A randomized trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations (PExs) in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 second (ppFEV1) in CF PExs not responding to antibiotic therapy. METHODS: This was a randomized, double-blind, placebo-controlled trial in pwCF treated with intravenous (IV) antibiotics for a PEx. At Day 7, those who had not returned to >90% baseline ppFEV1 were randomized to adjuvant prednisone 1 mg·kg-1 twice daily (max 60 mg/day) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline ppFEV1 at Day 14 of IV antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomized. 50% of subjects in the prednisone group recovered baseline FEV1 on Day 14 compared to 39% of subjects in the placebo group for a difference of 11% (95% CI -11, 34%, p=0.34). The mean (sd) change in ppFEV1 from Day 7 to Day 14 was 6.8% predicted (8.8) in the prednisone group and 4.6% (6.9) in the placebo group (mean difference 2.2% predicted 95% CI -1.5, 5.9%, p=0.24). Time to subsequent exacerbation was not prolonged in prednisone treated subjects (HR 0.83, 95% CI 0.45, 1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in ppFEV1 recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of IV antibiotic therapy for PExs.

Treatment response to pulmonary exacerbation in primary ciliary dyskinesia.

INTRODUCTION: Pulmonary exacerbation (Pex) are common in pediatric primary ciliary dyskinesia (PCD), however changes in forced expiratory volume in 1 s precent predicted (FEV1pp) during Pex are not well described. AIM: To assess the evolution of FEV1pp during Pex and to define factors associated with failure to return to baseline lung function. METHOD: This was a retrospective study of patients with PCD between 2010 and 2022. Pex were defined as the presence of increased respiratory symptoms treated with intravenous (IV) antibiotics. The main outcomes were the changes in FEV1 during therapy and the proportion of patients (responders) achieving ≥90% of baseline FEV1pp values at the end of admission. RESULTS: The study included 52 Pex events in 28 children with PCD. The rate of responders was 32/41 (78%) at the end of admission. Nonresponse was associated with lower median body mass index (BMI) Z-score (-2.4 vs. -0.4, p < .01) and with a history of IV treated Pex in the previous year (p = .06). For the 22 Pex with available FEV1pp measurements at mid admission, the median relative and absolute improvement from admission to Day 7 was 9.1% and 6.2%, respectively (p- .001), and from Days 7 to 14 was 4.4% and 2.8%, respectively (p = .08). CONCLUSION: In children with PCD treated with IV antibiotics, the majority of lung function recovery happens during the first week of IV therapy. Lower BMI was associated with nonresponse to therapy.

Efficacy of Antibiotic Eradication Therapy of Early Pseudomonas aeruginosa Infection in Children with Primary Ciliary Dyskinesia.

Rationale: Chronic infection with Pseudomonas aeruginosa (PsA) negatively impacts lung disease in patients with primary ciliary dyskinesia (PCD). There is currently limited evidence regarding the efficacy of PsA antibiotic eradication therapy (AET) in children with PCD. Objectives: To assess the effectiveness of AET of early PsA infection in children with PCD. Methods: This retrospective study included pediatric patients with a confirmed PCD diagnosis according to the American Thoracic Society guidelines at the Hospital for Sick Children between 2010 and 2022. Children with newly acquired PsA infection underwent AET using a stepwise protocol. The protocol included the following steps: step 1, 28 days of tobramycin inhalation solution (TIS); step 2, repeat TIS if culture positive after step 1; and step 3, 14 days of intravenous antibiotics followed by 28 days of TIS if culture positive after step 2. Step 3 was also used for patients who presented with pulmonary exacerbation symptoms. The main outcome was a PsA-negative culture result based on the microbiological results of the first culture after completion of each step of treatment. Results: During the study period, 31 children had a new PsA infection and underwent AET. Of the 27 children who had been asymptomatic at the time of the PsA infection, negative PsA culture results were achieved in 20 (74%) of 27, 1 (14%) of 7, and 5 (83%) of 6 after steps 1, 2, and 3 of AET, respectively. All four symptomatic patients who initially were treated with step 3 had successful clearance of PsA. The overall cumulative success rate of the protocol for negative culture results after AET was 97% (30 of 31). For patients in whom AET was successful, the probability of staying PsA free for at least 1 year was 70%. Conclusions: AET for early PsA infection is highly effective in PCD, with sustained efficacy in most individuals. These data suggest that AET should be considered in all children with PCD who have early PsA infection.

High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification.

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of CFTR haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a PRSS2 missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are PRSS2 pancreas eQTLs (p = 9.5 × 10-7 and p = 1.4 × 10-4, respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.

Comparative analysis of respiratory symptom scores to detect acute respiratory events in children with cystic fibrosis.

BACKGROUND: Patient-reported outcomes (PROs) are important outcome measures in research and clinical practice. This study describes the longitudinal variability the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score and the Chronic Respiratory Infection Symptom Score (CRISS), as well as their ability to identify acute respiratory events in children with CF. METHODS: In this prospective observational study, the parent-proxy (6 -13 years) and self-reported (6-18 years) CFQ-R Respiratory score and CRISS (6-18 years) were measured every 3 months over 2 years. The lung clearance index (LCI) and FEV1 were also measured. We compared the diagnostic accuracy of the PROs in distinguishing acute respiratory events and clinically stable visits, using the minimal important difference of each PRO as the threshold. RESULTS: A total of 98 children with CF were included. On average, the symptom scores did not change between clinically stable visits. The positive predictive value (PPV) and negative predictive value (NPV) of a ≥8.5-point worsening in the parent-proxy CFQ-R score to identify acute respiratory events (n=119) (PPV 70.2% and NPV 87.0%) were higher than for the self-reported CFQ-R score (PPV 58.9% and NPV 72.2%). The PPV and NPV of an ≥11-point change in the CRISS for acute respiratory events (n=137) was 56.5% and 79.6%, respectively. The PPV and NPV of all PROs were increased when combined with the LCI and/or FEV1pp. CONCLUSION: Symptoms scores differ in their ability to identify acute respiratory events in children with CF; PPV and NPV of all PROs were improved when combined with lung function outcomes.

Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls.

BACKGROUND: The limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change. METHODS: In a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up. RESULTS: Clinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up. CONCLUSION: The limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.

Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease.

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Aquagenic wrinkling of the palms in cystic fibrosis patients treated with ivacaftor.

Aquagenic wrinkling of palms (AWP) in cystic fibrosis (CF) patients and common CFTR mutations is recognized as a frequent symptom of the disease. The long-term effect of CFTR targeting therapy on AWP has not been studied. AWP was monitored in 16 CF patients (8 children and 8 adults) before and for 6 months after initiation of ivacaftor therapy. Thirteen (81.3%) patients had at least mild and 8/16 (50%) moderate-to-severe AWP at baseline. AWP improved with ivacaftor therapy. This observation suggests that AWP is also common in individuals with CF and relatively rare mutations and is directly related to CFTR function.

Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children. METHODS: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes. RESULTS: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls. CONCLUSIONS: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.

Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.

Bronchodilator responsiveness in cystic fibrosis children treated for pulmonary exacerbations.

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbations (PEx) are associated with a significant drop in pulmonary function. The clinical value of measuring bronchodilator (BD) responsiveness during treatment for PEx to monitor or predict recovery of lung function is unclear. METHODS: A retrospective analysis of spirometry with BD response testing obtained during hospital admissions for PEx in pediatric CF patients. Repeated events were included for patients with BD testing during multiple admissions. RESULTS: Two hundred forty-nine spirometries with BD testing in 102 patients were completed around Day 7 (Days 4-10) of hospital admission for treatment of CF PEx. Median (IQR) forced expiratory volume in 1 s (FEV1 ) was 70.6% predicted (58.1, 84.6) before the PEx event (best FEV1 in 6 months before admission), 54.4% (41.5, 66.9) at admission, 62.3% (48.4, 74.7) around Day 7 of admission and 67.1% predicted (53.8, 78.2) at the end of treatment. BD response around Day 7 correlated poorly with FEV1 before PEx (r = -.16, p = .02) and did not correlate with recovery to baseline FEV1 at end of treatment (r = .08, p = .22). Only 23/249 (9%) individual tests had a BD response in FEV1 of ≥12% and 200 ml. BD response was not related to age or severity of lung disease and led to an immediate change in clinical management in only four cases. CONCLUSIONS: Significant BD response in CF patients treated for PEx is rare, shows poor correlation with baseline pulmonary function and does not correlate with the recovery of FEV1 with treatment. These data suggest that routine testing for BD response is not indicated during PEx.

Determinants of lung disease progression measured by lung clearance index in children with cystic fibrosis.

The lung clearance index (LCI) measured by the multiple breath washout (MBW) test is sensitive to early lung disease in children with cystic fibrosis. While LCI worsens during the preschool years in cystic fibrosis, there is limited evidence to clarify whether this continues during the early school age years, and whether the trajectory of disease progression as measured by LCI is modifiable.A cohort of children (healthy and cystic fibrosis) previously studied for 12 months as preschoolers were followed during school age (5-10 years). LCI was measured every 3 months for a period of 24 months using the Exhalyzer D MBW nitrogen washout device. Linear mixed effects regression was used to model changes in LCI over time.A total of 582 MBW measurements in 48 healthy subjects and 845 measurements in 64 cystic fibrosis subjects were available. The majority of children with cystic fibrosis had elevated LCI at the first preschool and first school age visits (57.8% (37 out of 64)), whereas all but six had normal forced expiratory volume in 1 s (FEV1) values at the first school age visit. During school age years, the course of disease was stable (-0.02 units·year-1 (95% CI -0.14-0.10). LCI measured during preschool years, as well as the rate of LCI change during this time period, were important determinants of LCI and FEV1, at school age.Preschool LCI was a major determinant of school age LCI; these findings further support that the preschool years are critical for early intervention strategies.

Lung Clearance Index to Track Acute Respiratory Events in School-Age Children with Cystic Fibrosis.

Rationale: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF), but its utility to identify and manage these events in school-age children with CF is not well defined.Objectives: To describe changes in LCI with acute respiratory events in school-age children with CF.Methods: In a multisite prospective observational study, the LCI and FEV1 were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1% predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1% predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject.Measurements and Main Results: A total of 98 children with CF were followed for 2 years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% confidence interval, 6.5 to 11.3) and FEV1% predicted (-6.6%; 95% confidence interval, -8.3 to -5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared with a decline in FEV1% predicted (41.7% vs. 30.0%; P = 0.012); 53.9% of events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit.Conclusions: In school-age children with CF, the LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. In combination, the LCI and FEV1 capture a higher proportion of events with functional impairment.

Lung transplant referrals for individuals with cystic fibrosis: A pediatric perspective on the cystic fibrosis foundation consensus guidelines.

Lung transplant referral guidelines for individuals with cystic fibrosis (CF) were published recently. Most of the recommendations focus on the specific indications and barriers to transplantation in adults with CF. Although the number of children with CF and end-stage lung disease continues to decrease, the specific issues related to pediatric patients merit further elucidation. We address each recommendation from the recent publication with a pediatric perspective. Furthermore, we note some significant differences between the practice and policy related to lung transplantation between Canada and the United States.

Incidence and Risk Factors of Obesity in Childhood Solid-Organ Transplant Recipients.

BACKGROUND: Obesity is a significant public health concern; however, the incidence post solid-organ transplantation is not well reported. METHODS: This study determined the incidence and risk factors of obesity among pediatric solid-organ transplant recipients (heart, lung, liver, kidney, multiorgan) at The Hospital for Sick Children (2002-2011), excluding prevalent obesity. Follow-up occurred from transplantation until development of obesity, last follow-up, or end of study. Incidence of obesity was determined overall, by baseline body mass index, and organ group. Risk factors were assessed using Cox proportional-hazards regression. RESULTS: Among 410 (55% male) children, median transplant age was 8.9 (interquartile range [IQR]: 1.0-14.5) years. Median follow-up time was 3.6 (IQR: 1.5-6.4) years. Incidence of obesity was 65.2 (95% confidence interval [CI]: 52.7-80.4) per 1000 person-years. Overweight recipients had a higher incidence, 190.4 (95% CI: 114.8-315.8) per 1000 person-years, than nonoverweight recipients, 56.1 (95% CI: 44.3-71.1). Cumulative incidence of obesity 5-years posttransplant was 24.1%. Kidney relative to heart recipients had the highest risk (3.13 adjusted hazard ratio [aHR]; 95% CI: 1.53-6.40) for obesity. Lung and liver recipients had similar rates to heart recipients. Those with higher baseline body mass index (z-score; 1.72 aHR; 95% CI: 1.39-2.14), overweight status (2.63 HR; 95% CI: 1.71-4.04), and younger transplant age (y; 1.18 aHR; 95% CI: 1.12-1.25) were at highest risk of obesity. Higher cumulative steroid dosage (per 10 mg/kg) was associated with increased risk of obesity after adjustment. CONCLUSIONS: Among all transplanted children at The Hospital for Sick Children, 25% developed obesity within 5-years posttransplant. Kidney recipients, younger children, those overweight at transplant, and those with higher cumulative steroid use (per 10 mg/kg) were at greatest risk. Early screening and intervention for obesity are important preventative strategies.

Neuropsychological outcomes following pediatric lung transplantation.

OBJECTIVE: Lung transplantation (LTx) is a treatment option for eligible children with end-stage pulmonary diseases. Improving our understanding of longer-term developmental outcomes in pediatric LTx recipients is important for strategized interventions targeting cognitive difficulties. METHODS: Neuropsychological assessments were completed for children who received LTx at our center (2009-2017). Assessments comprised tasks of general intellect, memory, visual-perception, academics, and executive functioning as well as caregiver questionnaires of adaptive, executive, emotional, and behavioral functioning. Results were compared to age-matched population norms. Between-group nonparametric tests were performed pre-LTx vs post-LTx and for children with a primary diagnosis of cystic fibrosis (CF) vs other diagnoses (non-CF). RESULTS: Neuropsychological outcomes were assessed for 21 children post-LTx, with a median age (interquartile range) at the time of transplant of 11.52 (6.89, 14.12) years. Eleven children completed pre- and post-transplant assessments and within this group, improvements for verbal learning (P = .02), aspects of mood, behavior, and adaptive functioning were observed over time (all P < .05). Post-transplant whole group analysis suggested age-appropriate abilities across most cognitive domains, with a relative weakness for executive functioning. Emotional or behavioral difficulties were not endorsed by caregivers. Across pulmonary diagnoses, higher levels of emotional, behavioral, and executive functioning difficulty were reported in the non-CF group (all P < .05). CONCLUSIONS: Overall, LTx has a positive impact on cognitive functioning, particularly learning, adaptive functioning, mood, and behavior. Children transplanted for non-CF related diseases demonstrated greater challenges, highlighting the need for targeted assessments and interventions across the transplant process to support the complex needs of this population.

Lung transplantation for cystic fibrosis.

BACKGROUND: The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. We aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time. METHODS: A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan-Meier method and analyzed with log-rank tests. RESULTS: From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF retransplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and retransplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction. CONCLUSIONS: Lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.

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.

Posttransplant Lymphoproliferative Disorder in Pediatric Patients: Characteristics of Disease in EBV-seropositive Recipients.

BACKGROUND: Patients at greatest risk of posttransplant lymphoproliferative disorder (PTLD) are those who acquire primary Epstein-Barr virus (EBV) infection after solid organ transplantation. The incidence of PTLD among patients who are EBV-seropositive before transplant is lower, and little is known about the differences in presentation and outcome of this population. We describe the characteristics of EBV-seropositive transplant recipients (R+) who developed PTLD and compare survival outcomes with EBV-seronegative recipients (R-). METHODS: A hospital-based registry was used to identify all patients with biopsy-proven PTLD for the period 2000-2014. Characteristics and outcomes were compared between R+ and R- patients with PTLD. RESULTS: Sixty-nine patients were included, among which 20 (29.0%) were R+ and 49 (71.0%) were R-. Multiorgan transplant patients accounted for 25% of PTLD cases in R+ patients, while accounting for only 2.1% of all transplants during the study period. There was no difference in PTLD site between R+ and R- patients. PTLD among R+ individuals occurred during the second year after transplant (median: 1.92; range: 0.35-3.09 y) compared with during the first year for R- individuals (median: 0.95; range: 0.48-2.92 y; P = 0.380). There was a trend for a higher overall mortality among R+ individuals (log rank: 0.09). PTLD-related mortality did not differ between R+ and R- individuals (log rank: 0.17). CONCLUSIONS: PTLD among R+ individuals was more likely to occur among multiorgan recipients, and there was a tendency for poorer outcomes at 1 and 5 years after the diagnosis of PTLD.

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis.

BACKGROUND: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations. METHODS: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks. CONCLUSIONS: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.