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Original Investigation |

Respiratory Infections in Early Life and the Development of Islet Autoimmunity in Children at Increased Type 1 Diabetes Risk:  Evidence From the BABYDIET Study FREE

Andreas Beyerlein, PhD1; Fabienne Wehweck1; Anette-Gabriele Ziegler, MD1,2; Maren Pflueger, PhD1
[+] Author Affiliations
1Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes der Technischen Universität München, Munich, Germany
2Forschergruppe Diabetes e. V. am Helmholtz Zentrum München, Munich, Germany
JAMA Pediatr. 2013;167(9):800-807. doi:10.1001/jamapediatrics.2013.158.
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Published online

Importance  There is evidence for a role of infections within the pathogenesis of islet autoimmunity and type 1 diabetes mellitus (T1D), but previous studies did not allow assessment of potential critical time windows in this context.

Objective  To examine whether early, short-term, or cumulative exposures to episodes of infection and fever during the first 3 years of life were associated with the initiation of persistent islet autoimmunity in children at increased T1D risk.

Design  Prospective cohort study with daily infection records and regular assessment of islet autoimmunity.

Setting  Diabetes Research Institute, Munich, Germany.

Participants  A total of 148 children at high T1D risk with documentation of 1245 infectious events in 90 750 person-days during their first 3 years of life.

Main Outcomes and Measures  Hazard ratios (HRs) for seroconversion to persistent islet autoantibodies were assessed in Cox regression models with numbers of respiratory, gastrointestinal, and other infections, adjusting for sex, delivery mode, intervention group, season of birth, and antibiotic use.

Results  An increased HR of islet autoantibody seroconversion was associated with respiratory infections during the first 6 months of life (HR = 2.27; 95% CI, 1.32-3.91) and ages 6.0 to 11.9 months (HR = 1.32; 95% CI, 1.08-1.61). During the second year of life, no meaningful effects were detected for any infectious category. A higher number of respiratory infections in the 6 months prior to islet autoantibody seroconversion was also associated with an increased HR (HR = 1.42; 95% CI, 1.12-1.80).

Conclusions and Relevance  Respiratory infections in early childhood are a potential risk factor for the development of T1D.

Figures in this Article

The incidence of type 1 diabetes mellitus (T1D) is increasing worldwide,1 but its etiology is still not well understood. Infections have been discussed as important environmental determinants in the pathogenesis of T1D.24 Retrospective case-control studies showed that patients with newly diagnosed T1D had higher titers of enterovirus antibodies5 and were more likely to be positive for enterovirus RNA6,7 compared with healthy controls. Prospective studies from Finland confirmed the potential association between enterovirus infections and islet autoimmunity,8,9 while others from Germany and the United States did not.1012

These studies were based on a nested case-control design, which has only a limited ability to control for potential confounding factors. Furthermore, the approaches used did not allow detailed analyses on whether there are critical time windows in which infections might have a particularly strong influence on the development of islet autoimmunity. Moreover, infectious agents other than enteroviruses, eg, rotaviruses, have been reported to be related to T1D.1315

The occurrence of fever is also of interest in this context, as fever indicates a strong immune response and therefore a potentially sufficient and fast removal of the possibly autoimmunity-triggering pathogen.16,17 However, fever might also indicate a severe infection and excessive immune response leading to tissue damage and activation of autoreactive cells.18,19 Therefore, it is not yet known whether fever is a favorable or unfavorable prognostic factor in the pathogenesis of autoimmune diseases.

The aim of this study was to examine whether infections and fever episodes during the first 3 years of life were associated with the risk of developing islet autoimmunity. We hypothesized 3 scenarios to explain how infectious diseases might be involved in this context. First, early exposure, eg, in the first months of life, may be instrumental in inducing a state of susceptibility for future seroconversion. Alternatively, infections may have a short-term effect, causing islet autoantibody seroconversion in the following few months. Third, infections might have a cumulative effect such that the frequency of infectious events would increase the likelihood of islet autoimmunity irrespective of when they occur. To study this, we took advantage of data from children at high risk for T1D who had been followed up from 3 months of age within the BABYDIET study.

Data Collection

The BABYDIET study is an intensively monitored German dietary intervention study testing the potential effect of delayed gluten exposure on the development of islet autoimmunity in children at increased risk for diabetes. The study cohort is still followed up and has been described in detail elsewhere.20,21 In brief, 150 children younger than 3 months with at least 1 first-degree relative with T1D and 1 of 3 specific T1D-associated HLA genotypes were recruited between August 2000 and August 2006 (participation rate, 88.8%) and randomized to exposure to dietary gluten in the first year of life. After inclusion, children were followed up in 3-monthly intervals until age 3 years and yearly thereafter for efficacy (persistent islet autoantibodies) and safety assessment, including intensive monitoring with 3-monthly sample collections of venous blood, urine, and stool.

The BABYDIET study was conducted at the Diabetes Research Institute, Munich, Germany, and approved by the ethics committee of the Ludwig-Maximilian University, Munich.

Assessment of Infectious Episodes

At the child’s age of 3 months, parents completed a detailed questionnaire on their children’s history of infections, fever, and medication. Specifically, they were asked about fever, infectious symptoms (such as diarrhea, vomiting, constipation, and allergies), and the names of administered pharmaceutical agents or their active ingredients with starting date and duration of infections and medication. The questionnaire additionally addressed the occurrence of diabetes and other autoimmune diseases in the child or his or her family and lifestyle habits such as smoking during pregnancy. All families then received a BABYDIET book in which they were asked to record all infections and fever events (temperature >38°C) together with medication and health visits of their children on a daily basis until age 3 years. Parents were instructed to report disease-free days in the BABYDIET book as well. The diseases were classified using the International Statistical Classification of Diseases, 10th Revision (ICD-10) code from 2011 based on the physicians’ diagnosis (if medical care had been sought) or on parental reports of symptoms.

Infectious disease was defined as an acute event according to the ICD-10 code or by a symptom indicating an infectious genesis. Infectious events were assigned to a specific time interval by their date of onset. We defined 3 categories of infectious diseases: (1) infections of the respiratory tract, of the ear, nose, and throat, and of the eye (if inflammatory symptoms of the respiratory tract were reported); (2) gastrointestinal tract infections (if the main symptoms were diarrhea and/or vomiting); and (3) other infections (eg, with symptoms of skin or mucosa lesions). Other disease events such as allergies or accidents were not considered as infectious diseases. Separate infectious diseases of 1 category were defined as 1 infectious event if there were less than 6 days of potential remission between the respective infections, as these seemed likely to be caused by the same infectious agent. Additionally, we defined a category of “any infections” in which infectious diseases of different categories were considered as 1 infectious event if their time intervals overlapped.

Assessment of Islet Autoantibody Seroconversion

Seroconversion was defined as the development of persistent autoantibodies to 1 or more of the following antigens: insulin, glutamic acid decarboxylase 65, insulinoma antigen 2, or zinc transporter 8. Only the first event of seroconversion in each subject was taken into account. Measurement of autoantibodies has been described elsewhere.21 The upper limits of normal were determined using quantile-quantile plots, corresponded to the 99th percentile of control children, and were 1.5 local units/mL for insulin autoantibodies, 35 World Health Organization units/mL for glutamic acid decarboxylase antibodies, 5 World Health Organization units/mL for insulinoma antigen 2 antibodies, 16 units/mL for zinc transporter 8–arginine antibodies, and 30 units/mL for zinc transporter 8–tryptophan antibodies. Using these thresholds for positivity, the assays had respective sensitivities and specificities of 70% and 99% (insulin autoantibodies), 86% and 93% (glutamic acid decarboxylase antibodies), 72% and 100% (insulinoma antigen 2 antibodies), and 84% and 100% for multiple islet autoantibodies in the Diabetes Antibody Standardization Program proficiency workshop.22 Persistence was defined as being positive in at least 2 consecutive samples and in the last available sample. Islet autoantibodies were measured in venous blood samples from all scheduled visits and therefore every 3 months. Diabetes development was monitored and diagnosed according to the American Diabetes Association Expert Committee on the Diagnosis and Classification of Diabetes Mellitus criteria.23

Statistical Analysis

From the daily records in the BABYDIET books, which also covered disease-free days, it was possible to distinguish between documented days (with or without disease) and undocumented days. To avoid potential bias due to variation in the number of documented days between subjects and time periods, we calculated the numbers of infectious disease and fever events per 100 documented days for each child as a measure of incidence. Due to the detailed questionnaire at the child’s age of 3 months, we considered all days from birth to this visit as being documented. The analyses were restricted to observations based on at least 20 documented days in the respective time interval.

To address the early-exposure hypothesis, we calculated hazard ratios (HRs) of time until seroconversion to islet autoantibodies with respective 95% CIs by the number of infectious events per 100 documented days in the intervals of 0 to 5.9 months, 6.0 to 11.9 months, and 12.0 to 23.9 months of age using Cox proportional hazard regression model. For any time point, we calculated 4 models, using total number of infectious events as predictor in the first model, numbers of respiratory, gastrointestinal, and other infections as separate predictors in the second model, number of any fever events (recorded with or without an infectious episode) as predictor in the third model, and number of fever events without infection in the fourth model. In total, the data set included 26 events of islet autoantibody seroconversion, which occurred at ages 0.59 to 7.90 years. There were no observations with reported islet autoantibody seroconversion in the first 6 months of life; those with seroconversion at ages 6.0 to 11.9 months were excluded from the analysis of ages 12.0 to 23.9 months.

To examine the short-term effect hypothesis, we calculated Cox regression models with numbers of infectious and fever events per 100 documented days in the last 6 months before autoantibody seroconversion within the first 3 years of life as time-varying predictors.24

To disentangle potential early-exposure and short-term effects, we performed 2 sensitivity analyses. In the first, we restricted the models with infectious or fever events during the first half year of life to those seroconversion events that occurred after the first year of life. In the second, we restricted the models with time-varying predictors to those seroconversion events that happened between ages 1.5 and 3 years.

All Cox regression models were adjusted for sex, delivery mode (cesarean or vaginal), intervention group, season of birth (March-May; June-August; September-November; December-February), and frequency of antibiotic use and were tested for interaction with the virus-sensing interferon induced with helicase C domain 1 (IFIH1) gene polymorphism.25

With respect to the cumulative-exposure hypothesis, we compared the distributions of the recorded numbers of infectious events in children with and without autoantibody seroconversion during their first 2 years of life in 3-monthly intervals.

One subject dropped out of the study after the first visit, and another one had less than 20 documented days in every age interval examined. Both children were therefore excluded from the sample, leaving a final sample size of 148 subjects.

The level of significance was set to .05 in all analyses. All calculations were carried out with SAS version 9.2 statistical software (SAS Institute, Inc). Plotting was done using R version 2.14.1 statistical software (http://cran.r-project.org).

Descriptive Statistics

In total, our data comprised 90 750 documented days (Table 1). Overall, 1245 events (8.41 per child) and 431 events (2.91 per child) had been reported with respect to infections and fever, respectively. Children with islet autoantibody seroconversion during follow-up were significantly more exposed to respiratory and gastrointestinal infections as well as to fever, both during the first year of life and overall (Table 2). The median number of documented days decreased from 350.5 in the first year of life to 177.5 in the second year and 12.5 in the third year. The median number of documented days and median follow-up time per child were similar in both groups.

Table Graphic Jump LocationTable 1.  Total Documented Days and Numbers of Infectious and Fever Events in 148 Participants in the BABYDIET Study
Table Graphic Jump LocationTable 2.  Description of the BABYDIET Study Populationa

While there were no islet autoantibody seroconversion events observed in the first 6 months of life, the incidence rates of seroconversion per 100 person-years were 8.51 in the second half year, 4.07 in the second year, and 3.67 in the third year of life. The mean incidences of the 3 infection categories also increased considerably after the first 6 months of life and remained relatively constant thereafter, with a slight decline in the third year of life (Figure 1). The same tendency was observed for the incidence of fever. Respiratory infections constituted the majority of the infections recorded.

Place holder to copy figure label and caption
Figure 1.
Incidences of Infectious and Fever Events

Mean incidences of infectious and fever events per 100 documented days in the first 3 years of life in the BABYDIET data.

Graphic Jump Location
Addressing the Early-Exposure Hypothesis

Despite the overall lower incidence of infections in the first 6 months of life, the number of infections during this age period per 100 documented days was associated with an increase in the HR for islet autoantibody seroconversion in both crude and adjusted analyses (Table 3). The effect size was particularly high for respiratory infections (adjusted HR = 2.27; 95% CI, 1.32-3.91), while there were no significant associations with gastrointestinal and other infections in this early period. The results were similar when we excluded all seroconversion events that happened during the first year of life (data not shown).

Table Graphic Jump LocationTable 3.  Islet Autoantibody Seroconversion at Any Time During Follow-up by Number of Infectious Diseases and Fever Events per 100 Documented Days During Ages 0 to 5.9 Months and 6.0 to 11.9 Months

In the following 6 months of life, any infections and respiratory infections were again significantly associated with islet autoantibody seroconversion. However, the effect size was much lower than in the preceding period (eg, respiratory infections: adjusted HR = 1.32; 95% CI, 1.08-1.61). There were no significant associations with fever events in any of the 2 periods. During the second year of life, no meaningful effects were detected for infections or fever (data not shown). We did not detect significant interactions with IFIH1 genotype in any model (data not shown).

When we explored the associations observed in the Cox regression analyses in further detail (Figure 2), we found that the rate of islet autoantibody seroconversion was highest in children with more than 5 recorded events of respiratory infections in the first year of life. For all seroconverters, at least 2 infections had been reported in this period, including respiratory infections for all except 1 case.

Place holder to copy figure label and caption
Figure 2.
Rates of Islet Autoantibody Seroconversion

Rates of islet autoantibody seroconversion by total number of infectious events, including any infections (A) and respiratory infections (B), in the first year of life as recorded in the BABYDIET data.

Graphic Jump Location
Addressing the Short-term Effect Hypothesis

Calculations with time-dependent covariates indicated that the HR for seroconversion was significantly increased by a higher number of respiratory infections per 100 documented days within the preceding 6 months (adjusted HR = 1.42; 95% CI, 1.12-1.80) (Table 4). Again, gastrointestinal and other infections did not have a positive association with the seroconversion rate. However, we detected significant associations with any fever events and fever events without infection. When we restricted these analyses to seroconversion events after 1.5 years of life to disentangle potential effects of the first year of life and the preceding 6 months, the results were similar but not significant, with the exception of any fever events. Again, we found no interactions with IFIH1 genotype (data not shown). For all seroconverters, at least 1 infection had been reported within 6 months prior to the seroconversion event, including respiratory infections for all except 2 cases (data not shown).

Table Graphic Jump LocationTable 4.  Islet Autoantibody Seroconversion at Ages 0 to 3 Years and 1.5 to 3 Years, by Number of Infectious Diseases and Fever Events per 100 Documented Days in the 6 Months Prior to Seroconversion
Addressing the Cumulative-Exposure Hypothesis

Between 9 and 18 months of life, subjects with later islet autoantibody seroconversion had on average a higher total number of infectious events recorded than their peers without seroconversion as determined by Mann-Whitney U tests (data not shown). The respective interquartile ranges of their number of cumulative infections differed accordingly, although the highest exposures were observed in children without seroconversion (Figure 3). The upper quartiles (75th percentiles) of the distributions of the cumulative numbers of respiratory infections increased considerably faster in seroconverters compared with healthy peers during the first year of life, but this difference remained relatively constant thereafter (Figure 4). There were no meaningful results with respect to gastrointestinal and other infections. Therefore, the average higher cumulative infection number in children with later seroconversion (as concluded from higher interquartile ranges) reflected mainly a higher exposure to respiratory infections during the first year of life. All these findings were similar when we compared numbers of events per 100 documented days (data not shown).

Place holder to copy figure label and caption
Figure 3.
Total Cumulative Numbers of Any Infections in Children With and Without Islet Autoantibody Seroconversion

A, Interquartile ranges of cumulative number of infections are depicted in 3-monthly intervals up to age 24 months. For each time point, subjects with prior seroconversion were excluded from the respective calculations. B, Cumulative numbers of infections at age 24 months are shown in detail.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Seventy-fifth Percentiles of Distributions of Total Cumulative Numbers of Infections

Seventy-fifth percentiles of the distributions of total cumulative numbers of respiratory, gastrointestinal, and other infections in children with and without islet autoantibody seroconversion in 3-monthly intervals up to age 24 months. For each time point, subjects with prior seroconversion were excluded from the respective calculations.

Graphic Jump Location
Additional Analyses

In an attempt to identify specific infectious diseases that might be mainly responsible for the increased rate of seroconversion by respiratory infections, we compared infection rates between children with and without seroconversion. We observed significantly higher rates of infections of the upper respiratory tract (Mann-Whitney U test, P = .005) and among these of acute rhinopharyngitis (ICD-10 code J00, P = .001). When we used infections of the upper respiratory tract as predictor variable in the Cox regression models, we found significant associations at ages 0 to 5.9 months, at ages 6.0 to 11.9 months, and for 6 months before seroconversion (Table 5). We observed no significant associations with infections of the lower respiratory tract (Table 5), of ear, nose, and throat, and of the eye (data not shown).

Table Graphic Jump LocationTable 5.  Islet Autoantibody Seroconversion by Number of Infections in the Upper and Lower Respiratory Tract and of Acute Rhinopharyngitis per 100 Documented Days

Through the daily documentation of illnesses and fever in children with a family history of T1D during the first 3 years of life, we could demonstrate that exposure to infectious diseases, and in particular to respiratory infections, in early life predicted the development of islet autoimmunity. Primarily, we found strong associations with infections occurring in the first year of life, confirming the early-exposure hypothesis.

There was also some evidence for the short-term effect hypothesis, as infections and fever events within 6 months prior to islet autoantibody seroconversion were also associated with an increased risk of islet autoimmunity. Notably, all children who developed islet autoimmunity had at least 2 infections in the first year of life and at least 1 infection within 6 months before islet autoantibody seroconversion. However, cumulative exposure alone seemed not to be instrumental, as potential differences in the cumulative disease numbers between children with and without islet autoantibody seroconversion mainly reflected different exposure to infections in the first year of life only. Fever seemed to be associated with a detrimental rather than protective effect, particularly with respect to short-term effects, but these findings were not conclusive.

These results are novel. To our knowledge, this study for the first time prospectively assessed infectious diseases together with their starting date and duration in children at risk for T1D. Overall, only few data exist about the incidence of infections and fever in infancy. Our finding that the infection rates increased largely after the first 6 months of life and remained relatively stable thereafter is comparable to results from another study26 and appears likely to reflect protection by maternal passive immunity, which is known to decline during the first year of life.2729 Extrapolated to yearly rates, our incidences of respiratory infections were comparable to those observed in another German population.30 Other strengths of our study lie in the frequent 3-monthly measurement of all 4 relevant islet autoantibodies and in the fact that parents reported disease-free days as well, so that we were able to estimate disease frequencies without reporting bias. Accompanied collection of medication data even enabled us to rule out that our results were confounded by antibiotic use.

A potential limitation is the sample size, but such frequent follow-up of study subjects, detailed phenotyping, and daily documentation of infectious events constitute a challenge for both investigators and participants, so that it appears difficult to obtain a larger population size with such a study design. As a consequence, our data did not allow us to finally exclude that infections other than upper respiratory tract infections might also have a potential effect on development of islet autoimmunity, as the statistical power might simply have been too low to detect such associations. Apparently for the same reason, we were not able to finally exclude that potential short-term associations observed in our data might be due to early-exposure effects. Although we performed a number of sensitivity analyses, it appears unlikely that this has resulted in a multiple-testing problem. The results of these analyses were only used to assess the validity of the main analyses (which had been performed beforehand) and were not interpreted otherwise.

Various mechanisms have been discussed to explain how infectious diseases might induce autoreactivity in T1D. Results from animal studies indicate that different viruses can affect the development of islet autoimmunity via various mechanisms such as direct beta-cell lysis, bystander activation of autoreactive T cells, loss of regulatory T cells, and molecular mimicry,31,32 which might therefore also be relevant in humans.3336

The period between ages 6 months and 3 years has been identified as the peak incidence period of islet autoimmunity in the BABYDIET data as well as in other studies,3739 implying that most of the relevant causative events occur at or before this time. Our results indicate that early exposure to infections increases the susceptibility for developing islet autoantibodies. Although it might appear plausible that such a state of susceptibility would soon lead to islet autoantibody seroconversion, we found that exposure to infections in the first 6 months of life was also associated with seroconversion after the first year of life, thus also indicating longer-term effects by early exposure.

Potential prevention strategies against T1D derived from studies like this might address early vaccination against specific infectious agents. Unfortunately, we were not able to identify a single infectious agent that might be instrumental in the development of T1D. Our results point to a potential role of infections in the upper respiratory tract and specifically of acute rhinopharyngitis. These results are partly supported by the MIDIA study,40 which also indicated that respiratory infections are associated with the development of islet autoimmunity. In general, our findings are in accordance with other previous studies that showed associations with enterovirus infections,5,6,8,9 as rhinoviruses—an enterovirus species—are known to be the major causative agents of respiratory infections.4143

In conclusion, our study identified respiratory infections in early childhood, especially in the first year of life, as a risk factor for the development of T1D. We also found some evidence for short-term effects of infectious events on development of autoimmunity, while cumulative exposure alone seemed not to be causative.

Corresponding Author: Anette-Gabriele Ziegler, MD, Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, D-85764, Germany (anette-g.ziegler@helmholtz-muenchen.de).

Published Online: July 1, 2013. doi:10.1001/jamapediatrics.2013.158

Author Contributions: Beyerlein had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ziegler is the principal investigator of the BABYDIET study.

Study concept and design: Beyerlein, Ziegler.

Acquisition of data: Ziegler, Pflueger.

Analysis and interpretation of data: Beyerlein, Wehweck.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Ziegler.

Statistical analysis: Beyerlein, Wehweck.

Obtained funding: Ziegler.

Administrative, technical, and material support: Pflueger.

Study supervision: Ziegler.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants ZI 310/14-1, ZI 310/14-2, and BE 4682/1-1from Deutsche Forschungsgemeinschaft and by Stiftung “Das zuckerkranke Kind.”

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Additional Contributions: Sandra Hummel, PhD, coordinated the study at the start, Christiane Winkler, PhD, provided database management, Kerstin Adler, PhD, and Ramona Puff, PhD, provided laboratory management, and Annette Knopff, Steffi Krause, Anita Gavrisan, and Marlon Scholz provided expert technical assistance.

Additional Information: This work is partly based on the dissertation of Wehweck at the Technische Universität München.

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Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(suppl 1):S5-S20.
PubMed   |  Link to Article
Singer  JD, Willett  JB. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. New York, NY: Oxford University Press; 2003.
Winkler  C, Lauber  C, Adler  K,  et al.  An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. Diabetes. 2011;60(2):685-690.
PubMed   |  Link to Article
Koch  A, Sørensen  P, Homøe  P,  et al.  Population-based study of acute respiratory infections in children, Greenland. Emerg Infect Dis. 2002;8(6):586-593.
PubMed   |  Link to Article
Gold  BD, Khanna  B, Huang  LM, Lee  CY, Banatvala  N.  Helicobacter pylori acquisition in infancy after decline of maternal passive immunity. Pediatr Res. 1997;41(5):641-646.
PubMed   |  Link to Article
Desgrandchamps  D, Schaad  UB, Glaus  J, Tusch  G, Heininger  U.  Seroprevalence of IgG antibodies against measles, mumps and rubella in Swiss children during the first 16 months of life [in German]. Schweiz Med Wochenschr. 2000;130(41):1479-1486.
PubMed
Derya  A, Necmi  A, Emre  A, Akgün  Y.  Decline of maternal hepatitis a antibodies during the first 2 years of life in infants born in Turkey. Am J Trop Med Hyg. 2005;73(2):457-459.
PubMed
Grüber  C, Keil  T, Kulig  M, Roll  S, Wahn  U, Wahn  V; MAS-90 Study Group.  History of respiratory infections in the first 12 yr among children from a birth cohort. Pediatr Allergy Immunol. 2008;19(6):505-512.
PubMed   |  Link to Article
van der Werf  N, Kroese  FG, Rozing  J, Hillebrands  JL.  Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev. 2007;23(3):169-183.
PubMed   |  Link to Article
Colli  ML, Nogueira  TC, Allagnat  F,  et al.  Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim/Mcl-1 imbalance. PLoS Pathog. 2011;7(9):e1002267.
PubMed   |  Link to Article
Wucherpfennig  KW.  Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest. 2001;108(8):1097-1104.
PubMed
Roivainen  M, Klingel  K.  Virus infections and type 1 diabetes risk. Curr Diab Rep. 2010;10(5):350-356.
PubMed   |  Link to Article
Richardson  SJ, Willcox  A, Bone  AJ, Morgan  NG, Foulis  AK.  Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol. 2011;33(1):9-21.
PubMed   |  Link to Article
Ylipaasto  P, Smura  T, Gopalacharyulu  P,  et al.  Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. Diabetologia. 2012;55(12):3273-3283.
PubMed   |  Link to Article
Williams  AJ, Bingley  PJ.  Worth the wait: type 1 diabetes prospective birth cohort studies enter adolescence. Diabetologia. 2012;55(7):1873-1876.
PubMed   |  Link to Article
Ziegler  AG, Bonifacio  E; BABYDIAB-BABYDIET Study Group.  Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia. 2012;55(7):1937-1943.
PubMed   |  Link to Article
Parikka  V, Näntö-Salonen  K, Saarinen  M,  et al.  Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia. 2012;55(7):1926-1936.
PubMed   |  Link to Article
Rasmussen  T, Witsø  E, Tapia  G, Stene  LC, Rønningen  KS.  Self-reported lower respiratory tract infections and development of islet autoimmunity in children with the type 1 diabetes high-risk HLA genotype: the MIDIA study. Diabetes Metab Res Rev. 2011;27(8):834-837.
PubMed   |  Link to Article
Mäkelä  MJ, Puhakka  T, Ruuskanen  O,  et al.  Viruses and bacteria in the etiology of the common cold. J Clin Microbiol. 1998;36(2):539-542.
PubMed
Monto  AS.  Epidemiology of viral respiratory infections. Am J Med. 2002;112(suppl 6A):4S-12S.
PubMed   |  Link to Article
Billaud  G, Peny  S, Legay  V, Lina  B, Valette  M.  Detection of rhinovirus and enterovirus in upper respiratory tract samples using a multiplex nested PCR. J Virol Methods. 2003;108(2):223-228.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Incidences of Infectious and Fever Events

Mean incidences of infectious and fever events per 100 documented days in the first 3 years of life in the BABYDIET data.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Rates of Islet Autoantibody Seroconversion

Rates of islet autoantibody seroconversion by total number of infectious events, including any infections (A) and respiratory infections (B), in the first year of life as recorded in the BABYDIET data.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Total Cumulative Numbers of Any Infections in Children With and Without Islet Autoantibody Seroconversion

A, Interquartile ranges of cumulative number of infections are depicted in 3-monthly intervals up to age 24 months. For each time point, subjects with prior seroconversion were excluded from the respective calculations. B, Cumulative numbers of infections at age 24 months are shown in detail.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Seventy-fifth Percentiles of Distributions of Total Cumulative Numbers of Infections

Seventy-fifth percentiles of the distributions of total cumulative numbers of respiratory, gastrointestinal, and other infections in children with and without islet autoantibody seroconversion in 3-monthly intervals up to age 24 months. For each time point, subjects with prior seroconversion were excluded from the respective calculations.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Total Documented Days and Numbers of Infectious and Fever Events in 148 Participants in the BABYDIET Study
Table Graphic Jump LocationTable 2.  Description of the BABYDIET Study Populationa
Table Graphic Jump LocationTable 3.  Islet Autoantibody Seroconversion at Any Time During Follow-up by Number of Infectious Diseases and Fever Events per 100 Documented Days During Ages 0 to 5.9 Months and 6.0 to 11.9 Months
Table Graphic Jump LocationTable 4.  Islet Autoantibody Seroconversion at Ages 0 to 3 Years and 1.5 to 3 Years, by Number of Infectious Diseases and Fever Events per 100 Documented Days in the 6 Months Prior to Seroconversion
Table Graphic Jump LocationTable 5.  Islet Autoantibody Seroconversion by Number of Infections in the Upper and Lower Respiratory Tract and of Acute Rhinopharyngitis per 100 Documented Days

References

Patterson  CC, Gyürüs  E, Rosenbauer  J,  et al.  Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012;55(8):2142-2147.
PubMed   |  Link to Article
Forlenza  GP, Rewers  M.  The epidemic of type 1 diabetes: what is it telling us? Curr Opin Endocrinol Diabetes Obes. 2011;18(4):248-251.
PubMed   |  Link to Article
Christen  U, Bender  C, von Herrath  MG.  Infection as a cause of type 1 diabetes? Curr Opin Rheumatol. 2012;24(4):417-423.
PubMed   |  Link to Article
Smura  T, Ylipaasto  P, Klemola  P,  et al.  Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. J Med Virol. 2010;82(11):1940-1949.
PubMed   |  Link to Article
Gamble  DR, Kinsley  ML, FitzGerald  MG, Bolton  R, Taylor  KW.  Viral antibodies in diabetes mellitus. Br Med J. 1969;3(5671):627-630.
PubMed   |  Link to Article
Clements  GB, Galbraith  DN, Taylor  KW.  Coxsackie B virus infection and onset of childhood diabetes. Lancet. 1995;346(8969):221-223.
PubMed   |  Link to Article
Yeung  WC, Rawlinson  WD, Craig  ME.  Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ. 2011;342:d35.
PubMed   |  Link to Article
Sadeharju  K, Hämäläinen  AM, Knip  M,  et al; Finnish TRIGR Study Group.  Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial. Clin Exp Immunol. 2003;132(2):271-277.
PubMed   |  Link to Article
Salminen  K, Sadeharju  K, Lönnrot  M,  et al.  Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. J Med Virol. 2003;69(1):91-98.
PubMed   |  Link to Article
Füchtenbusch  M, Irnstetter  A, Jäger  G, Ziegler  AG.  No evidence for an association of coxsackie virus infections during pregnancy and early childhood with development of islet autoantibodies in offspring of mothers or fathers with type 1 diabetes. J Autoimmun. 2001;17(4):333-340.
PubMed   |  Link to Article
Graves  PM, Rotbart  HA, Nix  WA,  et al.  Prospective study of enteroviral infections and development of beta-cell autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY). Diabetes Res Clin Pract. 2003;59(1):51-61.
PubMed   |  Link to Article
Simonen-Tikka  ML, Pflueger  M, Klemola  P,  et al.  Human enterovirus infections in children at increased risk for type 1 diabetes: the Babydiet study. Diabetologia. 2011;54(12):2995-3002.
PubMed   |  Link to Article
Honeyman  MC, Coulson  BS, Stone  NL,  et al.  Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes. 2000;49(8):1319-1324.
PubMed   |  Link to Article
Honeyman  M.  How robust is the evidence for viruses in the induction of type 1 diabetes? Curr Opin Immunol. 2005;17(6):616-623.
PubMed   |  Link to Article
Coppieters  KT, Boettler  T, von Herrath  M.  Virus infections in type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(1):a007682.
PubMed   |  Link to Article
Cunha  BA.  Fever myths and misconceptions: the beneficial effects of fever as a critical component of host defenses against infection. Heart Lung. 2012;41(1):99-101.
PubMed
Jiang  Q, Cross  AS, Singh  IS, Chen  TT, Viscardi  RM, Hasday  JD.  Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 2000;68(3):1265-1270.
PubMed   |  Link to Article
Horwitz  MS, Ilic  A, Fine  C, Balasa  B, Sarvetnick  N.  Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells. Clin Immunol. 2004;110(2):134-144.
PubMed   |  Link to Article
Strieter  RM, Lynch  JP  III, Basha  MA, Standiford  TJ, Kasahara  K, Kunkel  SL.  Host responses in mediating sepsis and adult respiratory distress syndrome. Semin Respir Infect. 1990;5(3):233-247.
PubMed
Schmid  S, Buuck  D, Knopff  A, Bonifacio  E, Ziegler  AG.  BABYDIET, a feasibility study to prevent the appearance of islet autoantibodies in relatives of patients with type 1 diabetes by delaying exposure to gluten. Diabetologia. 2004;47(6):1130-1131.
PubMed   |  Link to Article
Hummel  S, Pflüger  M, Hummel  M, Bonifacio  E, Ziegler  AG.  Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care. 2011;34(6):1301-1305.
PubMed   |  Link to Article
Schlosser  M, MUELLER  PW, Törn  C, Bonifacio  E, Bingley  PJ; Participating Laboratories.  Diabetes Antibody Standardization Program: evaluation of assays for insulin autoantibodies. Diabetologia. 2010;53(12):2611-2620.
PubMed   |  Link to Article
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(suppl 1):S5-S20.
PubMed   |  Link to Article
Singer  JD, Willett  JB. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence. New York, NY: Oxford University Press; 2003.
Winkler  C, Lauber  C, Adler  K,  et al.  An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. Diabetes. 2011;60(2):685-690.
PubMed   |  Link to Article
Koch  A, Sørensen  P, Homøe  P,  et al.  Population-based study of acute respiratory infections in children, Greenland. Emerg Infect Dis. 2002;8(6):586-593.
PubMed   |  Link to Article
Gold  BD, Khanna  B, Huang  LM, Lee  CY, Banatvala  N.  Helicobacter pylori acquisition in infancy after decline of maternal passive immunity. Pediatr Res. 1997;41(5):641-646.
PubMed   |  Link to Article
Desgrandchamps  D, Schaad  UB, Glaus  J, Tusch  G, Heininger  U.  Seroprevalence of IgG antibodies against measles, mumps and rubella in Swiss children during the first 16 months of life [in German]. Schweiz Med Wochenschr. 2000;130(41):1479-1486.
PubMed
Derya  A, Necmi  A, Emre  A, Akgün  Y.  Decline of maternal hepatitis a antibodies during the first 2 years of life in infants born in Turkey. Am J Trop Med Hyg. 2005;73(2):457-459.
PubMed
Grüber  C, Keil  T, Kulig  M, Roll  S, Wahn  U, Wahn  V; MAS-90 Study Group.  History of respiratory infections in the first 12 yr among children from a birth cohort. Pediatr Allergy Immunol. 2008;19(6):505-512.
PubMed   |  Link to Article
van der Werf  N, Kroese  FG, Rozing  J, Hillebrands  JL.  Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev. 2007;23(3):169-183.
PubMed   |  Link to Article
Colli  ML, Nogueira  TC, Allagnat  F,  et al.  Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim/Mcl-1 imbalance. PLoS Pathog. 2011;7(9):e1002267.
PubMed   |  Link to Article
Wucherpfennig  KW.  Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest. 2001;108(8):1097-1104.
PubMed
Roivainen  M, Klingel  K.  Virus infections and type 1 diabetes risk. Curr Diab Rep. 2010;10(5):350-356.
PubMed   |  Link to Article
Richardson  SJ, Willcox  A, Bone  AJ, Morgan  NG, Foulis  AK.  Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol. 2011;33(1):9-21.
PubMed   |  Link to Article
Ylipaasto  P, Smura  T, Gopalacharyulu  P,  et al.  Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. Diabetologia. 2012;55(12):3273-3283.
PubMed   |  Link to Article
Williams  AJ, Bingley  PJ.  Worth the wait: type 1 diabetes prospective birth cohort studies enter adolescence. Diabetologia. 2012;55(7):1873-1876.
PubMed   |  Link to Article
Ziegler  AG, Bonifacio  E; BABYDIAB-BABYDIET Study Group.  Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia. 2012;55(7):1937-1943.
PubMed   |  Link to Article
Parikka  V, Näntö-Salonen  K, Saarinen  M,  et al.  Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia. 2012;55(7):1926-1936.
PubMed   |  Link to Article
Rasmussen  T, Witsø  E, Tapia  G, Stene  LC, Rønningen  KS.  Self-reported lower respiratory tract infections and development of islet autoimmunity in children with the type 1 diabetes high-risk HLA genotype: the MIDIA study. Diabetes Metab Res Rev. 2011;27(8):834-837.
PubMed   |  Link to Article
Mäkelä  MJ, Puhakka  T, Ruuskanen  O,  et al.  Viruses and bacteria in the etiology of the common cold. J Clin Microbiol. 1998;36(2):539-542.
PubMed
Monto  AS.  Epidemiology of viral respiratory infections. Am J Med. 2002;112(suppl 6A):4S-12S.
PubMed   |  Link to Article
Billaud  G, Peny  S, Legay  V, Lina  B, Valette  M.  Detection of rhinovirus and enterovirus in upper respiratory tract samples using a multiplex nested PCR. J Virol Methods. 2003;108(2):223-228.
PubMed   |  Link to Article

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