Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with ...CF who underwent NBS has not been well described.
To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS.
The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up.
Cystic fibrosis.
Attained weight and length for age and World Health Organization normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori).
Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean z score, -0.15; 95% CI, -0.27 to -0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean z score, -0.56; 95% CI, -0.70 to -0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake.
Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.
The cystic fibrosis transmembrane regulator protein (CFTR) is an ion channel in the apical surface of epithelial membranes that regulates other ion channels. Dysfunction of CFTR leads to the clinical ...entity of CF when mutations in CFTR are inherited in an autosomal recessive fashion. Although airway obstruction, inflammation, and infection are usually the most serious consequences of CFTR dysfunction because they lead to respiratory failure, CFTR dysfunction affects the intestinal tract and the pancreatic and hepatobiliary ducts in a similar fashion, leading to significant morbidity. This review outlines pathophysiology and common gastrointestinal ailments in the CF population along with current medical and surgical management.
The article reviews advances in gastrointestinal aspects of cystic fibrosis (CF) published in the literature over the past year, and highlights new and interesting research.
Animal models can be used ...to understand the pathophysiology of gastrointestinal complications in CF. The CF mouse is useful for studying distal intestinal obstruction, dysmotility and dysbiosis, and the CF pig model has helped us better understand meconium ileus and pancreatic and hepatobiliary secretory problems. Studies in humans help elucidate the evolution of pancreatic insufficiency, how reflux may lead to lung disease, problems with intestinal dysmotility, mechanisms leading to pancreatitis and the increased prevalence of gastrointestinal cancer. Biomarkers are shedding light on CF-related liver disease. Rectal biopsies can help in diagnosis and in studying new drugs for CF.
Gastrointestinal complications of CF are likely to be seen with increasing frequency as patients with CF lead longer lives. CF animal models and modern research techniques are providing new insights into extrapulmonary complications. CF clinicians should be familiar with diagnosis and management of common gastrointestinal complications and should build bridges with specialists so that referrals can be made when needed.
Background and Aims
The effect of the cystic fibrosis transmembrane conductance regulator protein (CFTR) defect in pancreatic insufficient (PI) patients with cystic fibrosis (CF) on the ...gastrointestinal pH profile is poorly defined. Adequate and efficient neutralization of the gastric acidity in the duodenum is important for nutrient absorption and timely release of pancreatic enzyme replacement therapy (PERT). We utilized a wireless motility capsule (WMC) to study intestinal pH profile and gastrointestinal transit profile in CF subjects.
Methods
WMC studies were done on ten adult CF patients with PI while off acid suppression medication and ten age, gender and BMI matched healthy controls. Mean pH over 1 min increments and area under the pH curve over 5 min increments was calculated for the first hour post gastric emptying. Paired t-test was used to compare means of the pH recordings, transit profiles and analysis of time interval required to reach and maintain pH >5.5 and 6.0.
Results
A statistically significant difference was observed between mean pH values during the first 23 min of small bowel transit (
p
< 0.05). In CF subjects, there was a significant delay in time interval required to reach and sustain pH 5.5 and pH 6.0 (
p
< 0.001), which is required for PERT dissolution. Only small bowel transit in CF subjects was noted to be significantly delayed (
p
= 0.004) without a compensatory increase in whole gut transit time.
Conclusions
We have demonstrated a significant delay in the small intestinal transit and a deficient buffering capacity required to neutralize gastric acid in the proximal small bowel of patients with CF.
Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.
To evaluate ivacaftor in a ...postapproval setting and determine mechanism of action and response of clinically relevant markers.
We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor.
Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs ...in at least 85% of people with CF.
PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months.
Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV
(ppFEV
), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms.
Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV
improved 9.76 percentage points (95% confidence interval CI, 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline.
ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV
in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).
Background
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gating mutation
G551D
prevents sufficient ion transport due to reduced channel-open probability. Ivacaftor, an oral CFTR ...potentiator, increases the channel-open probability.
Aim
To further analyze improvements in weight and body mass index (BMI) in two studies of ivacaftor in patients aged ≥6 years with CF and the
G551D
mutation.
Methods
Patients were randomized 1:1 to ivacaftor 150 mg or placebo every 12 h for 48 weeks. Primary end point (lung function) was reported previously. Other outcomes included weight and height measurements and CF Questionnaire-Revised (CFQ-R).
Results
Studies included 213 patients (aged ≤ 20 years,
n
= 105; aged > 20 years,
n
= 108). In patients ≤20 years, adjusted mean change from baseline to week 48 in body weight was 4.9 versus 2.2 kg (ivacaftor vs. placebo,
p
= 0.0008). At week 48, change from baseline in mean weight-for-age
z
-score was 0.29 versus −0.06 (
p
< 0.0001); change in mean BMI-for-age
z
-score was 0.26 versus −0.13 (
p
< 0.0001). In patients >20 years, adjusted mean change from baseline to week 48 in body weight was 2.7 versus −0.2 kg (
p
= 0.0003). Mean BMI change at week 48 was 0.9 versus −0.1 kg/m
2
(
p
= 0.0003). There was no linear correlation evident between changes in body weight and improvements in lung function or sweat chloride. Significant CFQ-R improvements were seen in perception of eating, body image, and sense of ability to gain weight.
Conclusions
Nutritional status improved following treatment with ivacaftor for 48 weeks.
The natural history and the possible changes of celiac disease (CD) prevalence over time are still unclear.
1) To establish whether loss of tolerance to gluten may occur at any age; 2) to investigate ...possible changes of CD prevalence over time; and 3) to investigate CD-related co-morbidities.
We analyzed 3,511 subjects with matched samples from 1974 (CLUE I) and 1989 (CLUE II). To avoid a selection bias regarding survival, we also screened 840 CLUE I participants who deceased after the 1974 survey. Outcome measure. CD autoimmunity (positivity to auto-antibodies) over time.
CD autoimmunity was detected in seven subjects in 1974 (prevalence 1:501) and in an additional nine subjects in 1989 (prevalence 1:219). Two cases of CD autoimmunity were found among the 840 subjects deceased after CLUE I. Compared to controls, untreated CD subjects showed increased incidence of osteoporosis and associated autoimmune disorders, but they did not reach statistical significance.
During a 15-year period CD prevalence increased 2-fold in the CLUE cohort and 5-fold overall in the US since 1974. The CLUE study demonstrated that this increase was due to an increasing number of subjects that lost the immunological tolerance to gluten in their adulthood.
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