Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis.

OBJECTIVES: To evaluate the relationship between nutritional status early in life and the timing and velocity of height growth, lung function, complications of cystic fibrosis, and survival. STUDY DESIGN: Prospective, observational study using data from the Cystic Fibrosis Foundation Registry (US) for patients born between 1989 and 1992 (n = 3142). RESULTS: Weight-for-age percentile (WAP) at 4 years of age was positively associated with height-for-age percentiles throughout childhood. Age 4 years WAP >10% was associated with better lung function from 6-18 years of age. In boys and girls with current WAP >50%, peak pubertal height velocities approximated but remained lower than that of the healthy reference population. By age 18 years, patients with an age 4 years WAP >50% suffered fewer acute pulmonary exacerbations, spent fewer days in the hospital, and had lower rates of impaired glucose tolerance or diabetes. Patients attaining higher age 4 years WAP and height-for-age percentiles had a survival advantage throughout childhood. CONCLUSION: For the population studied, greater weight at age 4 years is associated with greater height, better pulmonary function, fewer complications of cystic fibrosis, and better survival through age 18 years. Furthermore, greater weight-for-age in the peripubertal period is associated on average with improved tempo and timing of pubertal height growth.

Comparative analysis of FcεRI expression patterns in patients with eosinophilic and reflux esophagitis.

BACKGROUND AND OBJECTIVE: Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus. The IgE receptors on immune cells that infiltrate the esophagus are poorly defined. The high-affinity receptor for IgE, FcεRI, may play a role in EoE. The objective of the present study is to identify and compare the IgE receptors in the esophageal epithelium of patients with EoE, reflux esophagitis (RE), and normal controls. PATIENTS AND METHODS: A retrospective case-control study of 62 patients (19 EoE, 22 RE, 21 normal controls) was conducted. Biopsies were immunostained for FcεRI, CD23, galectin-3, c-kit, CD1a, and langerin. RESULTS: FcεRI was the only IgE receptor present in the esophageal epithelium of patients with EoE. The FcεRI-positive cell count varied by diagnosis (proximal biopsies EoE 32.6 ± 19.0 cells/high-power field, RE 26.7 ± 16.6, controls 15.6 ± 8.3, ANOVA P = 0.005; distal biopsies EoE 24.2 ± 16.2, RE 35.7 ± 27.6, controls 15.3 ± 8.4, P = 0.006). In the proximal esophagus, the FcεRI count was higher in EoE than in controls (P = 0.006); in the distal esophagus, the FcεRI count was higher in RE than in controls (P = 0.004). EoE and RE had similar FcεRI-positive cell counts. A subset of FcεRI-positive cells was similar in morphology and distribution to Langerhans cells (CD1a and langerin positive). CONCLUSIONS: The presence of FcεRI-positive cells in high numbers in the esophageal epithelium implies this receptor must be critical in the IgE-mediated activation of immune cells in the esophagus. Langerhans cells in the esophageal epithelium appear to express FcεRI. The role of Langerhans cells in the pathophysiology of EoE needs to be elucidated.

Differences between WHO AND CDC early growth measurements in the assessment of Cystic Fibrosis clinical outcomes.

BACKGROUND: Early childhood growth status has been used to predict long-term clinical outcomes in Cystic Fibrosis (CF) patients. Adulthood CF outcomes based on early weight-for-length (WFL) measurements, using either World Health Organization (WHO) or Centers for Disease Control (CDC) scales, have not been compared. METHODS: Cystic Fibrosis Foundation registry patients were studied (n=3014). Participants were categorized at age two years as WFL <50th percentile on both WHO and CDC scales, ≥50th percentile on WHO but not CDC, or ≥50th percentile on both. Pulmonary function and overall survival were assessed at age 18years. RESULTS: Stepwise gains in pulmonary function and lung transplant-free survival were noted across the three increasing WFL categories. CONCLUSIONS: Children with CF who achieve higher WFL at age two years have improved pulmonary and survival outcomes into adulthood. CF providers should continue to utilize current early growth recommendations, with goal WFL ≥50th percentile on CDC growth charts before age two.

Lipoid pneumonia due to Mexican folk remedies: cultural barriers to diagnosis.

OBJECTIVE: To describe 2 cases of lipoid pneumonia in Mexican American infants after administration of vegetable- or animal-derived oils and the cultural barriers to diagnosis. Various folk remedies have been documented in the international medical literature that involve the oral or nasal administration of vegetable- or animal-derived oils to children for the treatment of common ailments, including nasal stuffiness, constipation, and colic. Lipoid pneumonia is a known complication of such practices in Mexico, India, Saudi Arabia, and other countries. METHODS: Case reports of 2 Mexican American infants with respiratory distress and interviews with 30 immigrant families of Mexican origin. RESULTS: In both cases, language and cultural barriers resulted in a delayed diagnosis of lipoid pneumonia. Interviews with immigrant families confirmed that oil administration to children is a common traditional therapy in Mexican cultures. CONCLUSIONS: These findings underscore the need for primary care providers to be aware of the traditional practice of oil administration to infants in many cultures, its pathophysiological consequences, the potential cultural barriers to timely diagnosis, and the opportunity to prevent cases of lipoid pneumonia through anticipatory guidance.

Development and validation of a standardized ELISA for the detection of soluble Fc-epsilon-RI in human serum.

The aim of this study was to develop a standardized enzyme-linked immunosorbent assay (ELISA) for detection of human soluble Fc-epsilon-RI (sFcεRI), a serum isoform of the high affinity IgE receptor. A recombinant version of sFcεRI was produced in baculovirus and used as standard. ELISA plates were coated with anti-mouse IgG followed by incubation with the monoclonal capture antibody CRA1. This FcεRI-alpha-specific antibody binds to the stalk region of the protein and does not inhibit IgE-binding. After incubation with standards or serum samples, plates were incubated with chimeric IgE followed by detection with horseradish peroxidase conjugated anti-human IgE. Enzymatic activity was visualized with (3,3',5,5')-tetramethylbenzidine. Specificity was demonstrated by omission of capture or detection reagents. Units (U) of detection were established and the dynamic range of the assay was defined as 10-640 U/ml for a 1/5 serum dilution. Parameters of linearity (R(2)>0.999), matrix interference test (recovery of 70-110%), intra-assay variability (coefficient of variation (CV) <20%) and inter-assay variability (CV <20%) met acceptance criteria for immunoassay validation. Correlation analysis of serum units of sFcεRI measured with the new ELISA and serum IgE levels confirmed earlier published data describing a weak correlation of the two parameters in patients with elevated serum IgE while no correlation in patients with normal serum IgE or the total patient group was found. In summary, we established and validated a standardized ELISA for the detection of sFcεRI. This novel method now allows for comparative analysis of sFcεRI levels in health and disease.

A soluble form of the high affinity IgE receptor, Fc-epsilon-RI, circulates in human serum.

Soluble IgE receptors are potential in vivo modulators of IgE-mediated immune responses and are thus important for our basic understanding of allergic responses. We here characterize a novel soluble version of the IgE-binding alpha-chain of Fc-epsilon-RI (sFcεRI), the high affinity receptor for IgE. sFcεRI immunoprecipitates as a protein of ∼40 kDa and contains an intact IgE-binding site. In human serum, sFcεRI is found as a soluble free IgE receptor as well as a complex with IgE. Using a newly established ELISA, we show that serum sFcεRI levels correlate with serum IgE in patients with elevated IgE. We also show that serum of individuals with normal IgE levels can be found to contain high levels of sFcεRI. After IgE-antigen-mediated crosslinking of surface FcεRI, we detect sFcεRI in the exosome-depleted, soluble fraction of cell culture supernatants. We further show that sFcεRI can block binding of IgE to FcεRI expressed at the cell surface. In summary, we here describe the alpha-chain of FcεRI as a circulating soluble IgE receptor isoform in human serum.

Ca2+-dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathway.

The Fcgamma receptor FcRn transports immunoglobulin G (IgG) so as to avoid lysosomal degradation and to carry it bidirectionally across epithelial barriers to affect mucosal immunity. Here, we identify a calmodulin-binding site within the FcRn cytoplasmic tail that affects FcRn trafficking. Calmodulin binding to the FcRn tail is direct, calcium-dependent, reversible, and specific to residues comprising a putative short amphipathic alpha-helix immediately adjacent to the membrane. FcRn mutants with single residue substitutions in this motif, or FcRn mutants lacking the cytoplasmic tail completely, exhibit a shorter half-life and attenuated transcytosis. Chemical inhibitors of calmodulin phenocopy the mutant FcRn defect in transcytosis. These results suggest a novel mechanism for regulation of IgG transport by calmodulin-dependent sorting of FcRn and its cargo away from a degradative pathway and into a bidirectional transcytotic route.