The Italian external quality assessment program for Cystic Fibrosis sweat chloride test: CFTR modulators and the impact of a new sweat test report form.

Background: The advent of CFTR modulators highlighted that the sweat test (ST) for CF can be used also as an outcome measure for the basic defect of CFTR. Despite the technological advances, ST still remains operator-dependent and its execution should be strongly paired with guidelines. In 2022, due to the advent of CFTR modulators, the Italian CF Society introduced a specific ST report. The aim of the present paper is to discuss the impact of this new report in the 2022-23 round of the Italian External Quality Assessment program for ST (I-EQA-SCT). Methods: The scheme of the I-EQA-SCT is prospective, enrolment is voluntary, the payment of a fee is required and results are shared through a web-facility. Assessment covers analysis, interpretation, and reporting of results. In the 2022-23 round, 2 out of the 3 mock clinical information referred to patients who started modulators. Results: Fourteen laboratories completed the 2022-23 I-EQA-SCT round. Three of them failed in the interpretation of results from these two mock cases and/or used a wrong report not consistent with the more recent Italian Sweat Test Recommendations. Conclusions: The overall results obtained from the laboratories involved in the I-EQA-SCT program clearly showed that the laboratories' qualitative and quantitative performance improved significantly. Results emerged from this round highlighted an issue in the report form used for monitoring patients on CFTR modulator therapy thus stressing the importance of these programs in improving both the performance of lab services and ameliorating the sweat test recommendations.

A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres.

OBJECTIVE: We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres. METHODS: All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected. RESULTS: We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%). CONCLUSIONS: We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.

The Italian External Quality Assessment Program for Cystic Fibrosis Sweat Chloride Test: Does Active Participation Improve the Quality?

(1) Background: Diagnostic testing for cystic fibrosis (CF) is based on a sweat chloride test (SCT) considering the appropriate signs and symptoms of the disease and results of a gene mutation analysis. In 2014, the Istituto Superiore di Sanità (ISS) established a pilot Italian external quality assessment program for CF SCT (Italian EQA-SCT), which is now a third party service carried out by the ISS. (2) Methods: The ongoing scheme is prospective, enrollment is voluntary, and the payment of a fee is required. Results are shared through a dedicated web-facility. Assessment covers the analysis, interpretation, and reporting of results. (3) Results: Thirteen, fifteen, sixteen, and fifteen different laboratories, respectively, participated from 2015 to 2016 and from 2018 to 2019 in the Italian EQA-SCT scheme. Eleven different laboratories participated each year in all four rounds of the Italian EQA-SCT. (4) Conclusions: The overall results obtained from the laboratories participating constantly clearly show that their qualitative and quantitative performance improved significantly. This is due to the opportunity-after receiving the EQA results-to constantly review their performance and address any inconsistencies. We firmly believe that participation in the EQA program will improve the quality of participating laboratories and that EQA participation should become mandatory as a fundamental requirement for laboratory accreditation.

Cystic Fibrosis Mortality in Childhood. Data from European Cystic Fibrosis Society Patient Registry.

Data collected in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database were used to investigate whether risk factors for death in childhood and adolescents CF patients have different impact in countries of different income. In this way, it is possible to recognize where interventions could improve the quality of care and survival in these patients. We matched deceased and alive patients by age, country, year of follow-up. Multivariable logistic models were developed. In the years of this study, the ECFSPR collected information on 24,416 patients younger than 18 years: 7830 patients were from countries with low/middle income and 16,586 from countries with high income; among these the dead are 102 and 107 (p < 0.001), respectively. The use of oxygen, forced expiratory volume in one second (FEV1) below 40% and BMI standard deviation score (SDS) below -2 represent risk factors for death. However, some patients from countries with high income remain alive even if their values of FEV1% and BMI-SDS were low, and some deceased patients from countries with high income had high values of FEV1% (>60%). Evaluation of mortality in pediatric age may reflect the availability of resources for CF diagnosis and treatment in some countries.

The Italian pilot external quality assessment program for cystic fibrosis sweat test.

OBJECTIVES: Sweat chloride test is the gold standard test for cystic fibrosis (CF) diagnosis. In 2014 the Istituto Superiore di Sanità established the Italian pilot external quality assessment program for CF sweat test (IEQA-ST). DESIGN AND METHODS: Ten laboratories, included among the 33 Italian CF Referral Centers, were selected and enrolled on the basis of their attitude to perform sweat test (ST) analysis by using methods recommended by the Italian Guidelines. They received three different sweat-like samples (normal, borderline and pathologic chloride concentration), with mock clinical indications, for analysis according to routine procedures. Assessment, performed by a panel of experts, covered analytical performance, interpretation and reporting of results; categories of "poor" and "satisfactory" performance were not defined. All data were managed through a web utility. RESULTS: The program identified important areas of interest and, in some case, of concern. It is important to underline that results are referred to a small proportion, i.e. about 30%, of Italian laboratories performing CF ST in the context of the Referral Centers. CONCLUSIONS: Data collected highlight the importance of participation in EQA programs as it may improve laboratory/clinical performance; our study represents a model for the setting up of a large-scale EQA scheme for ST.

Growth assessment of paediatric patients with CF comparing different auxologic indicators: A multicentre Italian study.

OBJECTIVES: To evaluate growth in Italian patients with cystic fibrosis (CF). PATIENTS AND METHODS: A multicentre cross-sectional study was carried out on patients with CF attending Italian reference centres. Anthropometric data were evaluated using the Centers for Disease Control and Prevention 2000 reference data. Nutritional failure was defined as height-for-age percentile (HAP) <5th (all patients); weight-for-length percentile (WLP) <10th (patients <2 years); body mass index percentile (BMIp) <15th (patients between 2 and 18 years). The risk of malnutrition (defined as HAP, WLP, and BMIp <25th) and the proportion of patients below the "BMIp goal" (BMIp > or =50th) were also evaluated. Nutritional status was evaluated in the whole population and in relation to age, sex, pancreatic insufficiency, meconium ileus, and lung function. RESULTS: A total of 892 patients with CF (50.7% males, mean age 9.2 years, range 0.1-18 years) were enrolled. The proportion of children with HAP <5th, WLP<10th and BMIp<15th was 12.2%. 12.9%, 20.9%, respectively, and 54.4% did not fulfill the BMIp > or =50th goal. HAP <25th identified the highest proportion of children at risk of malnutrition, whereas BMIp <15th identified the highest proportion of children with nutritional failure. Whatever the criterion used to define malnutrition, the highest proportion of children with nutritional failure was found in adolescence (11-18 years). z scores for height, weight, and BMI were significantly associated with pancreatic status and lung function. Differences among centres for the auxologic parameters were not significant, except for BMIp. CONCLUSIONS: Nutritional failure is present in a minority of Italian patients with CF, particularly during adolescence. Different auxologic indicators should be used for identifying children at risk for or with actual malnutrition.