Long-term clinical outcomes of elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis and advanced pulmonary disease.

BACKGROUND: The combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) has been approved for treatment of cystic fibrosis (CF) patients (pwCF) homozygous and heterozygous for Phe508del. We aim to assess the long-term effects of ELX/TEZ/IVA therapy on clinical outcomes in severe pwCF. METHODS: Lung function, pulmonary exacerbation (PEx), sweat chloride concentration, body mass index (BMI) and the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R RD) were prospectively evaluated in a cohort of pwCF who were candidates for inclusion in a compassionate program of ELX/TEZ/IVA therapy. All procedures were performed at baseline and then at 12 and 24 months after initiation of modulator therapy. The number of PExs in the year before the study enrollment was collected from our records. RESULTS: Thirty-six adult pwCF (median age 36.7 years; BMI 19.8 kg/m2; FEV1 36.5% predicted) were recruited from 2019. At 12 and 24 months after initiation, the absolute change in ppFEV1 (percent predicted forced expiratory volume in 1 s) from baseline was +12.5% (p < 0.0001) and +13% (p < 0.0001), respectively. A median of 4.0 exacerbations per patient was reported in the preceding year, while the median number of PExs was 0.0 and 1.0 after 12 and 24 months, respectively, of modulator therapy (both p < 0.0001). After 12 and 24 months of ELX/TEZ/IVA therapy, the CFQ-R RD score improved by 22.4 points (p < 0.0001) and 16.7 points (p < 0.0001), and sweat chloride levels decreased by 65.5 mmol/L (p < 0.0001) and 60 mmol/L (p < 0.0001), respectively. BMI significantly increased. CONCLUSIONS: Long-term ELX/TEZ/IVA combination therapy markedly impacts the clinical status of patients with severe CF, showing a sustained improvement in lung function and PEx rate.

Immunogenicity and Safety of the BNT162b2 COVID-19 Vaccine in Patients with Cystic Fibrosis with or without Lung Transplantation.

Cystic fibrosis (CF) is characterized by a progressive decline in lung function, which may be further impaired by viral infections. CF is therefore considered a comorbidity of coronavirus disease 2019 (COVID-19), and SARS-CoV-2 vaccine prioritization has been proposed for patients with (pw)CF. Poor outcomes have been reported in lung transplant recipients (LTR) after SARS-CoV-2 infections. LTR have also displayed poor immunization against SARS-CoV-2 after mRNA-based BNT162b2 vaccination, especially in those undergoing immunosuppressive treatment, mostly those receiving mycophenolate mofetil (MMF) therapy. We aimed to determine here the immunogenicity and safety of the BNT162b2 vaccine in our cohort of 260 pwCF, including 18 LTR. Serum levels of neutralizing anti-SARS-CoV-2 IgG and IgA antibodies were quantified after the administration of two doses. PwCF displayed a vaccine-induced IgG and IgA antiviral response comparable with that seen in the general population. We also observed that the immunogenicity of the BNT162b2 vaccine was significantly impaired in the LTR subcohort, especially in patients undergoing MMF therapy. The BNT162b2 vaccine also caused minor adverse events as in the general population, mostly after administration of the second dose. Overall, our results justify the use of the BNT162b2 vaccine in pwCF and highlight the importance of a longitudinal assessment of the anti-SARS-CoV-2 IgG and IgA neutralizing antibody response to COVID-19 vaccination.

Occurrence, outcomes and predictors of portal hypertension in cystic fibrosis: A longitudinal prospective birth cohort study.

BACKGROUND: The reported prevalence of portal hypertension (PH) in Cystic Fibrosis is variable, incidence rates rarely provided and the utility of liver function tests (LFT's) early in life to predict PH is questionable. The aims were to (1) determine PH prevalence (P) and incidence rate (IR) and combined mortality transplant (MTX) data in PH vs non-PH patients and (2) to assess association of LFTs in early life with liver disease and PH. METHOD: (1) A double centre longitudinal cohort study of 577 CF patients diagnosed by newborn screening (NBS) with annual examinations for PH up to 18.5 years of age (max) was performed over 28 years for P, IR, and MTX data; (2) Cox proportional hazard models were used to assess the association of elevated LFTs on 2 or more occasions over 0-6.5 years and PH. RESULTS: 51/577(8.8%) developed PH with an average IR of near 3/1000 patient years per 5 year interval representing young, mid and late childhood respectively in patients 3-18 years of age. Combined mortality/liver transplant occurred in 12/51 (23.5%) PH and 25/526 (4.8%) non-PH (p < 0.001). Elevated enzymes particularly GGT (HR:5.71, 95% CI 3.11-10.47); ALT/GGT (HR: 5.56, 95% CI 2.82-10.98); and ALP/GGT (HR: 5.74, 95% CI 2.78-11.86) were associated with the onset of PH. CONCLUSION: This birth cohort with annual examination for PH provides an accurate assessment of the prevalence, and IR of PH and MTX of PH vs non-PH. Early elevated LFTs are associated with onset of MBC/PH.

Early diagnosis from newborn screening maximises survival in severe cystic fibrosis.

Newborn screening (NBS) for cystic fibrosis (CF) has been gradually established in several countries, but scant data are available on its long-term effects on survival. Our objective was to evaluate the long-term effects of CF NBS on survival. 586 patients, diagnosed and followed between 1971 and 2014 at the Verona CF Centre were analysed. Eligibility was confirmed in 342 cases diagnosed by NBS, 101 with meconium ileus and 143 through symptoms (44 out of 143 were NBS false negatives). The primary end-point was the 30-year overall survival in patients diagnosed by NBS. Patients were grouped according to the number of hospitalisations for respiratory or nutritional symptoms in the first 3 years of life: 0 (mild), 1-2 (moderate) and ≥3 (severe). Survival in NBS and symptoms groups was compared. The 30-year survival probability of the NBS group was 80.1% (95% CI 71.4-86.4%); in the symptoms group it was 71.0% (95% CI 62.2-78.2%). The 20-year survival was significantly higher in the NBS versus symptoms group in the severe (85% versus 64%, p=0.007) and moderate (94% versus 86%, p=0.016) groups. An adjusted Cox-model estimation confirmed differences in both the groups. Poor outcome associated with early severe presentation of CF is tempered by NBS.

Lung function comparison between two decades in cystic fibrosis children: A single centre study.

OBJECTIVES: The purpose of this study was to compare two cohorts of cystic fibrosis (CF) patients born and treated in two different decades, diagnosed through a CF neonatal screening program. METHODOLOGY: We compared pulmonary function decline from 10 to 15 years of age in patients with cystic fibrosis born between 1979 and 1984 (Cohort 1) and between 1991 and 1996 (Cohort 2). Forced expiratory volume in 1 sec (FEV1%) and forced expiratory flow from 25% to 75% (FEF 25-75%) were analyzed by a linear mixed model approach. The differences between the two cohorts were estimated and the overall cohort effect was tested. RESULTS: Ninety-two patients (51 males, 41 females) fulfilled the selection criteria. Pancreatic insufficiency and CF related diabetes were present in 91% and 20% of patients, respectively. The mean absolute decrement of FEV1% was 9.2 (standard deviation [SD] 11.2) in Cohort 1 and 0.6 (SD 10.4) in Cohort 2 (P < 0.001). The mean decrement of FEF 25-75% was 16.3 (SD 19.5) in Cohort 1 and 1.3 (SD 16.8) in Cohort 2 (P < 0.001) and the Pseudomonas aeruginosa (Pa) colonization was 28% and 15% respectively (P = 0.1). CONCLUSIONS: Our results show that pulmonary function has clearly ameliorated over a decade in young CF patients, in a period during which several significant therapeutic changes have been introduced, such as dornase alfa, tobramycin and hypertonic saline. To our knowledge this is the first study showing a cohort effect in patients diagnosed after neonatal screening.

Active Video Game Playing in Children and Adolescents With Cystic Fibrosis: Exercise or Just Fun?

BACKGROUND: Xbox Kinect has been proposed as an exercise intervention in cystic fibrosis (CF), but its potential has not been compared with standard training modalities. METHODS: Using a crossover design, subjects were randomized to 2 intervention groups: Xbox Kinect and a traditional stationary cycle. Heart rate, SpO2, dyspnea, and fatigue were measured. Subject satisfaction was tested. RESULTS: Thirty subjects with CF (11 males, mean ± SD age of 12 ± 2.5 y, mean ± SD FEV1 of 73 ± 16% of predicted) were enrolled. Xbox Kinect provided a cardiovascular demand similar to a stationary cycle, although the modality was different (interval vs. continuous). Maximum heart rates were similar (P = .2). Heart rate target was achieved more frequently with a stationary cycle (P = .02). Xbox Kinect caused less dyspnea (P = .001) and fatigue (P < .001) and was more enjoyable than a stationary cycle (P < .001). CONCLUSIONS: Subjects preferred Xbox Kinect for its interactivity. Xbox Kinect has the potential to be employed as an exercise intervention in young subjects with CF, but investigation over longer periods is needed.

Hepatic adverse drug reactions: a case/non-case study in Italy.

OBJECTIVE: Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. METHODS: Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with "certain", "probable" or "possible" causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4-3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6-4.6), NSAIDs (ROR = 2.9; 95% CI 2.1-3.9) and macrolides (ROR = 1.7; 95% CI 1.2-2.3). CONCLUSION: Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence.

Drug-induced anaphylaxis : case/non-case study based on an italian pharmacovigilance database.

OBJECTIVE: To identify the number of cases of anaphylaxis reported in association with different classes of drugs and compare it with other reports contained in the same database. METHODS: The data were obtained from a database containing all of the spontaneous reports of adverse drug reactions (ADRs) coming from the Italian regions of Emilia Romagna, Lombardy and the Veneto, which are the main contributors to the Italian spontaneous surveillance system. The ADRs reported between January 1990 and December 2003 with a causality assessment of certainly, probably or possibly drug related (according to the WHO criteria) were analysed using a case/non-case design. The cases were defined as the reactions already coded by the WHO preferred terms of 'anaphylactic shock' or 'anaphylactoid reaction' (this last term also included anaphylactic reaction) and those with a time of event onset that suggested an allergic reaction and involved at least two of the skin, respiratory, gastrointestinal, CNS or cardiovascular systems; the non-cases were all of the other ADR reports. The frequency of the association between anaphylaxis and the suspected drug in comparison with the frequency of anaphylaxis associated to all of the other drugs was calculated using the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: Our database contained 744 cases (including 307 cases of anaphylactic shock with 10 deaths) and 27 512 non-cases. The percentage of anaphylaxis cases reported in inpatients was higher than that among outpatients (59.1% vs 40.9%). This distribution is significantly different from that of the other ADR reports that mainly refer to outpatients. After intravenous drug administrations, anaphylactic shock cases were more frequent than anaphylactoid reactions or other ADRs, but more than one-third of these reactions were caused by an oral drug. Blood substitutes and radiology contrast agents had the highest RORs. Among the systemic antibacterial agents, anaphylaxis was disproportionally reported more often for penicillins, quinolones, cephalosporins and glycopeptides, but diclofenac was the only NSAID with a significant ROR. As a category, vaccines had a significantly lower ROR, thus indicating that anaphylaxis is reported proportionally less than other ADRs. CONCLUSIONS: Anaphylaxis is a severe ADR that may also occur with commonly used drugs. It represents 2.7% of all of the ADRs reported in an Italian spontaneous reporting database.