RESUMEN
Rationale: 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. Objectives: 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. Methods: 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 FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: 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, ppFEV1 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. Conclusions: 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 ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).
Asunto(s)
Fibrosis Quística , Adulto , Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Niño , Agonistas de los Canales de Cloruro/uso terapéutico , Cloruros/análisis , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Combinación de Medicamentos , Humanos , Indoles , Mutación , Estudios Prospectivos , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Resultado del TratamientoRESUMEN
BACKGROUND: Alteration of the airway microbiota is a hallmark of cystic fibrosis (CF) pulmonary disease. Dysfunction of cystic fibrosis transmembrane regulator (CFTR) in the intestine also promotes changes in local microbiota such as small intestinal bacterial overgrowth (SIBO), which is common in CF. We evaluated whether therapy with the CFTR modulator combination lumacaftor/ivacaftor (luma/iva) has a beneficial impact on SIBO as measured by breath testing (BT). METHODS: A multicenter longitudinal study of CFTR-dependent disease profiling (NCT02477319) included a prospective evaluation for SIBO by BT. Tidal breath samples were collected after fasting and 15, 30, 45, 60, 90, and 120 minutes after ingestion of glucose, before and 1 month after subjects initiated luma + iva. RESULTS: Forty-two subjects enrolled in the sub-study (mean age = 23.3 years; 51% female; 9.5% Latinx); 38 completed a hydrogen BT at both time points, of which 73.7% had a positive BT before luma/iva (baseline) and 65.8% had a positive test after luma/iva ( P = 0.44); shifts from negative to positive were also seen. Use of azithromycin (63.1%) and inhaled antibiotics (60.5%) were not associated with positive BT. Acid-blocking medications were taken by 73% of those with a negative BT at baseline and by 35% with a positive baseline BT ( P = 0.04). CONCLUSION: We found a high rate of positive hydrogen breath tests in individuals with CF, confirming that SIBO is common. One month of luma/iva did not significantly change the proportion of those with positive breath hydrogen measurements.
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Pruebas Respiratorias , Fibrosis Quística , Glucosa , Hidrógeno , Adulto , Aminofenoles/uso terapéutico , Aminopiridinas , Benzodioxoles , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Glucosa/análisis , Humanos , Hidrógeno/análisis , Estudios Longitudinales , Masculino , Mutación , Quinolonas , Adulto JovenRESUMEN
OBJECTIVES: To identify factors that increase the risk of gastrointestinal-related (GI-related) hospitalization of infants with cystic fibrosis (CF) during the first year of life. METHODS: The Baby Observational and Nutrition Study was a longitudinal, observational cohort of 231 infants diagnosed with CF by newborn screening. We performed a post-hoc assessment of the frequency and indications for GI-related admissions during the first year of life. RESULTS: Sixty-five participants had at least one admission in the first 12âmonths of life. High pancreatic enzyme replacement therapy (PERT) dosing (>2000âlipase units/kg per meal; hazard ratio [HR]â=â14.75, Pâ=â0.0005) and use of acid suppressive medications (HRâ=â4.94, Pâ=â0.01) during the study period were positively associated with subsequent GI-related admissions. High levels of fecal calprotectin (fCP) (>200âµg/g) and higher relative abundance of fecal Klebsiella pneumoniae were also positively associated with subsequent GI-related admissions (HRâ=â2.64, Pâ=â0.033 and HRâ=â4.49, Pâ=â0.002, respectively). During the first 12âmonths of life, participants with any admission had lower weight-for-length z scores (WLZ) (Pâ=â0.01). The impact of admission on WLZ was particularly evident in participants with a GI-related admission (Pâ<â0.0001). CONCLUSIONS: Factors associated with a higher risk for GI-related admission during the first 12âmonths include high PERT dosing, exposure to acid suppressive medications, higher fCP levels, and/or relative abundance of fecal K pneumoniae early in life. Infants with CF requiring GI-related hospitalization had lower WLZ at 12âmonths of age than those not admitted as well as those admitted for non-GI-related indications.
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Fibrosis Quística , Estudios de Cohortes , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Terapia de Reemplazo Enzimático , Hospitalización , Humanos , Lactante , Recién Nacido , Tamizaje NeonatalRESUMEN
OBJECTIVES: The aim of the study is to describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal (GI) symptoms. METHODS: We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit. Diaries with infant diet, pancreatic enzyme replacement therapy (PERT) dosing, stool frequency and consistency, and pain were completed by a parent/guardian for 3 days before each visit. RESULTS: Two hundred and thirty-one infants were enrolled in the main study; 205 of these met criteria for pancreatic insufficiency (PI). PERT dose between birth and 6 months was on average 1882âLU/kg per meal (range: 492-3727) and was similar between 6 and 12 months (mean: 1842âLU/kg per mean, range: 313-3612). PERT dose had a weak, negative association with weight z score at 3 and 6 months (râ=â-0.16, 95% confidence interval [CI] -0.29 to -0.02 and râ=â-0.18, 95% CI -0.31 to -0.04, respectively) but not at 12 months. There was not a clear relationship between PERT dosing and number of stools per day, stool consistency or pain. One hundred and forty-four infants (70%) were placed on acid suppression medication. Weight z score mean was 0.37 higher in infants using proton pump inhibitors (PPIs) exclusively versus those using histamine-2 blockers exclusively (95% CI -0.02 to 0.76, Pâ=â0.06). CONCLUSIONS: We did not observe that centers with a higher PERT dosing strategy yielded greater clinical benefit than dosing at the lower end of the recommended range.
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Fibrosis Quística/terapia , Terapia de Reemplazo Enzimático/métodos , Insuficiencia Pancreática Exocrina/terapia , Antropometría , Desarrollo Infantil/efectos de los fármacos , Estudios de Cohortes , Fibrosis Quística/complicaciones , Relación Dosis-Respuesta a Droga , Insuficiencia Pancreática Exocrina/etiología , Humanos , Lactante , Recién Nacido , Tamizaje Neonatal/métodos , Estudios Prospectivos , Resultado del Tratamiento , Estados UnidosRESUMEN
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.
Asunto(s)
Aminofenoles/administración & dosificación , Regulador de Conductancia de Transmembrana de Fibrosis Quística/agonistas , Fibrosis Quística/tratamiento farmacológico , Moduladores del Transporte de Membrana/administración & dosificación , Mutación , Estado Nutricional/efectos de los fármacos , Quinolonas/administración & dosificación , Aumento de Peso/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Niño , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Método Doble Ciego , Esquema de Medicación , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Fenotipo , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
RATIONALE: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. OBJECTIVES: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. METHODS: 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, ß-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. CONCLUSIONS: 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.
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Aminofenoles/farmacología , Fibrosis Quística/tratamiento farmacológico , Intestino Delgado/efectos de los fármacos , Pulmón/efectos de los fármacos , Quinolonas/farmacología , Fármacos del Sistema Respiratorio/farmacología , Adolescente , Adulto , Aminofenoles/uso terapéutico , Biomarcadores/metabolismo , Niño , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/microbiología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado/efectos de los fármacos , Marcadores Genéticos , Hospitalización/estadística & datos numéricos , Humanos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Intestino Delgado/metabolismo , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/fisiopatología , Masculino , Microbiota/efectos de los fármacos , Depuración Mucociliar/efectos de los fármacos , Mutación , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/diagnóstico , Infecciones por Pseudomonas/prevención & control , Pseudomonas aeruginosa/aislamiento & purificación , Quinolonas/uso terapéutico , Fármacos del Sistema Respiratorio/uso terapéutico , Esputo/metabolismo , Esputo/microbiología , Sudor/efectos de los fármacos , Sudor/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/deficiencia , Fibrosis Quística/complicaciones , Enfermedades Gastrointestinales/patología , Conductos Biliares Extrahepáticos/patología , Tracto Gastrointestinal/patología , Humanos , Conductos Pancreáticos/patologíaRESUMEN
PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.
Asunto(s)
Fibrosis Quística/complicaciones , Fibrosis Quística/fisiopatología , Enfermedades del Sistema Digestivo/etiología , Enfermedades del Sistema Digestivo/fisiopatología , Animales , Fibrosis Quística/patología , Enfermedades del Sistema Digestivo/patología , Modelos Animales de Enfermedad , Disbiosis , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/fisiopatología , Humanos , Ileus/etiología , Ileus/fisiopatología , Obstrucción Intestinal/etiología , Obstrucción Intestinal/fisiopatología , Hepatopatías/etiología , Hepatopatías/fisiopatología , Meconio , Ratones , Enfermedades Pancreáticas/etiología , Enfermedades Pancreáticas/fisiopatología , Pronóstico , Recto/patología , Recto/fisiopatología , PorcinosRESUMEN
OBJECTIVES: Patients with inflammatory bowel disease (IBD) are at risk for vitamin and mineral deficiencies because of long-term inflammation in the gut mucosa and decreased oral intake. The aim of the study is to investigate the prevalence of vitamin and zinc deficiencies in patients with newly diagnosed IBD compared with a control group. METHODS: This is a retrospective chart review of all of the patients diagnosed as having IBD from 2006 to 2010, ages 1 to 18 years. Patients who had fat- and water-soluble vitamins (A, E, D 25-OH, folate, and B(12)) and zinc levels obtained at time of diagnosis were included in the study. A total of 61 patients with IBD and 61 age- and sex-matched controls were included. RESULTS: None of the 61 patients with IBD had folate or vitamin B12 deficiency. Vitamin D deficiency was found in 62% of the patients, vitamin A deficiency in 16%, vitamin E deficiency in 5%, and zinc deficiency in 40%. The control group had vitamin D and E and zinc deficiency in 75%, 8%, and 19% patients, respectively. CONCLUSIONS: We conclude that vitamin B12 and folate deficiencies are rare in children with newly diagnosed IBD in the United States and we question whether routine monitoring is warranted. Vitamin A and zinc deficiency are common in patients with newly diagnosed IBD and levels should be assessed at the time of diagnosis so that enteral repletion can commence. Vitamin D deficiency is common in all of the children in the Buffalo, NY, area, and routine screening for this deficiency is warranted.
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Avitaminosis/etiología , Enfermedades Carenciales/etiología , Enfermedades Inflamatorias del Intestino/complicaciones , Minerales/sangre , Estado Nutricional , Vitaminas/sangre , Zinc/sangre , Adolescente , Avitaminosis/sangre , Avitaminosis/epidemiología , Estudios de Casos y Controles , Niño , Enfermedades Carenciales/sangre , Enfermedades Carenciales/epidemiología , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Masculino , Prevalencia , Estudios Retrospectivos , Zinc/deficienciaRESUMEN
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.
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Endoscopía Capsular/instrumentación , Fibrosis Quística/metabolismo , Intestinos/química , Adolescente , Adulto , Femenino , Motilidad Gastrointestinal , Humanos , Concentración de Iones de Hidrógeno , Masculino , Proyectos Piloto , Adulto JovenRESUMEN
Previous wireless motility capsule (WMC) studies demonstrated decreased small intestinal pH in people with CF (PwCF) however the data is lacking on the colonic pH profile. We re-analyzed previously published WMC data to determine colonic pH/bicarbonate concentration and single cell RNA sequencing (sc-RNAseq) to examine the normal expression of acid-base transporters in the colon/rectum.CF patients showed significantly lower pH and bicarbonate concentration values, particularly in the distal rectosigmoid region. There was no difference in colonic motility parameters between CF and non-CF subjects. SLC26A3 is highly expressed bicarbonate transporter in the colon and rectum, more so than CFTR. While dysmotility can alter intraluminal pH, observed changes likely originate from alterations in intestinal ion transport rather than colonic dysmotility. SLC26A3 is abundantly expressed in the human colon and rectum and may be a therapeutic target for restoration of bicarbonate transport. These findings may help better understand the gastrointestinal symptoms in PwCF.
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Fibrosis Quística , Humanos , Adulto , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Bicarbonatos/metabolismo , Intestino Delgado/metabolismo , Colon/metabolismo , Concentración de Iones de Hidrógeno , Motilidad GastrointestinalRESUMEN
BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear. METHODS: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex. RESULTS: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change. CONCLUSIONS: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.
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Fibrosis Quística , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Calidad de Vida , Estudios Prospectivos , Aminofenoles , Benzodioxoles/uso terapéutico , Estreñimiento , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Elastasa Pancreática , MutaciónRESUMEN
BACKGROUND: Concerns related to stool consistency are common in the first year of life among children with cystic fibrosis (CF). However, normal stool patterns for infants with CF have not been described. METHODS: Secondary analysis was completed from the previously described BONUS cohort which followed 231 infants with CF through the first 12 months of life. Pain, stool category, stool frequency, feeding type, PERT dose, acid suppression medication, antibiotics usage, stool softener usage and fecal calprotectin were described at 3, 6, and 12 months. Repeated measure ANOVA was used to test the difference in mean stool number. Generalized linear mixed models were used to investigate the relationship between stool characteristics and various factors. RESULTS: The frequency of constipation was stable throughout the first year of life (10-13%) while watery stool significantly decreased from 21.3% at 3 months to 5.8% at 12 months (p=<0.001). The number of stools at months 6 (mean=2.40) and 12 (mean=2.50) are significantly lower than in month 3 (mean=2.83), p<0.025. Exclusive breast feeding was associated with an increased risk for constipation (OR=2.64 [1.60-4.37], p = 0.002) while exclusive formula feeding and acid suppression was associated with decreased risk for constipation (OR=0.40 [0.26-0.61], p=<0.0001 and OR=0.59 [0.39-0.89], p = 0.01 respectively). Pain was not significantly associated with stool consistency. CONCLUSION: Stool frequency and consistency evolves in infant with CF in a fashion similar to that reported in non-CF infants over the first year. Constipation was not associated with pain and was less common among infants receiving acid suppression or exclusively formula feeding.
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Fibrosis Quística , Antibacterianos , Lactancia Materna , Niño , Estreñimiento/diagnóstico , Estreñimiento/epidemiología , Estreñimiento/etiología , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/epidemiología , Heces , Femenino , Humanos , Lactante , Complejo de Antígeno L1 de LeucocitoRESUMEN
Rationale: The combination of lumacaftor (LUM) and ivacaftor (IVA) is an approved CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator treatment for homozygous F508del patients with CF.Objectives: To evaluate the effectiveness of LUM/IVA in children (6 yr or more) and adults (more than 18 yr) in a postapproval setting.Methods: This longitudinal cohort study, performed at 38 centers in the U.S. CF Therapeutics Development Network, enrolled homozygous F508del patients with CF ages 6 years old and older with no prior exposure to LUM/IVA. Study assessments were performed at baseline and at 1, 3, 6, and 12 months after LUM/IVA initiation.Results: A total of 193 patients initiated LUM/IVA, and 85% completed the study through 1 year. Baseline mean percent-predicted forced expiratory volume in 1 second (ppFEV1) was 85 (standard deviation, 22.4) in this cohort. No statistically significant change in ppFEV1 was observed from baseline to any of the follow-up time points, with a mean absolute change at 12 months of -0.3 (95% confidence interval [CI], -1.8 to 1.2). Body mass index improved from baseline to 12 months (mean change, 0.8 kg/m2; P < 0.001). Sweat chloride decreased from baseline to 1 month (mean change, -18.5 mmol/L; 95% CI, -20.7 to -16.3; P < 0.001), and these reductions were sustained through the study period. There were no significant changes in hospitalization rate for pulmonary exacerbations and Pseudomonas aeruginosa infection status with treatment.Conclusions: In this real-world multicenter cohort of children and adults, LUM/IVA treatment was associated with significant improvements in growth and reductions in sweat chloride without statistically significant or clinically meaningful changes in lung function, hospitalization rates, or P. aeruginosa infection.Clinical trial registered with www.clinicaltrials.gov (NCT02477319).
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Aminofenoles , Aminopiridinas , Benzodioxoles , Fibrosis Quística , Quinolonas , Adolescente , Adulto , Niño , Estudios de Cohortes , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Volumen Espiratorio Forzado , Humanos , Estudios Longitudinales , Masculino , Mutación , Adulto JovenRESUMEN
Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.
Asunto(s)
Agonistas de los Canales de Cloruro/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Combinación de Medicamentos , Humanos , Estudios Observacionales como AsuntoRESUMEN
Importance: 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. Objective: To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS. Design, Setting, and Participants: 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. Exposure: Cystic fibrosis. Main Outcome and Measures: 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). Results: 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. Conclusions and Relevance: 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.
Asunto(s)
Fibrosis Quística/diagnóstico , Tamizaje Neonatal/métodos , Aumento de Peso/fisiología , Antropometría/métodos , Peso al Nacer/fisiología , Estatura/fisiología , Peso Corporal/fisiología , Lactancia Materna , Fibrosis Quística/fisiopatología , Estudios de Seguimiento , Edad Gestacional , Crecimiento/fisiología , Humanos , Lactante , Fenómenos Fisiológicos Nutricionales del Lactante/fisiología , Recién Nacido , Estado Nutricional , Apoyo Nutricional/métodosRESUMEN
OBJECTIVES: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator. METHODS: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule (n=10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment. RESULTS: One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying (P<0.05). Area under the pH curve analyses indicate increased bicarbonate mass (P<0.05 for select 5 min intervals and all segments >30 min); mean weight gain was 1.1 kg (P=0.08). No difference in abdominal pain or regional transit times was seen. CONCLUSIONS: CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement.