Early environmental risk factors and coeliac disease in adolescents: a population-based cohort study in Denmark.

OBJECTIVES: Our aim was to investigate the association between early environmental factors and the development of coeliac disease (CeD) in adolescents, recruited from a cohort nested in the Danish National Birth Cohort (DNBC). DESIGN: The study was designed as a prospective cohort study, nested in DNBC PARTICIPANTS: The Glutenfunen cohort comprises 1266 participants, nested in DNBC. All participants were screened for CeD, and in total, 28 cases of biopsy proven CeD were identified. Data about breastfeeding, timing of introduction to solid food in infancy, use of antibiotics, infections and symptoms were parentally reported prospectively at 6 months and 18 months, respectively. We estimated ORs and 95% CIs of CeD in adolescents using logistic regression analysis. RESULTS: Viral croup reported at 18 months of age was associated with CeD in adolescents with an OR of 3.2 (95% CI: 1.2 to 8.7). Furthermore, otitis media also reported at 18 months of age was linked with CeD with an OR of 3.2 (95% CI: 1.5 to 7.3). We were not able to find any statistical associations between CeD and breastfeeding, frequency of infections, parentally reported use of antibiotic and timing of solid foods. CONCLUSION: In this study, we present an overview of the relationship between early environmental factors and occurrence of CeD in adolescents. Our findings, despite limitations due to a limited number of cases of CeD, suggest a role of viral infections in the pathogenesis of CeD.

Feeding Practice, Nutrition, and Growth in Infants with Abdominal Wall Defects and Esophageal Atresia: A Retrospective Case-Control Study.

INTRODUCTION: Infants born with abdominal wall defects and esophageal atresia (EA) are at risk of impaired growth. Little is known about the optimal nutritional strategy and its impact on growth for these infants. This study aims to explore nutrition, focusing on breastfeeding, and the presumed impact on infant growth during the first year of life. MATERIALS AND METHODS: We performed a registry study. The participants comprised infants born with gastroschisis, omphalocele, or EA from 2009 to 2020. Breastfed healthy infants from the Odense Child Cohort served as the control group. Descriptive statistics were applied when presenting data on nutrition. Growth data were converted to weight z-scores at birth and at discharge, and estimated weight z-scores at 6 and 12 months were calculated. Univariate regression analysis was applied. RESULTS: The study included 168 infants in the study group and 403 infants in the control group. Exclusive breastfeeding rates at discharge were as follows: 55.7% (gastroschisis), 58.3% (omphalocele), 50.9% (EA), and 7.7% (long-gap EA). For the study group our data demonstrate no difference in growth at 1 year of age when comparing mother's milk to formula feeding. During the first year of life, infants in the study group showed slower growth compared with the control group. At 12 months of age, all infants had a mean weight z-score above -2. CONCLUSION: Breastfeeding in infants with abdominal wall defects and EA can be established without compromising growth. Mother's milk can be recommended for infants with abdominal wall defects and EA.

Pediatric Celiac Disease and Selective IgA Deficiency: Unexpected Sequence of Events.

PURPOSE: Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified. METHODS: Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA. RESULTS: We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa. CONCLUSION: Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation.

Induction of Susceptibility to Disseminated Infection with IgA1 Protease-Producing Encapsulated Pathogens Streptococcus pneumoniae, Haemophilus influenzae Type b, and Neisseria meningitidis.

Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the principal causes of bacterial meningitis. It is unexplained why only occasional individuals develop invasive infection, while the vast majority remain healthy and develop immunity when encountering these pathogens. A capsular polysaccharide and an IgA1 protease are common to these pathogens. We tested the hypothesis that patients are primed to susceptibility to invasive infection by other bacteria that express the same capsular polysaccharide but no IgA1 protease. Thereby, the subsequently colonizing pathogen may protect its surface with IgA1 protease-generated Fab fragments of IgA1 devoid of Fc-mediated effector functions. Military recruits who remained healthy when acquiring meningococci showed a significant response of inhibitory antibodies against the IgA1 protease of the colonizing clone concurrent with serum antibodies against its capsular polysaccharide. At hospitalization, 70.8% of meningitis patients carried fecal bacteria cross-reactive with the capsule of the actual pathogen, in contrast to 6% of controls (P < 0.0001). These were Escherichia coli K100, K1, and K92 in patients with infection caused by H. influenzae type b and N. meningitidis groups B and C, respectively. This concurred with a significant IgA1 response to the capsule but not to the IgA1 protease of the pathogen. The demonstrated multitude of relationships between capsular types and distinct IgA1 proteases in pneumococci suggests an alternative route of immunological priming associated with recombining bacteria. The findings support the model and offer an explanation for the rare occurrence of invasive diseases in spite of the comprehensive occurrence of the pathogens. IMPORTANCE Why some individuals develop invasive infection, including meningitis, with Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b is unexplained. The vast majority of humans are colonized with the three pathogens but remain healthy and develop immunity. The findings of this study support the hypothesis that patients are primed for disease by time-shifted acquisition of two different bacteria, an immunogenic commensal followed by the pathogen, but both expressing the same capsular polysaccharide. The IgA1 protease common to the three pathogens cleaves the preexisting IgA1 antibodies induced by the commensal. This eliminates Fc-mediated protective mechanisms and releases capsule-binding monomeric Fab fragments that enhance bacterial adherence and block access of other isotypes of antibody molecules. This concept provides new insight into the pathogenesis of bacterial meningitis and potential new strategies for prevention.

The effect of gluten in adolescents and young adults with gastrointestinal symptoms: a blinded randomised cross-over trial.

BACKGROUND: The popularity of the gluten-free diet and sales of gluten-free products have increased immensely. AIMS: To investigate whether gluten induces gastrointestinal symptoms, measured by self-reported questionnaires, as well as mental health symptoms in adolescents from a population-based cohort. METHODS: The eligible participants (n = 273) were recruited from a population-based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run-in phase where the participants lived gluten-free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross-over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7-day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed. RESULTS: In total, 54/273 participants entered the run-in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2-20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was -0.01 (95% confidence interval -2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health. CONCLUSION: Compared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population-based cohort. The trial registration number is NCT04639921.

PET/CT imaging detects intestinal inflammation in a mouse model of doxorubicin-induced mucositis.

Introduction: A severe side effect of cancer chemotherapy is the development of gastrointestinal mucositis, characterised by mucosal inflammation. We investigated if 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography combined with computed tomography (2-[18F]FDG-PET/CT) could visualise gastrointestinal mucositis in mice treated with the chemotherapeutic agent doxorubicin. Methods: In this study, gastrointestinal inflammation was longitudinally evaluated by 2-[18F]FDG-PET/CT scans before and 1, 3, 6, and 10 days after treatment with doxorubicin. Doxorubicin-treated mice were compared to saline-treated littermates using the abdominal standard uptake value of 2-[18F]FDG corrected for body weight (SUVBW). Results: Abdominal SUVBW was significantly increased on day 1 (p < 0.0001), day 3 (p < 0.0001), and day 6 (p < 0.05) in the doxorubicin-treated group compared to controls. Abdominal SUVBW returned to baseline levels on day 10. In the doxorubicin group, the largest weight loss was observed on day 3 (control vs doxorubicin, mean percent of baseline weight: (98.5 ± 3.2% vs 87.9 ± 4.6%, p < 0.0001). Moreover, in the doxorubicin-treated group, villus lengths were decreased by 23-28% on days 1 and 3 in the small intestine (p < 0.05), and jejunal levels of tumour necrosis factor and interleukin-1ß were significantly increased on day 3 (p < 0.05). Discussion: Together, these findings indicate that sequential 2-[18F]FDG-PET/CT scans can objectively quantify and evaluate the development and resolution of intestinal inflammation over time in a mouse model of doxorubicin-induced mucositis.

Pregnancy Exposure to Perfluoroalkyl Substances and Associations With Prolactin Concentrations and Breastfeeding in the Odense Child Cohort.

CONTEXT: Human exposure to perfluoroalkyl substances (PFAS) has been associated with reduced duration of breastfeeding, although not consistently so, and mechanisms by which PFAS might affect breastfeeding are unknown. OBJECTIVE: To examine the association between early pregnancy serum-PFAS concentrations and breastfeeding termination and to elucidate the potential role of serum-prolactin concentrations in pregnancy. MATERIALS AND METHODS: Pregnant women from the Odense Child Cohort provided blood samples for analysis of 5 major PFAS (n = 1300) and prolactin concentrations (n = 924). They subsequently provided information about the duration of breastfeeding in questionnaires at 3 and 18 months postpartum, and a subgroup also provided breastfeeding information via weekly cell phone text messages. Associations between serum-PFAS concentrations and breastfeeding termination were analyzed using Cox regressions, while linear regression was used to assess associations between serum-PFAS and prolactin concentrations. RESULTS: Increased serum concentrations of perfluorooctane sulfonic acid, perfluorooctanoic acid, perfluorononanoic acid, and ∑PFAS were associated with a 16% (95% CI: 4%-30%), 14% (95% CI: 2%-26%), 14% (95% CI: 3%-27%), and 20% (95% CI: 6%-36%), respectively, increased risk of terminating breastfeeding at any given time after childbirth. Serum-PFAS concentrations were not associated with serum-prolactin concentrations. CONCLUSIONS: These findings are of public health importance due to the global exposures to PFAS. Because breastfeeding is crucial to promote both child health and maternal health, adverse PFAS effects on the ability to breastfeed may have long-term health consequences.

High Prevalence of Celiac Disease Among Danish Adolescents: A Population-based Study.

OBJECTIVES: The objective of this study was to establish an unselected cohort of Danish adolescents and estimate the prevalence of undiagnosed celiac disease (CeD). METHODS: The Glutenfunen cohort participants were recruited from an unselected subsample of the Danish National Birth Cohort, defined as participants living in the Island of Funen, Denmark. We invited all 7431 eligible participants in the age range of 15 to 21 years to a clinical visit. CeD diagnosis was based on screening with IgA transglutaminase antibodies (TG2-IgA) and if positive, was followed by duodenal biopsies compatible with CeD (Marsh 2-3). We calculated the prevalence of CeD in the Glutenfunen cohort as the number of CeD cases diagnosed before and during the study divided by the number of participants in the Glutenfunen cohort. RESULTS: We included 1266 participants in the Glutenfunen cohort (17%, 1266/7431). 1.1% (14 of 1266 participants) had CeD diagnosed before entering the cohort and based on the Danish National Patient Register, 0.2% of the nonparticipants (14 of 6165) had a diagnosis of CeD. In total, 2.6% (33 participants) had TG2 IgA above the upper limit of normal. Nineteen participants had duodenal biopsies compatible with CeD. The prevalence of CeD in the Glutenfunen cohort was 2.6% [(14 + 19)/1266]. CONCLUSIONS: Our study suggests that CeD is much more common than expected among Danish adolescents, comparable to other European countries, and that the majority were asymptomatic or oligosymptomatic and were only found because of the screening procedure.

Pregnancy exposure to bisphenol A and duration of breastfeeding.

INTRODUCTION: Bisphenol A (BPA) is frequently used in the production of plastics. It is an endocrine disruptor, and BPA exposure in mice has been associated with reduced offspring growth due to insufficient milk production. However, human studies of associations between BPA exposure and duration of breastfeeding are sparse. METHODS: Pregnant women from the Odense Child Cohort (n = 725) donated a third trimester morning urine sample, which was analyzed for BPA by LC-MS/MS. Information about duration of exclusive and any breastfeeding was obtained through questionnaires three and 18 months postpartum, and a subgroup of women responded to weekly text messages about breastfeeding. Associations between pregnancy BPA exposure and duration of breastfeeding were analyzed using Cox regression adjusting for potential confounders. RESULTS: The median urine BPA concentration was 1.29 ng/mL. Compared to women within the lowest tertile of BPA exposure, women in the second and third tertile were slightly more likely to terminate breastfeeding at any given time; HRs (95% CI) were 1.05 (0.87; 1.26) and 1.06 (0.89; 1.27), respectively, and to terminate exclusive breastfeeding at any time up to 20 weeks after birth, HRs (95% CI) were 1.07 (0.88; 1.28) and 1.06 (0.88; 1.27), respectively. However, confidence intervals were also compatible with no effect or even a protective effect. DISCUSSION: This study indicated that high BPA exposure in pregnancy was associated with shorter duration of breastfeeding. Although our findings were not statistically significant, all estimates were above one suggesting increased risk of early breastfeeding termination with high exposure. Using a single spot morning urine sample to measure BPA has likely caused imprecision as it might not adequately reflect long term exposure. Future studies should consider measuring BPA more than once, including other timepoints during pregnancy and after birth.

Nesfatin-1 in Human Milk and Its Association with Infant Anthropometry.

Breastfed infants have different growth patterns to formula-fed infants and are less likely to develop obesity later in life. Nesfatin-1 is an anorexigenic adipokine that was discovered in human milk more than a decade ago, and its role in infant appetite regulation is not clear. Our aim was to describe nesfatin-1 levels in human milk collected 3-4 months postpartum, associations with infant anthropometry, and factors (maternal pre-pregnancy body mass index (mBMI), high weight gain during pregnancy, milk fat, and energy content) possibly influencing nesfatin-1 levels. We hypothesized that nesfatin-1 levels in mother's milk would differ for infants that were large (high weight-for-age Z-score (WAZ)) or small (low WAZ) at the time of milk sample collection. We used enzyme-linked immunosorbent assay to detect the nesfatin-1 concentration in milk samples from mothers to high WAZ (n = 50) and low WAZ (n = 50) infants. We investigated associations between nesfatin-1 levels and infant anthropometry at 3-4 months of age and growth since birth, using linear regression adjusted for mBMI, birth weight, infant sex, and exclusivity of breastfeeding. We found no difference in nesfatin-1 levels between the two groups and no association with infant anthropometry, even after adjusting for potential confounders. However, high nesfatin-1 levels were correlated with low mBMI. Future research should investigate serum nesfatin-1 level in both mothers, infants and associations with growth in breastfed children.

Transient congenital hyperinsulinism and hemolytic disease of a newborn despite rhesus D prophylaxis: a case report.

BACKGROUND: In neonates, rhesus D alloimmunization despite anti-D immunoglobulin prophylaxis is rare and often unexplained. Rhesus D alloimmunization can lead to hemolytic disease of the newborn with anemia and unconjugated hyperbilirubinemia. In past reports, transient congenital hyperinsulinism has been described as a rare complication of rhesus D alloimmunization. Our case report illustrates that rhesus D alloimmunization can result in a pseudosyndrome with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia, despite correctly administered anti-D immunoglobulin prophylaxis. CASE PRESENTATION: We report of a 36-year-old, Caucasian gravida 1, para 1 mother with A RhD negative blood type who received routine antenatal anti-D immunoglobulin prophylaxis. Her full term newborn boy presented with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia up to 295 µmol/L (ref. < 9), accounting for 64% of the total bilirubin. Syndromic congenital hyperinsulinism was suspected. Examinations showed a positive direct antiglobulin test, initially interpreted as caused by irregular antibodies; diffuse congenital hyperinsulinism by 18F-DOPA positron emission tomography/computed tomography scan; normal genetic analyses for congenital hyperinsulinism; mildly elevated liver enzymes; delayed, but present bile excretion by Tc99m-hepatobiliary iminodiacetic acid scintigraphy; and cholestasis and mild fibrosis by liver biopsy. The maternal anti-D titer was 1:16,000 day 20 postpartum. Y-chromosome material in the mother's blood could not be identified. This could, however, not exclude late intrapartum fetomaternal hemorrhage as the cause of immunization. No causative genetic findings were deetrmined by trio whole exome sequencing. The child went into clinical remission after 5.5 months. CONCLUSION: Our case demonstrates that rhesus D alloimmunization may present as a pseudosyndrome with transient congenital hyperinsulinism, anemia, and inspissated bile syndrome with conjugated hyperbilirubinaemia, despite anti-D immunoglobulin prophylaxis, possibly due to late fetomaternal hemorrhage.

No effect of deleted in malignant brain tumors 1 deficiency on chemotherapy induced murine intestinal mucositis.

Mucositis is a serious adverse effect of chemotherapeutic treatment. During intestinal mucositis, the mucosal barrier is compromised, increasing the risk of severe infections. Mucositis necessitates dose reduction or pauses in treatment, which affect the outcome of the treatment. Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger protein with effects on innate immunity and epithelial regeneration. We have previously shown that jejunal DMBT1 expression is increased in piglets during chemotherapeutic treatment. We hypothesized that DMBT1 ameliorates doxorubicin-induced mucositis. Individually-caged Dmbt1+/+ (WT) and Dmbt1-/- (KO) female mouse littermates received intraperitoneal injections of either doxorubicin or saline. They were euthanized after three (D3) or seven days (D7). Weight loss was monitored every day, and serum citrulline levels were measured at termination. Intestinal tissue was analyzed for the expression of DMBT1 and proinflammatory cytokines (IL-1ß, IL-6, and TNF). Specimens from the small intestines and colon were scored for inflammation and epithelial and mucosal architecture changes. We detected no effect of DMBT1 on weight loss, serum citrulline levels, expression of proinflammatory cytokines, or histologic damage. We detected a significant increase in crypt depth in WT mice compared to that in KO mice on D3. In conclusion, DMBT1 does not affect doxorubicin-induced mucositis in mice.

An International Reporting Registry of Patients With Celiac Disease and COVID-19: Initial Results From SECURE-CELIAC.

Surveillance Epidemiology Under Research Exclusion for Celiac Disease (SECURE-CELIAC) is an international, de-identified adult and pediatric database created to monitor and report on the severity of coronavirus disease 2019 (COVID-19) outcomes in patients with celiac disease (CD).

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity.

Introduction: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a frequent, severe and dose-limiting side effect. Few treatments have proven effective for CIGT. CIGT is characterized by activation of the nuclear factor kappa B pathway which, leads to upregulation of proinflammatory cytokines. The innate immune protein peptidoglycan recognition peptide 2 (PGLYRP2) binds to and hydrolyzes microbial peptidoglycan. Expression of PGLYRP2 is upregulated in the intestine of chemotherapy-treated piglets. In this experimental study, we investigated the role of Pglyrp2 in the development and severity of murine CIGT. Methods: Pglyrp2 wildtype and Pglyrp2 knockout mice received intraperitoneal injections of chemotherapy (Doxorubicin 20 mg/kg) to induce CIGT. Weight was monitored daily, and animals were euthanized after 2 or 7 days. Expression of proinflammatory cytokines in the jejunum was measured by quantitative real-time polymerase-chain reaction and enzyme-linked immunosorbent assay. Villus height, crypt depth, and histologic inflammation were evaluated on haematoxylin and eosin stained tissue specimens. Results: Chemotherapeutic treatment induced weight loss (p < 0.05), shortening of the small intestine (p < 0.05), elongation of villus height (p < 0.05), increased crypt depth (p < 0.05), and led to elevated mRNA levels of II1ß (p < 0.05), II6 (p < 0.05), and Tnf (p < 0.001) at day 2. Protein levels of IL1ß, IL6, and TNFα did not change after exposure to chemotherapy. Doxorubicin treated wildtype mice had a more pronounced weight loss compared to knockout mice from day 3 to day 7 (D3-D6: p < 0.05 and D7: p < 0.01). No other phenotypic differences were detected. Conclusion: Pglyrp2 aggravates chemotherapy-induced weight loss but does not induce a specific pattern of inflammation and morphological changes in the small intestine.

Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP).

PURPOSE: Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. METHOD: BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. RESULTS: The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. ß-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. CONCLUSION: RI for ß-CTX, PINP, OC and bone ALP varies with age and sex. ß-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.

Exposure to perfluoroalkyl substances during fetal life and hospitalization for infectious disease in childhood: A study among 1,503 children from the Odense Child Cohort.

INTRODUCTION: The immunosuppressive properties of PFASs are widely recognized. Early-life exposure to PFAS has been linked to reduced immune response to childhood vaccinations and increased rates of common infectious diseases, but implications for hospitalizations are unclear. OBJECTIVES: To investigate the association between maternal serum concentrations of five PFASs during pregnancy and the child's rate of hospitalization due to common infectious diseases between birth and 4 years of age. METHODS: Serum samples from first trimester pregnant women from the Odense Child Cohort (OCC) collected in 2010-2012 were analyzed for concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and three other PFASs. Data on child hospitalizations with an ICD-10 code for infectious disease was obtained from the Danish National Patient Register. The following were identified: upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GI), and other infections. The Andersen-Gill Cox proportional hazard model for recurrent events was used to investigate the association between PFAS exposure and hospitalizations. The resulting estimates were hazard ratios (HRs), which express the relative change in the instantaneous risk of hospitalization with a doubling in maternal PFAS concentration. RESULTS: A total of 1,503 mother-child pairs were included, and 26% of the children were hospitalized at least once for infectious disease. A doubling in maternal PFOS concentration was associated with a 23% increase in the risk of hospitalization due to any infection (HR: 1.23 (95% CI: 1.05, 1.44). There was indication of an interaction between child sex and PFOS (p = 0.07) and PFDA (p = 0.06), although in opposite directions. Further, every doubling of PFOA or PFOS increased the risk of LRTI by 27% (HR: 1.27 (1.01, 1.59)) and 54% (HR: 1.54 (1.11, 2.15)), respectively. Similar tendencies were seen for URTI and the group of other infections. For GIs, the opposite pattern of association was seen as HR's were consistently below 1 (PFOA, HR: 0.55 (0.32, 0.95)). DISCUSSION: We found an association between PFOS and the overall risk of infectious disease, and between PFOS and PFOA exposures and the risk of LRTI's. These results are in agreement with previous findings from the OCC, in which maternal PFOS and PFOA concentrations were positively associated with the number of days that the children experienced fever, thereby suggesting that PFOS and PFOA may affect the prevalence of both mild and more severe infectious diseases even in a rather low-exposed population.