Quantity not sufficient rates and delays in sweat testing in US infants with cystic fibrosis

Background Diagnostic sweat testing is required for infants with positive newborn-screening (NBS) tests for cystic fibrosis (CF). Infants have “quantity not sufficient” (QNS) sweat volumes more often than older children. A comprehensive study of QNS sweat volumes in infants has not previously been reported. Methods We surveyed US CF Centers to obtain QNS rates in all infants who had sweat testing at under 14 days and under 3 months of age. We then calculated QNS rates reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60 days of life. We compared QNS sweat test rates in preterm (<37-weeks gestational age) vs term infants. We assessed age at sweat test and proportion of infants who did not have a sweat test reported by 60 days of age. Results Thirty-nine of 144 (27%) of CF Centers reported a mean QNS rate of 10.5% (range, 0-100) in infants 14-days-old or younger. CFFPR data showed the highest QNS rates in the youngest infants and in those born before 37 weeks of gestation. The median age at sweat testing decreased over time, but more than 22% of infants did not have a sweat test reported by 60 days. Conclusion Higher QNS rates are seen in the youngest infants with CF, but more than 80% of infants younger than 2 weeks of age have adequate sweat volumes. Sweat testing should not be delayed in infants with a positive CF NBS test

ALPINE2:Efficacy and safety of 14-day vs 28-day inhaled aztreonam for <i>Pa </i>eradication in children with cystic fibrosis

Background: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. Methods: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to &lt;18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above −20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). Results: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3–17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), −8.0% (−24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. Conclusions: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. ClinicalTrials.gov:</p

ALPINE2:Efficacy and safety of 14-day vs 28-day inhaled aztreonam for <i>Pa </i>eradication in children with cystic fibrosis

Background: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. Methods: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to &lt;18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above −20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). Results: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3–17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), −8.0% (−24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. Conclusions: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. ClinicalTrials.gov:</p

Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation

Objective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included

Diagnosis of Cystic Fibrosis in Screened Populations

Objective Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. Study design To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. Results After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. Conclusions It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis

Minorities are Underrepresented in Clinical Trials of Pharmaceutical Agents for Cystic Fibrosis

Rationale: Members of racial or ethnic minorities make up an appreciable proportion of patients with cystic fibrosis (CF) and have worse outcomes than non-Latino white individuals. Between 1,999 and 2014, the CF Foundation Patient Registry reported an increase in minorities from 5 to 8.2% for Latinos, from 3 to 4.6% for black individuals and from 1.4 to 3.1% for “Other.” Objectives: To evaluate the representation of racial and ethnic minorities in pharmacology clinical trials for CF. Methods: We analyzed pharmacology clinical trials in CF published between 1999 and 2015 by searching PubMed and published study reference lists for qualifying study reports. We examined whether the race and ethnicity of study subjects were reported and, if so, what percentage of subjects represented major minority groups. Measurements and Main Results: Among 147 pharmacology clinical trials, only 19.7% reported the race or ethnicity of study subjects. Latinos were verified as included in 7.5% of clinical trials, black individuals in 6.8%, and Asians in 2.0%. Inclusion of subjects described as “Other race” was reported in 7.5% of trials. In 29 clinical trials that reported race and ethnicity, the percentage of minorities included as subjects was 2.0% for Latinos, 1.0% for black individuals, and 0.1% for Asians. Conclusions: Although CF disproportionately affects non-Latino white individuals, members of other racial or ethnic groups are proportionally underrepresented in CF pharmacology clinical trials. Inadequate inclusion of minorities and failure to report the racial or ethnic background of study subjects limits information about factors influencing drug response and may contribute to health disparities for minorities with CF

Minorities Are Underrepresented in Clinical Trials of Pharmaceutical Agents for Cystic Fibrosis.

RationaleMembers of racial or ethnic minorities make up an appreciable proportion of patients with cystic fibrosis (CF) and have worse outcomes than non-Latino white individuals. Between 1,999 and 2014, the CF Foundation Patient Registry reported an increase in minorities from 5 to 8.2% for Latinos, from 3 to 4.6% for black individuals and from 1.4 to 3.1% for "Other."ObjectivesTo evaluate the representation of racial and ethnic minorities in pharmacology clinical trials for CF.MethodsWe analyzed pharmacology clinical trials in CF published between 1999 and 2015 by searching PubMed and published study reference lists for qualifying study reports. We examined whether the race and ethnicity of study subjects were reported and, if so, what percentage of subjects represented major minority groups.Measurements and main resultsAmong 147 pharmacology clinical trials, only 19.7% reported the race or ethnicity of study subjects. Latinos were verified as included in 7.5% of clinical trials, black individuals in 6.8%, and Asians in 2.0%. Inclusion of subjects described as "Other race" was reported in 7.5% of trials. In 29 clinical trials that reported race and ethnicity, the percentage of minorities included as subjects was 2.0% for Latinos, 1.0% for black individuals, and 0.1% for Asians.ConclusionsAlthough CF disproportionately affects non-Latino white individuals, members of other racial or ethnic groups are proportionally underrepresented in CF pharmacology clinical trials. Inadequate inclusion of minorities and failure to report the racial or ethnic background of study subjects limits information about factors influencing drug response and may contribute to health disparities for minorities with CF