Immunoreactive trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that immunoreactive trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF. METHODS: In this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016. RESULTS: Ninety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8-206.2) vs. 75.0 (61.0-105.9); P < 0.0001). Infants with CRMS/CFSPID→CF (n = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID (n = 83) (median (interquartile range): 108.9 (72.3-126.8) vs. 73.7(60.0-96.0); P = 0.02). CONCLUSIONS: Amongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Home Management of Childhood Asthma Exacerbations.

INTRODUCTION: Effective home management of childhood asthma by caregivers requires education along with a written asthma action plan (AAP), which should outline clear instructions for treatment during exacerbations. However, a large number of asthma exacerbations continue to be managed in the emergency department (ED) and in hospitals, particularly in Canada. The objective of this study was to assess caregiver management of acute asthma at home following the 2015 Global Initiative for Asthma (GINA) guidelines and to identify factors that may be associated with deviations from these guidelines. METHODS: 122 caregivers of children, aged 3-17 years, with physician diagnosed asthma, completed a paper-based questionnaire. Correct caregiver management (defined according to the GINA guidelines) of acute asthma as well as their use of an AAP were assessed. RESULTS: Out of all caregivers, 74.6% incorrectly treated their child's asthma exacerbation in a home setting. Among those who used an AAP, we observed significantly more ED visits (0.9 ± 1.2 versus 0.5 ± 0.9, p = 0.04) and hospitalizations (0.2 ± 0.4 versus 0.0 ± 0.0, p = 0.02) when compared to non-AAP users in the past 1 year. CONCLUSIONS: Caregivers of children with asthma in Canada may still lack skills for proper home management of asthma exacerbations. We found a higher number of ED visits and hospitalizations in those using an AAP compared to those who did not use an AAP. These data suggest that current AAPs may not be sufficient for home asthma management.

A novel double heterozygous Hb Fontainebleau/HbD Punjab hemoglobinopathy.

OBJECTIVES: To report the finding of a novel double heterozygous hemoglobinopathy, the coinheritance of Hb Fontainebleau (α-chain variant) with HbD-Punjab (ß-chain variant) discovered upon investigation of unexplained microcytosis in an infant. DESIGN AND METHODS: Hemoglobinopathy investigation was performed by high performance liquid chromatography (HPLC) using the ß-thalassemia Short Program on the Bio-Rad Variant II(TM) followed by gel electrophoresis at alkaline and acid pH (Sebia Hydrasys 2 Electrophoresis System) and molecular diagnostic testing. This study complied with our institutional board ethics requirements. RESULTS: HPLC and electrophoresis suggested a complex α- and ß-chain hemoglobinopathy with presumptive identification of the beta Hb variant as Hb D-Punjab. DNA sequencing analysis revealed the presence of a double heterozygous status for Hb Fontainebleau/Hb D-Punjab. CONCLUSIONS: In this paper we report the coinheritance of Hb Fontainebleau with Hb D-Punjab.

Albuterol aerosol delivered via metered-dose inhaler to intubated pediatric models of 3 ages, with 4 spacer designs.

OBJECTIVE: To determine the amount of albuterol, in various particle size ranges, delivered from a hydrofluoroalkane-propelled metered-dose inhaler (Airomir) in 3 models of pediatric intubation (ages 8 months, 4 years, and 16 years) using 4 types of aerosol reservoir: 3 spacers (ACE, AeroChamber HC MV, metal NebuChamber without 1-way valve) and 1 holding chamber (metal NebuChamber with 1-way valve). METHODS: Five reservoirs of each type were tested with albuterol sulfate delivered via metered-dose inhaler that delivers 100 microg of albuterol per actuation. Each reservoir was connected to an endotracheal tube (ETT) that corresponded to the given patient age (8 months = 4 French; 4 years = 5 French; 16 years = 7.5 French) and to a valved system that allowed connection of the ETT to a cascade impactor. Simulated tidal volumes representative of children of the given ages were passed through the reservoir. Both the cascade impactor and the ETT were enclosed within a 100% humidity, 37 degrees C environment. RESULTS: For the total amount of albuterol inhaled onto the impactor, and both the 1.1-4.7 microm and 1.1-3.3 microm inhaled fine-particle fractions, the NebuChamber-with-valve showed significantly greater drug delivery than the NebuChamber-without-valve, the AeroChamber HC MV, or the ACE (p < 0.001). Among the reservoirs without valves the NebuChamber showed significantly greater delivery than the AeroChamber HC MV or ACE (p < 0.001) for total drug deposition and for both the 1.1-4.7 microm and 1.1-3.3 microm fine-particle fractions. These results were consistent over all age groups. The AeroChamber HC MV had significantly greater delivery (total deposition) than the ACE (p < 0.001), except in the 4-year-old model. There were no significant differences between the AeroChamber HC MV and the ACE for either the 1.1-4.7 microm or the 1.1-3.3 microm fine-particle fraction. CONCLUSION: An aerosol reservoir with 1-way valve positioned between the spacer and the ETT improved the amount of inhaled albuterol 300-900%, compared to the other reservoirs.

Effects of positive end-expiratory pressure on oscillated volume during high frequency chest compression in children with cystic fibrosis.

OBJECTIVE: To investigate the effects of positive end-expiratory pressure (PEEP) on end-expiratory lung volume (EELV) and mean oscillated volume (V(osc)) during high frequency chest compression (HFCC). DESIGN: A clinic-based prospective intervention study. SETTING: Pulmonary function laboratory, University of Alberta, Edmonton, Alberta. POPULATION: Nine children with cystic fibrosis with little or no obstructive airway disease who were selected from the outpatient Cystic Fibrosis and Pediatric Pulmonary Clinics at the University of Alberta Hospital, Edmonton, Alberta. METHODS: Each child received HFCC alone (at 10 Hz with chest wall pressure of 8 cm H2O) and HFCC plus PEEP. A closed circuit spirometry system was used to measure HFCC- and PEEP-induced changes in EELV, expressed as per cent baseline functional residual capacity (FRC) measured using helium dilution. An isothermic chamber permitted measurement of V(osc). RESULTS: HFCC caused a significant 9% decrease in EELV. Adding 2.0 +/- 0.3 cm H2O of PEEP increased EELV back to at least the FRC level. With HFCC alone, Vosc was significantly lower during spontaneous expiration than during spontaneous inspiration, but adding PEEP to HFCC increased V(osc), especially during spontaneous expiration. CONCLUSIONS: Adding PEEP during HFCC prevents the decrease in EELV and increases V(osc). Therefore, PEEP may improve HFCC-induced mucus clearance in children with cystic fibrosis.

In vitro effect of a holding chamber on the mouth-throat deposition of QVAR (hydrofluoroalkane-beclomethasone dipropionate).

Experimental work has been conducted on the effect of an add-on holding chamber (Aerochamber) on the characteristics of deposition in a mouth-throat model using 100-microg hydrofluoroalkane-beclomethazone dipropionate (QVAR) metered dose inhalers at inhalation flow rates of 28.3, 60, and 90 L/min. A filter or cascade impactor downstream of the mouth-throat collected aerosol not depositing. The results emphasize the important well documented effect of a valved holding chamber (VHC), in reducing drug deposition in the mouth-throat. This reduction is largest (24% of nominal dose) at the lowest flow rate tested, becoming insignificant at 60 L/min. Total amount of drug delivered distal to the mouth-throat increases with flow rate both with and without a holding chamber, increasing from 42% to 69% of the nominal dose without a VHC as the inspiratory flow rate increases from 28.3 to 90 L/min. The effect of the holding chamber on post mouth-throat delivery was small, reaching significance only at the highest flow rate (90 L/min), where an increase by 8% of the nominal dose was observed. No significant effect on MMAD of beclomethasone-dipropionate occurred when the holding chamber was used. An argument based on the interaction between induced turbulence and particle inertia is used to shed light on the above observations.

Low bone mineral density in cystic fibrosis patients.

The goals of this practice-based, observational study were to describe the prevalence of low bone mineral density in patients at the Edmonton Cystic Fibrosis Centre, and to determine if body mass index and previous systemic corticosteroid use of over one month's duration were predictors of low bone mineral density. One hundred and thirteen pediatric and adult patients were studied. Bone mineral density of the lumbar spine region was measured using dual-energy X-ray absorptiometry. A total of 42.5% of patients had a bone mineral density Z-score of less than -1 standard deviation. Low bone mineral density was apparent at nine to 12 years of age, and was most evident in the 20- to 34-year-old group. All but one patient under age 20 with a Z-score of less than -2.5 also had a body mass index below the fifth percentile. A low Z-score was also associated with previous systemic corticosteroid use of over one month's duration (relative risk 1.81, p=0.003). We conclude that low bone mineral density is common in cystic fibrosis patients. Low body mass index percentiles may be used to identify children and adolescents at risk of low bone mineral density. These patients may benefit from aggressive nutrition therapy. Systemic corticosteroid use should be assessed carefully, as it is a risk factor for low bone mineral density.

Newborn screening for cystic fibrosis in Alberta: Two years of experience.

On April 1, 2007, Alberta became the first province in Canada to introduce cystic fibrosis (CF) to its newborn screening program. The Alberta protocol involves a two-tier algorithm involving an immunoreactive trypsinogen measurement followed by molecular analysis using a CF panel for 39 mutations. Positive screens are followed up with sweat chloride testing and an assessment by a CF specialist. Of the 99,408 newborns screened in Alberta during the first two years of the program, 221 had a positive CF newborn screen. The program subsequently identified and initiated treatment in 31 newborns with CF. A relatively high frequency of the R117H mutation and the M1101K mutation was noted. The M1101K mutation is common in the Hutterite population. The presence of the R117H mutation has created both counselling and management dilemmas. The ability to offer CF transmembrane regulator full sequencing may help resolve diagnostic dilemmas. Counselling and management challenges are created when mutations are mild or of unknown clinical significance.