effect Have Its Origin In Utero? Investigating Birth Order, Cord Blood Immunoglobulin E Concentration, and Allergic Sensitization at Age 4 Years

There is a great body of evidence that siblings have a protective effect against atopic manifestations such as hay fever, atopic eczema, allergic sensitization, or asthma. Factors that may explain this association remain largely unknown. One hypothesis is that siblings promote early infections in childhood, and repeated infections protect against atopic disorders. Another hypothesis, the potential in utero programming, has been neglected. The authors investigated if cord blood immunoglobulin E (IgE) is dependent upon birth order and if both are associated with an increased incidence of allergic sensitization (skin prick test) at the age of 4 years in a cohort of 981 newborns recruited between January 1989 and February 1990 on the Isle of Wight, England. The authors found that IgE is reduced with increasing birth order (first child: odds ratio (OR) = 1; second child: OR = 0.78, 95% confidence interval (CI): 0.57, 1.05; third child: OR = 0.59, 95% CI: 0.41, 0.83). Cord IgE, but not birth order, is a significant predictor of skin prick test positivity at age 4 (IgE below detection limit: OR = 1; IgE of 0.2-<0.5 kilounits/liter: OR = 1.11, 95% CI: 0.73, 1.68; IgE of >or=0.5 kilounits/liter: OR = 2.63, 95% CI: 1.62, 4.29). The findings suggest that cord IgE is reduced in pregnancies with higher order, indicating that the sibling effect may have its origin in utero.

Influence of atopy and asthma on exhaled nitric oxide in an unselected birth cohort study.

Background Asthma is considered to be associated with elevated levels of exhaled nitric oxide (FeNO). The nature of this relationship and how it is influenced by atopy are still not resolved. Methods The Isle of Wight birth cohort (N=1456) was reassessed at 18 years of age. Participants able to attend the research centre were assessed by questionnaires, skin prick testing and FeNO in order to explore the interrelationship between asthma, atopy and FeNO. Results Atopy was significantly associated with higher levels of FeNO. However, the level of FeNO for non-atopic asthmatic participants was no different to the non-atopic no-asthma group. The highest levels of FeNO were seen in subjects with both atopy and asthma. In addition, FeNO was positively associated with increasing atopic burden as evidenced by increasing FeNO with increasing skin prick testing positivity, and with increasing severity of atopic asthma as evidenced by the number of attacks of wheezing. FeNO and current inhaled corticosteroid use were not significantly associated. Conclusions FeNO behaves as a biomarker of atopy and the “allergic asthma” phenotype rather than asthma itself. This may explain why FeNO-guided asthma treatment outcomes have proved to be of limited success where atopic status has not been considered and accounted for.

Maternal levels of dichlorodiphenyl-dichloroethylene (DDE) may increase weight and body mass index in adult female offspring

Objectives: To investigate the effect of prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyl-dichloroethylene (DDE) on weight, height and body mass index (BMI) in adult female offspring of the Michigan fisheater cohort examined between 1973 and 1991. Methods: 259 mothers from the Michigan fisheater cohort were studied. Prenatal exposure to PCBs and DDE was estimated by extrapolating maternal measurements to the time that the women gave birth. 213 daughters aged 20–50 years in 2000 were identified and 83% of them participated in at least one of two repeated investigations in 2001/02 (n = 151) and 2006/07 (n = 129). To assess the effect of prenatal PCB and DDE exposure on anthropometric measurements, generalised estimating equations nested for repeated measurements (2001/02 and 2006/07) and for sharing the same mother were used. We controlled for maternal height and BMI and for daughters’ age, birth weight, having been breastfed and number of pregnancies. Results: Maternal height and BMI were significant predictors of the daughters’ height, weight and BMI. Low birth weight (<2500 g) was significantly associated with reduced adult offspring weight and BMI. The weight and BMI of adult offspring were statistically significantly associated with the extrapolated prenatal DDE levels of their mothers. Controlling for confounders and compared to maternal DDE levels of <1.503 μg/l, offspring BMI was increased by 1.65 when prenatal DDE levels were 1.503–2.9 μg/l and by 2.88 if levels were >2.9 μg/l. Prenatal PCB levels showed no effect. Conclusion: Prenatal exposure to the oestrogenic endocrine-disrupting chemical DDE may contribute to the obesity epidemic in women.

Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. Our objective was to prevent sensitization to house‐dust mite and food allergens, as well as the development of atopic symptoms during infancy, by the combination of an educational package and the use of mite allergen‐impermeable mattress encasings. A multicentre European, population‐based, randomized, controlled study of children at increased atopic risk [Study on the Prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, the UK, and Lithuania), and included three cohorts – schoolchildren, toddlers, and newborns. We report on the newborn cohort. A total of 696 newborns were included from Austria, the UK, and Germany. Inclusion criteria were: a positive history of parental allergy; and a positive skin‐prick test or specific immunoglobulin E (IgE) (IgE ≥ 1.43 kU/L) against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age, the overall sensitization rate against the tested allergens [dust‐mite allergens: Dermatophagoides pteronyssinus and Dermatophagoides farinae (Der p and Der f)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we were able to demonstrate, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero‐ and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of easy‐to‐perform preventive measures.

Sensitization to mite allergens is a risk factor for early and late onset of asthma and for persistence of asthmatic signs in children

BACKGROUND To describe the natural history of asthma between the ages of 7 and 10 years and to analyze risk factors for prevalences, as well as new onset of asthma-like symptoms, a longitudinal study of 1812 children was conducted. METHODS In four surveys, each 1 year apart, four asthma-like symptoms and several hypothetical risk factors were ascertained through standardized questionnaires. Sensitization to seven common inhalant allergens was measured by skin prick testing. Exposure to mite allergens (Der p I, Der f I) was assessed by measuring the antigen concentrations in the dust of each childs mattress. Occurrence of more than one asthma-like symptom closely related to the practioners diagnoses of bronchial asthma and recurrent wheezy bronchitis was used as the outcome variable. RESULTS After an initial prevalence of 14.5%, new onset of symptoms in children unaffected at the beginning was reported in 7.2% during the 3 years. Of the factors explaining prevalence and persistence of asthma-like symptoms (sensitization to mite allergens and animal danders, history of hay fever and eczema, low gestational age, male gender, parental atopy), only sensitization to mite allergens (odds ratio = 2.3, 95% confidence interval = 1.1-4.7) and parental atopy (odds ratio = 2.1, 95% confidence interval = 1.2-3.7) were also significantly associated with new onset. In a relatively small number of sensitized subjects with new onset of symptoms (n = 31), mite antigen concentration did not appear to be associated with incidence of symptoms. CONCLUSION Sensitization to mite allergens antedated the onset of asthma-like symptoms, and no strong effect of allergen exposure on clinical development could be found. Thus the primary focus should be on preventing sensitization to mite allergens by implementing avoidance measures in infancy or at early school age in order to reduce the onset of asthma at a later stage.

Maternal concentration of polychlorinated biphenyls and dichlorodiphenyl dichlorethylene and birth weight in Michigan fish eaters: a cohort study

BackgroundStudies on maternal exposure to polychlorinated biphenyls (PCBs) reported inconsistent findings regarding birth weight: some studies showed no effect, some reported decreased birth weight, and one study found an increase in weights. These studies used different markers of exposure, such as measurement of PCBs in maternal serum or questionnaire data on fish consumption. Additionally maternal exposures, such as dichlorodiphenyl-dichloroethylene (DDE), which are related to PCB exposure and may interfere with the PCB effect, were rarely taken into account.MethodsBetween 1973 and 1991, the Michigan Department of Community Health conducted three surveys to assess PCB and DDE serum concentrations in Michigan anglers. Through telephone interviews with parents, we gathered information on the birth characteristics of their offspring, focusing on deliveries that occurred after 1968. We used the maternal organochlorine (OC) measurement closest to the date of delivery as the exposure. Although one mother may have contributed more than one child, serum concentrations derived from measurements in different surveys could vary for different children from the same mother. The maternal DDE and PCB serum concentrations were categorized as follows: 0 -< 5 microg / L, 5 -< 15 microg / L, 15 -< 25 microg / L, ≥25 microg / L. Using repeated measurement models (Generalized Estimation Equation), we estimated the adjusted mean birth weight controlling for gender, birth order, gestational age, date of delivery as well as maternal age, height, education, and smoking status.ResultsWe identified 168 offspring who were born after 1968 and had maternal exposure information. We found a reduced birth weight for the offspring of mothers who had a PCB concentration ≥25 microg / L (adjusted birth weight = 2,958 g, p = 0.022). This group, however, was comprised of only seven observations. The association was not reduced when we excluded preterm deliveries. The birth weight of offspring was increased in women with higher DDE concentrations when controlling for PCBs; however, this association was not statistically significant.ConclusionOur results contribute to the body of evidence that high maternal serum PCB concentration may reduce the birth weight in offspring. However, only a small proportion of mothers may actually be exposed to PCB concentrations ≥25 microg / L.

Retinopathy of prematurity and risk factors: a prospective cohort study

BackgroundIncreased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants.MethodsNeonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993–2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio) associated with risk factors of ROP.ResultsOf the neonates with ≤ 1500 g birth weight, admitted to the neonatal intensive care unit, 85% (616/725) survived. Severe retinopathy of prematurity was detected in 7.8% of 576 neonates who had eye examinations. Neonates of lower gestational age (≤ 25 weeks and 26–28 weeks) had an increased odds ratio of 8.49 and 3.19 for the development of severe retinopathy of prematurity, respectively, compared to those 29 weeks and older. Late postnatal steroid treatment starting after 3 weeks of life showed 2.9-fold increased odds ratio, in particular administration for two weeks and more (OR: 4.09, 95% CI: 1.52–11.03). With increasing antenatal steroids courses the risk of severe retinopathy of prematurity decreased, however, it was not significant. Lower gestational age, dependence on ventilation, and use of postnatal steroids were intertwined. Simultaneous presence of these factors seems to indicate severe disease status.ConclusionProlonged and late postnatal steroids treatment in very low birth weight infants may pose an increased risk for the development of severe retinopathy of prematurity; however, use of postnatal steroids may also be a marker for severity of illness. Further studies need to focus on biologic markers in the pathogenesis of retinopathy of prematurity and to better understand the influence of therapies.