The foregut in cystic fibrosis.

The aerodigestive organs share a kindred embryologic origin that allows for a more complete explanation as to how the foregut can remain a barrier to normalcy in people with cystic fibrosis (pwCF). The structures of the aerodigestive tract include the nasopharynx, the oropharynx, the hypopharynx, the esophagus, the stomach, as well as the supraglottic, glottic, and subglottic tubular airways (including the trachea). Additional gastrointestinal (GI) luminal/alimentary organs of the foregut include the duodenum. Extraluminal foregut structures include the liver, the gall bladder, the biliary tree, and the pancreas. There are a variety of neurologic controls within these complicated anatomic compartments to separate the transit of food and liquid from air. These structures share the same origin from the primitive foregut/mesenchyme. The vagus nerve is a critical structure that unites respiratory and digestive functions. This article comments on the interconnected nature of cystic fibrosis and the GI tract. As it relates to the foregut, this has been typically treated as simple "reflux" as the cause of worsened lung function in pwCF. That terms like gastroesophageal reflux (GER), gastroesophageal reflux disease (GERD), heartburn, and regurgitation are used interchangeably to reflect pathology further complicates matters; we offer a more physiologically accurate term called "GI-related aspiration" or "GRASP." Broadly, this term reflects that aspiration of foregut contents from the duodenum through the stomach to the esophagus, into the pharynx and the respiratory tree in pwCF. As a barrier to normalcy in pwCF, GRASP is fundamentally two disease processes-GERD and gastroparesis-that likely contribute most to the deterioration of lung disease in pwCF. In the modulator era, successful GRASP management will be critical, particularly in those post-lung transplantation (LTx), only through successful management of both GERD and gastroparesis. Standardization of clinical management algorithms for GRASP in CF-related GRASP is a key clinical and research gap preventing normalcy in pwCF; what exists nearly exclusively addresses surgical evaluations or offers guidance for the management of GI symptoms alone (with unclear parameters for respiratory disease considerations). We begin first by describing the result of GRASP damage to the lung in various stages of lung disease. This is followed by a discussion of the mechanisms by which the digestive tract can injure the lungs. We summarize what we anticipate future research directions will be to reduce the impact of GRASP as a barrier to normalcy in pwCF.

Estimating minimal clinically important difference (MCID) for gastrointestinal symptoms in cystic fibrosis.

BACKGROUND: Minimal clinically important difference (MCID) is important to establish as a meaningful outcome in research when using patient reported outcome measures (PROMs). We determined the MCID using the distribution-based approach for three measurements used as part of the GALAXY study, which is an observational prospective study on gastrointestinal (GI) symptoms in cystic fibrosis (CF). METHODS: Four hundred and two persons with cystic fibrosis (PwCF) participated in the GALAXY study, all with baseline values available for all questionnaires. Mean age was 20.9 years (2.1- 61.1) with 75 females and 94 males under the age of 18 (42.04 %) and 118 females and 115 males aged 18 or older (57.99 %). MCID was measured for Patient Assessment of Constipation Symptoms (PAC-SYM), Patient Assessment of Upper Gastrointestinal Symptoms (PAGI-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL) and their subscales. Two distribution-based approaches, defined as multiplications of the standard deviation (SD) or standard error of the mean (SEM), were used to approximate the MCID. RESULTS: The two distribution-based approaches for determining the MCID estimates produced comparable results in trends in MCIDs across the subscales and total scores. In general, MCID estimates of subscales for all three measurements were higher than their total score MCIDs. The one-half SD- and SEM-based MCID estimates for total scores of each questionnaire are as follows: PAC-SYM: 0.26 and 0.14; PAGI-SYM: 0.32 and 0.15; PAC-QOL: 0.27 and 0.18, respectively. CONCLUSION: This paper establishes initial MCIDs estimated by the distribution-based approach for the PAC-SYM, PAGI-SYM and PAC-QOL that can now be used to evaluate interventional studies that may impact gastrointestinal symptoms in PwCF.

Essential Fatty Acid Deficiency Is Common After Total Pancreatectomy and Islet Autotransplantation.

OBJECTIVES: Total pancreatectomy and islet autotransplantation (TPIAT) for pancreatitis may induce risk for essential fatty acid deficiency (EFAD) due to exocrine pancreatic insufficiency and intestinal alterations. The prevalence of EFAD post-TPIAT is currently unknown. METHODS: We abstracted essential fatty acid (EFA) profiles (n = 332 samples) for 197 TPIAT recipients (72% adult, 33% male). Statistical analyses determined the prevalence of, and associations with, EFAD post-operatively. EFAD was defined as a Triene-to-Tetraene ratio ≥0.05 if <18 years old, or ≥0.038 if ≥18 years old. RESULTS: Prevalence of EFAD was 33%, 49%, and 53.5% at 1, 2, and ≥3 years. At 1-year post-TPIAT, older age at transplant ( P = 0.03), being an adult versus a child ( P = 0.0024), and obstructive etiology ( P = 0.0004) were significant predictors of EFAD. Only 6% of children had EFAD 1-year post-TPIAT versus 46% of adults. The alpha-linolenic acid levels were lower with lower body mass index at transplant ( P = 0.011). EFAD was associated with the presence of other intestinal diseases ( P < 0.0001). CONCLUSIONS: One-third of individuals had EFAD 1-year post-TPIAT, highlighting the need for systematic monitoring. Older age at transplant increased risk and adults were more affected than children. Other diagnoses affecting intestinal health may further increase risk for EFAD.

Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Change in Health-Related Quality of Life in Youth with Chronic Hepatitis B Living in North America: A 5-Year Cohort Study.

BACKGROUND: Greater hepatitis-related symptomology is associated with lower health-related quality-of-life (HRQoL) among untreated youth with chronic hepatitis B (CHB). How HRQoL changes over time in this population is unknown. METHODS: Children from 7 hepatology centers in North America positive for hepatitis B surface antigen, not taking anti-viral therapy, were enrolled in the Hepatitis B Research Network. A validated self-report HRQoL measure, the Child Health Questionnaire Child Report (CHQ-CF87), was completed annually by participants 10-17 years, with demographic variables, liver disease symptoms, and laboratory tests. Linear mixed-effects models were used to evaluate the 10 CHQ-CF87 subscale scores over 5 years among participants who completed the CHQ-CF87 at least twice. RESULTS: Participants (N = 174) completed the CHQ-CF87 a median of 4 times. Median age was 12 years (interquartile range: 10-14) at baseline; 60% were female, 79% Asian, and 47% adopted. The CHQ-CF87 subscale scores were high at baseline (median range: 75.4-100) and did not differ by time point, except for the Family Activities subscale (mean [95% CI]: 82.3 [79.8-84.8] at baseline; 90.8 [86.1-94.6] week 240). Most subscale scores lacked sufficient individual-level variability in change over time to evaluate predictors. Being White versus Asian predicted a more favorable change in Behavior (6.5 [95% CI: 2.0-11.0]). Older age predicted less favorable change in Mental Health (-0.8 [95% CI: -1.36 to -0.23] per year). Changes in liver enzymes and hepatitis B antigens, DNA, or symptom count were not related to changes in these subscale scores. CONCLUSION: HRQoL was generally good and consistent across 5 years in youth with CHB.

Bone health in children with recurrent and chronic pancreatitis: A multi-center cross sectional analysis.

BACKGROUND/OBJECTIVES: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied. METHODS: This retrospective study was performed at three sites and included data from INSPPIRE-2. RESULTS: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < -2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < -2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively). CONCLUSION: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted.

Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE.

OBJECTIVES: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. METHODS: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. RESULTS: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. CONCLUSIONS: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.

Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease.

BACKGROUND: This study examines whether heterogeneous (HTG) pattern on liver ultrasound (US) identifies children at risk for advanced cystic fibrosis liver disease (aCFLD). METHODS: Prospective 6-year multicenter case-controlled cohort study. Children with pancreatic insufficient cystic fibrosis (CF) aged 3-12 years without known cirrhosis underwent screening US. Participants with HTG were matched (by age, Pseudomonas infection status and center) 1:2 with participants with normal (NL) US pattern. Clinical status and laboratory data were obtained annually and US bi-annually for 6 years. Primary endpoint was development of nodular (NOD) US pattern consistent with aCFLD. RESULTS: 722 participants underwent screening US, with 65 HTG and 592 NL. Final cohort included 55 HTG and 116 NL with ≥ 1 follow-up US. ALT, AST, GGTP, FIB-4, GPR and APRI were higher, and platelets were lower in HTG compared to NL. HTG had a 9.5-fold increased incidence (95% confidence interval [CI]:3.4, 26.7, p<0.0001, 32.7% vs 3.4%) of NOD versus NL. HTG had a sensitivity of 82% and specificity of 75% for subsequent NOD. Negative predictive value of a NL US for subsequent NOD was 96%. Multivariate logistic prediction model that included baseline US, age, and log(GPR) improved the C-index to 0.90 compared to only baseline US (C-index 0.78). Based on survival analysis, 50% of HTG develop NOD after 8 years. CONCLUSIONS: Research US finding of HTG identifies children with CF with a 30-50% risk for aCFLD. A score based on US pattern, age and GPR may refine the identification of individuals at high risk for aCFLD. CLINICAL TRIAL REGISTRATION: Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF: NCT 01,144,507 (observational study, no consort checklist).

Need to study simplification of gastrointestinal medication regimen in cystic fibrosis in the era of highly effective modulators.

INTRODUCTION: The success of highly effective modulator therapy (HEMT) has led to consideration of simpler regimens for people with CF (PwCF) with opportunities to modify burdensome regimens. Despite the intuitive appeal of discontinuing chronic therapies no longer necessary, this process should be pursued systematically to ensure safety, adherence, and validate patient-centered preferences. We designed a questionnaire to determine the state of use of acid-suppressive medications (ASM) and pancreatic enzyme therapy (PERT), current self-withdrawal and provider-directed withdrawal practices, and interest in a standardized withdrawal study. METHODS: In collaboration with CF Foundation (CFF), a questionnaire was developed and distributed to members of Community Voice (CV, comprised of PwCF and their loved ones), and CF providers regarding the need to study simplifying the gastrointestinal (GI) regimen for PwCF on HEMT. RESULTS: Approximately 20-40% of CV or CF providers have decreased or stopped ASM for those on HEMT. For PERT, CV and CF providers have decreased dose (34%-48% and approximately 25%, respectively) more often than having stopped it altogether (13%-24% and 3%-12%, respectively). Cumulatively, there is interest in pursuing research in this area (86% CV and 89% CF providers) and willingness to enroll in such a study (80% CV and 89% CF providers). CONCLUSION: Systematically studying the withdrawal of common GI medications, ASM and PERT, is important to CV and CF providers. Decreases in dosing and withdrawal are already taking place without evidence to support this practice. This questionnaire is the first step in designing a GI medication simplification study in PwCF on HEMT.

Multicenter prospective study showing a high gastrointestinal symptom burden in cystic fibrosis.

BACKGROUND AND AIMS: People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF). METHODS: Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models. RESULTS: Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus <18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47). CONCLUSION: GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions. CLINICALTRIALS: GOV: NCT03801993.

Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI.

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.

Updates in Nutrition Management of Cystic Fibrosis in the Highly Effective Modulator Era.

Attainment and maintenance of good nutrition has been an important aspect of management in cystic fibrosis (CF) for decades. In the era of highly effective modulator therapy for CF, the quality of the nutrients we recommend is increasingly important. Our therapy must support our patients' health for many years beyond what we previously thought. Preventing cardiovascular disease, reducing hyperlipidemia, and optimizing lean body mass for active, longer lives now join the long-standing goal of promoting lung function through nutrition. This chapter summarizes recent developments in nutrition in people with CF, with an eye to the evolution of our practice.

Health-related Quality of Life in a Prospective Study of Ultrasound to Detect Cystic Fibrosis-related Liver Disease in Children.

OBJECTIVES: Cystic fibrosis liver disease (CFLD) begins early in life. Symptoms may be vague, mild, or nonexistent. Progressive liver injury may be associated with decrements in patient health before liver disease is clinically apparent. We examined Health-Related Quality of Life (HRQOL) in children enrolled in a multi-center study of CFLD to determine the impact of early CFLD on general and disease-specific QOL. METHODS: Ultrasound (US) patterns of normal (NL), heterogeneous (HTG), homogeneous (HMG), or nodular (NOD) were assigned in a prospective manner to predict those at risk for advanced CFLD. Parents were informed of results. We assessed parent/child-reported (age ≥5 years) HRQOL by PedsQL 4.0 Generic Core and CF Questionnaire-revised (CFQ-R) prior to US and annually. HRQOL scores were compared by US pattern at baseline (prior to US), between baseline and 1 year and at 5 years. Multivariate analysis of variance (MANOVA) with Hotelling-Lawley trace tested for differences among US groups. RESULTS: Prior to US, among 515 participants and their parents there was no evidence that HTG or NOD US was associated with reduced PedsQL/CFQ-R at baseline. Parents of NOD reported no change in PedsQL/CFQ-R over the next year. Child-report PedsQL/CFQ-R (95 NL, 20 NOD) showed improvement between baseline and year 5 for many scales, including Physical Function. Parents of HMG children reported improved CFQ-R scores related to weight. CONCLUSIONS: Early undiagnosed or pre-symptomatic liver disease had no impact on generic or disease-specific HRQoL, and HRQoL was remarkably stable in children with CF regardless of liver involvement.

Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children With Acute Recurrent or Chronic Pancreatitis.

OBJECTIVES: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). METHODS: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. RESULTS: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. CONCLUSIONS: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.

Outpatient Pain Management in Children With Chronic Pancreatitis: A Scoping Systematic Review.

OBJECTIVES: Although pain management is central to pediatric chronic pancreatitis (CP) care, no evidence-based guidelines exist. In this scoping systematic review, we sought promising strategies for CP pain treatment in children. METHODS: We systematically reviewed literature on pain management in children and adults with CP, and 2 conditions with similar pain courses: juvenile idiopathic arthritis and sickle cell disease. RESULTS: Of 8997 studies identified, 287 met inclusion criteria. There are no published studies of analgesic medications, antioxidants, dietary modification, integrative medicine, or regional nerve blocks in children with CP. In adults with CP, studies of nonopioid analgesics, pancreatic enzymes, and dietary interventions have mixed results. Retrospective studies suggest that endoscopic retrograde cholangiopancreatography and surgical procedures, most durably total pancreatectomy with islet autotransplant, improve pain for children with CP. Follow-up was short relative to a child's life. Large studies in adults also suggest benefit from endoscopic therapy and surgery, but lack conclusive evidence about optimal procedure or timing. Studies on other painful pediatric chronic illnesses revealed little generalizable to children with CP. CONCLUSIONS: No therapy had sufficient high-quality studies to warrant untempered, evidence-based support for use in children with CP. Multicenter studies are needed to identify pain management "best practices."

Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors.

OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001). CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial.

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).

The Inflammatory Cytokine Profile Associated With Liver Damage Is Broader and Stronger in Patients With Chronic Hepatitis B Compared to Patients With Acute Hepatitis B.

Liver damage in hepatitis B is immune driven and correlates with inflammatory markers in patient serum. There is no comparison of these markers to determine if inflammatory profiles are distinct to different types of liver damage across patients at different stages of disease. We measured 25 inflammatory markers in patients with acute hepatitis B and chronic hepatitis B with hepatitis B e antigen seroconversion and chronic patients stopping nucleoside analogue therapy. Myeloid markers dominated the inflammatory profile in all stages of hepatitis B. More inflammatory markers were detectable in chronic patients, including elevated concentrations of cytotoxic effectors Fas ligand, TRAIL, and TNF-α.