Filaggrin loss-of-function mutations are associated with persistence of egg and milk allergy.

BACKGROUND: A genetic defect in the epidermal barrier protein filaggrin (FLG) plays a major role in the etiology of eczema and associated allergic airways diseases. However, it is still controversial to what extend loss-of-function (LOF) mutations in FLG contribute to the development and persistence of food allergies. OBJECTIVES: This study tested association of FLG LOF mutations with allergic reactions to diverse foods and investigated their potential effect on the persistence of early food allergies. METHODS: This study recruited 890 children with challenge-proven food allergy for the German Genetics of Food Allergy Study (GOFA). Longitudinal data were available for 684 children. All children were clinically characterized, including their allergic responses to specific foods, and genotyped for the 4 most common LOF mutations in FLG; R501X, 2282del4, R2447X, and S3247X. Associations between FLG mutations and food allergies were analyzed by logistic regression using the German Multicenter Allergy Study cohort as the control population. RESULTS: FLG mutations were associated with allergies to diverse foods including hen's egg (HE), cow's milk (CM), peanut, hazelnut, fish, soy, cashew, walnut, and sesame with similar risk estimates. Effects remained significant after adjusting for the eczema status. Interestingly, FLG mutations increased the risk of a persistent course of HE and CM allergy. CONCLUSIONS: Using the gold standard for food allergy diagnosis, this study demonstrates that FLG LOF mutations confer a risk of any food allergy independent of eczema. These mutations predispose to the persistence of HE and CM allergy and should be considered in the assessment of tolerance development.

IRIS: Infection with RespIratory Syncytial Virus in infants-a prospective observational cohort study.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection in infants. Globally, RSV is responsible for approximately 3.2 million hospital admissions and about 60,000 in-hospital deaths per year. METHODS: Infection with RespIratory Syncytial Virus (IRIS) is an observational, multi-centre study enrolling infants with severe RSV infection and healthy controls. Inclusion criteria are age between 0 and 36 months and hospitalisation due to RSV infection at three German sites. Exclusion criteria are premature birth, congenital or acquired bronchopulmonary or cardiac diseases, and immunodeficiency. Healthy control probands are enrolled via recruitment of patients undergoing routine surgical procedures. Blood and respiratory specimens are collected upon admission, and RSV and other pathogens are analysed by multiplex polymerase chain reaction. Different biomaterials, including plasma, nasal lining fluid, blood cells, DNA, and RNA specimens, are sampled in a dedicated biobank. Detailed information on demographic characteristics and medical history is recorded, and comprehensive clinical data, including vital signs, medication, and interventions. DISCUSSION: The IRIS study aims to discover host and viral factors controlling RSV disease courses in infants. The approach including multi-omics characterisation in clinically well-characterized children with RSV bronchiolitis seeks to improve our understanding of the immune response against this virus. It may disclose novel diagnostic and treatment approaches for respiratory infections in infants. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04925310. Registered 01 October 2021-Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT04925310?cond=NCT04925310&draw=2&rank=1.

PedCAPNETZ - prospective observational study on community acquired pneumonia in children and adolescents.

BACKGROUND: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation. METHODS: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established. DISCUSSION: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future.

[Respiratory syncytial virus]. / Respiratorisches Synzytialvirus.

Respiratory syncytial virus (RSV) is worldwide a very important virus leading to infection of the respiratory system. In particular preterm babies, infants and elderly adults are prone to developing severe diseases such as bronchiolitis or pneumonia, which require intensive care and cause increased mortality. Although RSV is rapidly detected, preventive and therapeutic measures are limited. New antivirals are already in clinical trials.

Lung disease caused by ABCA3 mutations.

BACKGROUND: Knowledge about the clinical spectrum of lung disease caused by variations in the ATP binding cassette subfamily A member 3 (ABCA3) gene is limited. Here we describe genotype-phenotype correlations in a European cohort. METHODS: We retrospectively analysed baseline and outcome characteristics of 40 patients with two disease-causing ABCA3 mutations collected between 2001 and 2015. RESULTS: Of 22 homozygous (15 male) and 18 compound heterozygous patients (3 male), 37 presented with neonatal respiratory distress syndrome as term babies. At follow-up, two major phenotypes are documented: patients with (1) early lethal mutations subdivided into (1a) dying within the first 6 months or (1b) before the age of 5 years, and (2) patients with prolonged survival into childhood, adolescence or adulthood. Patients with null/null mutations predicting complete ABCA3 deficiency died within the 1st weeks to months of life, while those with null/other or other/other mutations had a more variable presentation and outcome. Treatment with exogenous surfactant, systemic steroids, hydroxychloroquine and whole lung lavages had apparent but many times transient effects in individual subjects. CONCLUSIONS: Overall long-term (>5 years) survival of subjects with two disease-causing ABCA3 mutations was <20%. Response to therapies needs to be ascertained in randomised controlled trials.

Genotype alone does not predict the clinical course of SFTPC deficiency in paediatric patients.

Patients with interstitial lung disease due to surfactant protein C (SFTPC) mutations are rare and not well characterised. We report on all subjects collected over a 15-year period in the kids-lung register with interstitial lung disease and a proven SFTPC mutation. We analysed clinical courses, interventions and outcomes, as well as histopathological and radiological interrelations. 17 patients (seven male) were followed over a median of 3 years (range 0.3-19). All patients were heterozygous carriers of autosomal dominant SFTPC mutations. Three mutations (p.L101P, p.E191 K and p.E191*) have not been described before in the context of surfactant protein C deficiency. Patients with alterations in the BRICHOS domain of the protein (amino acids 94-197) presented earlier. At follow-up, one patient was healthy (2 years), six patients were "sick-better" (2.8 years, range 0.8-19), seven patients were "sick-same" (6.5 years, 1.3-15.8) and three patients were "sick-worse" (0.3 years, 0.3-16.9). Radiological findings changed from ground-glass to increasing signs of fibrosis and cyst formation with increasing age. Empiric treatments had variable effects, also in patients with the same genotype. Prospective studies with randomised interventions are urgently needed and can best be performed in the framework of international registers.

Pathogen spectra in hospitalised and nonhospitalised children with community-acquired pneumonia.

Background: Paediatric community-acquired pneumonia (CAP) is a leading cause of paediatric morbidity. However, particularly for outpatients with paediatric CAP, data on aetiology and management are scarce. Methods: The prospective pedCAPNETZ study multicentrically enrols children and adolescents with outpatient-treated or hospitalised paediatric CAP in Germany. Blood and respiratory specimens were collected systematically, and comprehensive analyses of pathogen spectra were conducted. Follow-up evaluations were performed until day 90 after enrolment. Results: Between December 2014 and August 2020, we enrolled 486 children with paediatric CAP at eight study sites, 437 (89.9%) of whom had radiographic evidence of paediatric CAP. Median (interquartile range) age was 4.5 (1.6-6.6) years, and 345 (78.9%) children were hospitalised. The most prevalent symptoms at enrolment were cough (91.8%), fever (89.2%) and tachypnoea (62.0%). Outpatients were significantly older, displayed significantly lower C-reactive protein levels and were significantly more likely to be symptom-free at follow-up days 14 and 90. Pathogens were detected in 90.3% of all patients (one or more viral pathogens in 68.1%; one or more bacterial strains in 18.7%; combined bacterial/viral pathogens in 4.1%). Parainfluenza virus and Mycoplasma pneumoniae were significantly more frequent in outpatients. The proportion of patients with antibiotic therapy was comparably high in both groups (92.4% of outpatients versus 86.2% of hospitalised patients). Conclusion: We present first data on paediatric CAP with comprehensive analyses in outpatients and hospitalised cases and demonstrate high detection rates of viral pathogens in both groups. Particularly in young paediatric CAP patients with outpatient care, antibiotic therapy needs to be critically debated.

Interobserver agreement in interpretation of chest radiographs for pediatric community acquired pneumonia: Findings of the pedCAPNETZ-cohort.

Although chest radiograph (CXR) is commonly used in diagnosing pediatric community acquired pneumonia (pCAP), limited data on interobserver agreement among radiologists exist. PedCAPNETZ is a prospective, observational, and multicenter study on pCAP. N = 233 CXR from patients with clinical diagnosis of pCAP were retrieved and n = 12 CXR without pathological findings were added. All CXR were interpreted by a radiologist at the site of recruitment and by two external, blinded pediatric radiologists. To evaluate interobserver agreement, the reporting of presence or absence of pCAP in CXR was analyzed, and prevalence and bias-adjusted kappa (PABAK) statistical testing was applied. Overall, n = 190 (82%) of CXR were confirmed as pCAP by two external pediatric radiologists. Compared with patients with pCAP negative CXR, patients with CXR-confirmed pCAP displayed higher C-reactive protein levels and a longer duration of symptoms before enrollment (p < .007). Further parameters, that is, age, respiratory rate, and oxygen saturation showed no significant difference. The interobserver agreement between the onsite radiologists and each of the two independent pediatric radiologists for the presence of pCAP was poor to fair (69%; PABAK = 0.39% and 76%; PABAK = 0.53, respectively). The concordance between the external radiologists was fair (81%; PABAK = 0.62). With regard to typical CXR findings for pCAP, chance corrected interrater agreement was highest for pleural effusions, infiltrates, and consolidations and lowest for interstitial patterns and peribronchial thickening. Our data show a poor interobserver agreement in the CXR-based diagnosis of pCAP and emphasized the need for harmonized interpretation standards.

Five-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents.

The efficacy and safety of five-grass pollen 300IR sublingual immunotherapy (SLIT) tablets (Stallergènes SA, France) have previously been demonstrated in paediatric patients. This report presents additional data concerning efficacy at pollen peak, efficacy and safety according to age, nasal and ocular symptoms, use of rescue medication, satisfaction with treatment and compliance. Children (5-11 yr) and adolescents (12-17 yr) with grass pollen-allergic rhinoconjunctivitis were included in a multinational, randomized, double-blind, placebo-controlled study and received either a 300IR five-grass pollen tablet or placebo daily in a pre- (4 months) and co-seasonal protocol. The severity of six symptoms (sneezing, rhinorrhoea, nasal congestion, nasal and ocular pruritis, and tearing) was scored, and rescue medication use was recorded daily during the pollen season. Patient satisfaction was recorded at the season end. A total of 161 children and 117 adolescents were evaluated (n = 267). 300IR SLIT was effective over the whole season (p = 0.0010) and at the pollen peak (p = 0.0009). The adjusted mean difference between 300IR and placebo groups was significant for both nasal (p = 0.0183) and ocular (p < 0.0001) symptoms. Rescue medication use was statistically lower in the SLIT group during the pollen season and at the pollen peak (both p < 0.05). More patients in the SLIT group were satisfied with their treatment compared to placebo (83.2% vs. 68.1%, p = 0.0030), and compliance was high (SLIT 93.9% of patients were compliant, placebo 94.8% of patients were compliant). SLIT was well tolerated by children and adolescents. 300IR five-grass pollen tablets are effective and safe during the pollen season and at the pollen peak in children and adolescents with grass pollen rhinoconjunctivitis.

Persistent tachypnea of infancy: Follow up at school age.

BACKGROUND: Persistent tachypnea of infancy (PTI) is a rare pediatric lung disease of unknown origin. The diagnosis can be made by clinical presentation and chest high resolution computed tomography after exclusion of other causes. Clinical courses beyond infancy have rarely been assessed. METHODS: Patients included in the Kids Lung Register diagnosed with PTI as infants and now older than 5 years were identified. Initial presentation, extrapulmonary comorbidities, spirometry and clinical outcome were analyzed. RESULTS: Thirty-five children older than 5 years with PTI diagnosed as infants were analyzed. At the age of 5 years, 74% of the patients were reported as asymptomatic and did not develope new symptoms during the observational period at school-age (mean, 3.9 years; range, 0.3-6.3). At the age of about 10 years, none of the symptomatic children had abnormal oxygen saturation during sleep or exercise anymore. Lung function tests and breathing frequency were within normal values throughout the entire observational period. CONCLUSIONS: PTI is a pulmonary disease that can lead to respiratory insufficiency in infancy. As at school age most of the previously chronically affected children became asymptomatic and did not develop new symptoms. We conclude that the overall clinical course is favorable.

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants.

BACKGROUND: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. OBJECTIVES: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. METHODS: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. RESULTS: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). CONCLUSIONS: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

Hospitalized children with respiratory syncytial virus infection and neuromuscular impairment face an increased risk of a complicated course.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of viral respiratory tract infection in children. In contrast to other confirmed risk factors that predispose to a higher morbidity and mortality, the particular risk of a preexisting neuromuscular impairment (NMI) in hospitalized children with RSV infection has not been prospectively studied in a multicenter trial. METHODS: The DMS RSV Paed database was designed for the prospective multicenter documentation and analysis of all clinically relevant aspects of the management of inpatients with RSV infection. Patients with clinically relevant NMI were identified according to the specific comments of the attending physicians and compared with those without NMI. RESULTS: This study covers 6 consecutive seasons; the surveillance took place in 14 pediatric hospitals in Germany from 1999 to 2005. In total, 1568 RSV infections were prospectively documented in 1541 pediatric patients. Of these, 73 (4.7%) patients displayed a clinically relevant NMI; 41 (56%) NMI patients had at least 1 additional risk factor for a severe course of the infection (multiple risk factors in some patients; prematurity in 30, congenital heart disease in 19, chronic lung disease 6 and immunodeficiency in 8). Median age at diagnosis was higher in NMI patients (14 vs. 5 months); NMI patients had a greater risk of seizures (15.1% vs. 1.6%), and a higher proportion in the NMI group had to be mechanically ventilated (9.6% vs. 1.9%). Eventually, the attributable mortality was significantly higher in the NMI group (5.5% vs. 0.2%; P < 0.001 for all). Multivariate logistic regression confirmed that NMI was independently associated with pediatric intensive care unit (PICU) admission (OR, 4.94; 95% CI, 2.69-8.94; P < 0.001] and mechanical ventilation (OR, 3.85; 95% CI, 1.28-10.22; P = 0.017). CONCLUSION: This is the first prospective multicenter study confirming the hypothesis that children with clinically relevant NMI face an increased risk for severe RSV-disease. It seems reasonable to include NMI as a cofactor into the decision algorithm of passive immunization.

Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy.

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study.

BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743.

A splice-supporting intronic mutation in the last bp position of a cryptic exon within intron 6 of the CYBB gene induces its incorporation into the mRNA causing chronic granulomatous disease (CGD).

Chronic granulomatous disease (CGD) is caused by a defect in both the host's defenses and its regulation of inflammation normally provided by phagocytes and other leukocytes. As in the case described here, it is not uncommon that CGD patients are diagnosed late, only after organ-damaging manifestations have already progressed. In this patient, we found that CGD arose due to a splice-supporting mutation in the last position of a cryptic exon towards the middle of intron 6 of the CYBB (gp91-phox) gene. The mutation led to the insertion of 56 bp into most of the CYBB mRNA of leukocytes causing a frame shift and a premature stop codon. The normal cryptic exon was also found to be mildly active in some tissues other than leukocytes in healthy donors, to be conserved in many primates, and to a lesser degree in other mammals. Some sequence similarity suggests that the cryptic exon may have originated from a mammalian interspersed repetitive (MIR) element. Taken together, we clarify an unusual disease-causing mutation, indicate its evolutionary background and emphasize the importance of a timely diagnosis of CGD.

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial.

BACKGROUND: Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS: In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS: Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION: Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING: Deutsche Forschungsgemeinschaft.

The effect of the Val34Leu polymorphism in the factor XIII gene in infants with a birth weight below 1500 g.

OBJECTIVES: The 34Leu polymorphism of the factor XIII gene is associated with a low rate of brain infarction and a higher incidence of primary intracerebral hemorrhage in adults. We evaluated the effect of the polymorphism on the subsequent development of isolated intracranial hemorrhage and white matter disease in preterm infants with a birth weight <1500 g (very low birth weight [VLBW] infants). STUDY DESIGN: We studied 531 VLBW infants and 301 control infants born at term. The factor XIII 34Leu polymorphism was detected by polymerase chain reaction and restriction enzyme digestion. RESULTS: Allele frequencies were not different from term and VLBW infants (Val/Val, 53.1% and 57.8%; Val/Leu, 38.8% and 37.6%; Leu/Leu, 8.0% and 4.5%, respectively). VLBW infants carrying the Leu/Val or Leu/Leu allele had a significant reduced risk of the development of white matter disease (3.6% vs 10.4% in infants without the polymorphism, P =.003). In a multivariate logistic regression analysis, only gestational age <28 weeks (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P <.001), and the factor XIII 34Leu allele (odds ratio, 0.3; 95% confidence interval, 0.1-0.7; P =.005) had significant prognostic value in predicting subsequent white matter disease. However, VLBW infants who carried the factor XIII 34Leu allele also had a moderately increased risk of the subsequent development of isolated intraventricular hemorrhage (14.3% vs 10.1% in infants without the mutation, P =.17). CONCLUSIONS: VLBW infants carrying the factor XIII 34Leu polymorphism had a decreased risk for white matter disorders.