Pulmonary Exacerbations Research Articles

Clinical epidemiology and impact of Haemophilus influenzae airway infections in adults with cystic fibrosis

BackgroundHaemophilus influenzae is prevalent within the airways of persons with cystic fibrosis (pwCF). H. influenzae is often associated with pulmonary exacerbations (PEx) in pediatric cohorts, but in adults, studies have yielded conflicting reports around the impact(s) on clinical outcomes such as lung function decline. Accordingly, we sought to discern the prevalence, natural history, and clinical impact of H. influenzae in adult pwCF.MethodsThis single-centre retrospective cohort study reviewed all adult pwCF with H. influenzae sputum cultures between 2002 and 2016. From this cohort, persistently infected subjects (defined as: ≥2 samples with the same pulsotype and > 50% sputum culture-positive for H. influenzae in each year) were matched (1:2) to controls without H. influenzae. Demographic and clinical status (baseline health or during periods of PEx) were obtained at each visit that H. influenzae was cultured. Yearly biobank isolates were typed using pulsed-field gel electrophoresis (PFGE) to assess relatedness.ResultsOver the study period, 30% (n = 70/240) of pwCF were culture positive for H. influenzae, of which 38 (54%) were culture-positive on multiple occasions and 12 (17%) had persistent infection. One hundred and thirty-seven isolates underwent PFGE, with 94 unique pulsotypes identified. Two (1.5%) were serotype f with the rest non-typeable (98.5%). H. influenzae isolation was associated with an increased risk of PEx (RR = 1.61 [1.14–2.27], p = 0.006), however, this association was lost when we excluded those who irregularly produced sputum (i.e. only during a PEx). Annual lung function decline did not differ across cohorts.ConclusionsIsolation of H. influenzae was common amongst adult pwCF but often transient. H. influenzae infection was not associated with acute PEx or chronic lung function decline.

Association of Chronic Obstructive Pulmonary Disease Exacerbation with Type-2 Diabetes Mellitus Comorbidity: Possibility Role of IL-8

Introduction: Type-2 Diabetes Mellitus (type-2 DM) is associated with the incidence of respiratory tract infections which is a risk factor for Chronic Obstructive Pulmonary Disease (COPD) exacerbations. Interleukin-8 (IL-8) is one of inflammatory mediators both in COPD exacerbation and pathogenesis of type 2 DM. Method: We conducted literature searched in online database PUBMED and Google Sholar, all study published since 2015 until 2024. Conclusions: IL-8 is a proinflammatory cytokine that has been shown to play a role in COPD because it triggers mucus hypersecretion and bacterial colonization which is risk factor for exacerbation of COPD and causes adipose tissue dysfunction in type 2 diabetes. Keywords: COPD exacerbation; type-2 DM; prevalence; IL-8

Pulmonary embolism work-up in chronic obstructive pulmonary disease exacerbations: what is the best strategy for clinicians?

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural course of COPD, as they increase morbidity and mortality. Acute pulmonary embolism may mimic the symptoms of COPD exacerbations. However, the exact prevalence of pulmonary embolism in unexplained exacerbations of COPD is unclear based on the current data. This review provides a practical approach to patients with COPD complaining of worsening respiratory symptoms. A randomized clinical trial has shown that a routine pulmonary embolism diagnostic work-up does not improve care of patients with acute exacerbations of COPD. However, review of the recent literature suggests that a nonnegligible proportion of otherwise unexplained exacerbations of COPD may be caused by pulmonary embolism. To date, nevertheless, there are limited studies developing and validating clinical models that might aid in the identification of patients requiring additional tests for the diagnosis of pulmonary embolism. Until new evidence becomes available, we believe that a routine diagnostic strategy for pulmonary embolism is not appropriate for patients with acute exacerbations of COPD. Recommendations for routine pulmonary embolism diagnostic work-up necessitate further development of prognostic models and conduct of clinical trials that assess important health outcomes.

The Experiences and Perceptions of Telehealth in Patients Living With Advanced Chronic Obstructive Pulmonary Disease: A Qualitative Evidence Synthesis.

To systematically identify, appraise and synthesise qualitative research evidence which examined the impact of telehealth on the experiences and perceptions of patients living with advanced chronic obstructive pulmonary disease, to inform the development of patient-centred telehealth. Qualitative evidence synthesis. CINAHL, Cochrane, Embase, PUBMED, MEDLINE, EThOS, Web of Science, PsycINFO, Lenus, DART, RIAN and ProQuest were searched for primary qualitative studies undertaken between 2008 and 2023. A thematic synthesis of studies was undertaken to identify descriptive themes relating to patient views. Methodological quality was assessed using the Critical Appraisal Skills Programme framework, and confidence in review findings was assessed using the GRADE-CERQual approach. Nine studies met the inclusion criteria and were included in the final synthesis. Four analytical themes were generated (1) telehealth as a facilitator of independence, (2) the influence of patient and healthcare provider relationship on successful engagement with telehealth, (3) usability of telehealth to patients living with advanced chronic obstructive pulmonary disease and (4) trusting virtual health services and facilitating confidence in the patient/service user. Five descriptive themes emerged: (i) individualised telehealth chronic obstructive pulmonary disease care (ownership and control), (ii) managing chronic obstructive pulmonary disease exacerbations, (iii) being heard and feeling understood, (iv) telehealth as an education aid and (v) aging and virtual technology. Understanding the experiences of patients with chronic obstructive pulmonary disease and their engagement with telehealth is a necessary determinant of how best to utilise telehealth in this population and may serve to inform policymakers to further develop and implement telehealth into practice. Future research on patients and healthcare professionals' views on telehealth use in the palliative stage of this illness may also be valuable. Findings add value by providing healthcare providers with additional evidence to improve understanding of both telehealth complexity and human experiences and perceptions. It is anticipated that a deeper understanding of chronic obstructive pulmonary disease patients' experiences and perceptions will inform the development of strategies to maximise and enhance the application of patient-centred telehealth within the context of coping and living with a debilitating condition. No patient or public contribution was utilised in this study.

One-Year Effect of Elexacaftor/Tezacaftor/Ivacaftor Therapy on HbA1c Levels and Insulin Requirement in Patients with Insulin-Dependent Cystic Fibrosis-Related Diabetes: A Retrospective Observational Study.

The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial. The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population. A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T3mo), 6 months (T6mo) and 12 months (T12mo) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del). Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T3mo and T6mo, but not at T12mo, whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly. We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

Efficacy and safety of inhaled molecular hydrogen therapy in patients with respiratory failure due to chronic obstructive pulmonary disease exacerbation in post-COVID period

Molecular hydrogen (H2) is a powerful antioxidant and anti-apoptotic agent. H2 has been studied in a number of clinical studies in the recent years.The aim of this research was to investigate the efficacy and safety of H2 inhalation therapy in patients with hypoxemic and hypercapnic respiratory failure (RF) against exacerbation of chronic obstructive pulmonary disease (COPD) in the post-COVID (Corona Virus Disease 2019) period.Methods. The randomized prospective parallel comparative study included patients (n = 60: 40 men aged 71.2 ± 1.8 years, 20 women aged 70.9 ± 2.8 years) with a post-COVID-19 exacerbation of COPD complicated by hypoxemic/hypercapnic RF. The patients were divided into 2 groups: group 1 (main) (n = 30: 18 men, 12 women), group 2 (control) (n = 30: 18 men, 12 women). To maintain arterial blood saturation ≥ 90 %, patients in both groups received respiratory support (non-invasive ventilation) using the Prisma 25ST device (Lowenstein Medical, Germany) in the BiPAP S/T mode (BiLevel Positive Airway Pressure Spontaneous/Time spontaneous/forced mode 20–24/4–6 cm H2O and O2, respectively; the fractional oxygen concentration in the inhaled gas mixture was ≥ 24%). In addition to standard treatment, patients in the main group received additional H2 therapy (Suisonia device, Japan) through a nasal cannula for 90 minutes daily for 14 days.Results. In patients of the main group, a decrease in the stiffness index was detected from 14.6 ± 1.2 to 6.2 ± 0.6 m/s, and the arterial blood lactate level – from 2.84 ± 0.1 to 0.02 ± 0.1 mmol/l (p < 0.001), the calculated shunt fraction Qs/Qt (venous admixture) – from 27.21 ± 3.4 to 7.14 ± 1.23 (p < 0.01) and an increase in the following parameters: reflection index – from 42.2 ± 2.0 to 66.2 ± 4.9% (p < 0.05), virus-specific IgG level – from 134 ± 125 to 669 ± 164 (p < 0. 05), blood flow velocity in arterioles – from 473 ± 108 to 868 ± 64 μm/s (p < 0.05), blood flow velocity in venules – from 299 ± 56 to 862 ± 69 μm/s (p < 0.05), the 6-minute walk distance – from 57.1 ± 4.4 to 328.9 ± 33.7 m (p < 0.05).Conclusion. H2 inhalations were safe and increased the therapeutic effect when added to standard therapy for patients with hypoxemic and hypercapnic RF during exacerbation of COPD in the post-COVID period.

The Real-World Effectiveness of Antifungals in People with Cystic Fibrosis and Aspergillus-Positive Cultures.

The pathogenicity of Aspergillus in the cystic fibrosis (CF) airway is debated, leading to unclear clinical benefit of antifungal therapy for Aspergillus infection. To determine the real-world effectiveness of antifungal use in people with CF (PwCF) with Aspergillus species in the United States. We conducted a retrospective cohort study evaluating the association of antifungal use and respiratory outcomes in PwCF and Aspergillus positive cultures using the Cystic Fibrosis Foundation patient registry. Marginal structural models using inverse-probability treatment weighted estimators were used to test if antifungal exposure was associated with forced expiratory volume in one second percent predicted (FEV1pp) and pulmonary exacerbation rate, while controlling for fixed and time-varying confounders. We conducted sensitivity analyses on individuals with persistent Aspergillus and without concomitant allergic bronchopulmonary aspergillosis (ABPA). A total of 14,754 individuals with Aspergillus positive cultures between 2006 and 2019 were identified. Antifungals were prescribed to 3,575 (24.2%) unique PwCF during the study period. Antifungal use was not associated with FEV1pp (adjusted estimate -0.96 percentage points, 95% CI -2.21,0.29). Antifungal use was associated with 29% increased rate of pulmonary exacerbations requiring intravenous (IV) antibiotics (adjusted IRR=1.29, 95% CI 1.22, 1.37). In sensitivity analyses limited to individuals without ABPA< antifungals were associated with 1.88 lower FEV1pp (95% CI -3.35, -0.41) and an increased rate of pulmonary exacerbations (adjusted IRR= 1.30, 95% CI 1.21,1.40). Whereas, in patients with persistent Aspergillus and persistent Aspergillus without concomitant ABPA, antifungals were not associated with FEV1pp. Antifungal therapy in PwCF and Aspergillus positive cultures was not associated with improvements in FEV>1pp. While antifungal therapy was associated with increased risk for pulmonary exacerbations, this could reflect confounding by severity of disease. Randomized clinical trials examining the clinical efficacy of antifungals in Aspergillus infections are warranted.

Patent Foramen Ovale and Oxygenation in Patients with Cystic Fibrosis.

Patent foramen ovale (PFO) affects about 25% of the population. We studied outcomes in cystic fibrosis (CF). We conducted a case-control study of patients with CF (PwCF) and age and sex-matched controls who underwent agitated saline contrast (bubble) echocardiography, 1998-2020. We assessed PFO impacts using linear, logistic, quasipoisson and proportional hazards models. 59 of 64 PwCF and 88 of 93 controls underwent bubble studies to investigate unexplained hypoxemia or dyspnea. PwCF had higher mean pulmonary artery pressure (PAP, 6.9 mm Hg, 95% Confidence Interval [CI] = 2.35-11.4), reduced tricuspid annular plane systolic excursion (TAPSE, -3.78 mm, CI = -5.64 to -1.93) and similar right ventricular diastolic sizes. Absent hypoxemia, PFO incidence was similar between PwCF and controls; with hypoxemia, PFO was more common in CF (Odds Ratio [OR] = 5.00, CI = 1.32-19.0). In CF, oxygen supplementation occurred at a percent predicted forced expiratory volume in 1 s (FEV1%) 22.5 points higher with PFO. Adjusted for FEV1%, PFO was associated with 0.59 more prior year pulmonary exacerbations (CI = 0.20-0.98) and shorter time to next exacerbation (Hazard Ratio = 1.86, CI = 1.06-3.26). Associations between PFO and hypoxemia or exacerbations were insensitive to PAP, TAPSE and CF transmembrane regulator protein modulator treatments. PFO was not associated with CF time to death or lung transplantation (median 1.87 years) adjusted for age, sex, FEV1% and prior year exacerbation counts. PFO in CF is associated with hypoxemia at higher FEV1% and more pulmonary exacerbations but not survival.

A Three-year Longitudinal Assessment of Pseudomonas aeruginosa Antibiotic Susceptibility in Children With Cystic Fibrosis in the Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy

fibrosis is a genetic disease characterized by chronic lung infection, often with Pseudomonas aeruginosa, requiring repeated antibiotic treatment for pulmonary exacerbations. In the era of cystic fibrosis transmembrane conductance regulator modulator therapy, we assessed susceptibility to antipseudomonal antibiotics in modulator-eligible and modulator-ineligible children over 3 years and found that P. aeruginosa isolates largely remained susceptible to standard parenteral but not oral antimicrobial agents.

Epidemiology of bronchiectasis.

Bronchiectasis is a chronic respiratory disease characterised by permanent enlargement of the airways associated with cough, sputum production and a history of pulmonary exacerbations. In the past few years, incidence and prevalence of bronchiectasis have increased worldwide, possibly due to advances in imaging techniques and disease awareness, leading to increased socioeconomic burden and healthcare costs. Consistently, a mortality increase in bronchiectasis patient cohorts has been demonstrated in certain areas of the globe, with mortality rates of 16-24.8% over 4-5 years of follow-up. However, heterogeneity in epidemiological data is consistent, as reported prevalence in the general population ranges from 52.3 to more than 1000 per 100 000. Methodological flaws in the designs of available studies are likely to underestimate the proportion of people suffering from this condition worldwide and comparisons between different areas of the globe might be unreliable due to different assessment methods or local implementation of the same method in different contexts. Differences in disease severity associated with diverse geographical distribution of aetiologies, comorbidities and microbiology might explain an additional quota of heterogeneity. Finally, limited access to care in certain geographical areas is associated with both underestimation of the disease and increased severity and mortality. The aim of this review is to provide a snapshot of available real-world epidemiological data describing incidence and prevalence of bronchiectasis in the general population. Furthermore, data on mortality, healthcare burden and high-risk populations are provided. Finally, an analysis of the geographical distribution of determinants contributing to differences in bronchiectasis epidemiology is offered.

Population Pharmacokinetic Modeling of Cefepime, Meropenem, and Piperacillin-Tazobactam in Patients with Cystic Fibrosis.

Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. Management of these infections is increasingly challenging due to decreased antimicrobial susceptibility to beta-lactam antibiotics. The pharmacokinetics of these agents are inadequately characterized in patients with CF. One hundred fifty-five pediatric and adult participants with CF receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK analysis was conducted using nonlinear mixed-effects modeling. Clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations were performed to evaluate probability of target attainment (PTA) for different dosing regimens. Estimated creatinine clearance, and total or lean body weight, affected the pharmacokinetics of cefepime and meropenem. No covariates were identified for piperacillin and tazobactam. In the cefepime group, a 3-h infusion achieved higher PTA than a 0.5-h infusion for all participants. Estimated breakpoints (the respective minimum inhibitory concentration (MIC) up to which ≥90% of patients are predicted to reach a PK/PD target) were two- to four-fold higher in pediatric participants receiving a 3-h vs. 0.5-h infusion. In the meropenem group, increased creatinine clearance led to reduced PTA. In the piperacillin-tazobactam group, total daily dose and mode of administration were principal drivers of PTA. Standard dosing regimens fail to achieve specific MIC targets in patients with CF. Therefore, clinicians should incorporate local antibiograms and PK models to determine optimal dosing. Further PK optimization to account for interindividual differences could be achieved by real-time beta-lactam therapeutic drug monitoring.

Treatment of Psychological Symptoms in Patients with Cystic Fibrosis

The aim of this article is to identify and illustrate the most used psychological techniques in the field of cystic fibrosis (CF) and to help clinicians choose the most appropriate strategy among various possibilities. The disease and its medical treatments can be difficult to tolerate and can cause anxiety about health status or feelings of hopelessness and stress. The prevalence of depression and anxiety is 2.3 times higher in adults with CF than in community samples. A strong correlation has been identified between elevated psychological distress and unfavorable health outcomes, including, among others, impaired lung function, reduced BMI, an increased incidence of pulmonary exacerbations, and an elevated risk of transplantation. The use of psychological interventions is useful in addressing these common distresses in CF patients. Aware of the necessity of identifying efficacious interventions for all levels of depression and anxiety in CF patients, this study presents an overview of the research on psychological interventions for patients with CF, in order to complement the treatments suggested by the international guidelines on mental health in CF cases. In fact, the aim of this study is to conduct a review and quantitative synthesis of the psychological intervention techniques that are currently available for individuals with CF.

Effect of CFTR Modulators on Oxidative Stress and Autophagy in Non-CFTR-Expressing Cells.

The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the individual components and ETI may have potential off-target effects, highlighting the need to understand how these modulators impact cellular physiology, particularly in cells that do not express CF transmembrane conductance regulator (CFTR). We used HEK293 cells, as a cell model not expressing the CFTR protein, to evaluate the effect of ETI and each of its components on autophagic machinery and on the Rab5/7 components of the Rab pathway. We firstly demonstrate that the single modulators Teza and Iva, and the combinations ET and ETI, increased ROS production in the absence of their target while decreasing it in cells expressing the CFTR ∆F508del. This increase in cellular stress was followed by an increase in the total level of polyubiquitinated proteins as well as the p62 level and LC3II/LC3I ratio. Furthermore, we found that ETI had the opposite effect on Rabs by increasing Rab5 levels while decreasing Rab7. Interestingly, these changes were abolished by the expression of mutated CFTR. Overall, our data suggest that in the absence of their target, both the individual modulators and ETI increased ROS production and halted both autophagic flux and plasma membrane protein recycling.

Secular and modulator-specific drifts in the predictive performance of a rapid lung function decline algorithm: a cystic fibrosis patient registry study

PurposePredicting the onset of pulmonary exacerbation for people with cystic fibrosis (CF) is critical to identify those at high risk in advance and allows timely clinical intervention. The FEV1-indicated exacerbation signal (FIES) has been proposed by the CF Learning Network to identify pulmonary exacerbation events, but temporal predictive performance of this marker is unknown.MethodsTo assess the epidemiologic impact of secular trends in CF care and treatments on algorithms aimed at prediction of pulmonary exacerbation, we evaluated prediction model “drift” using a longitudinal retrospective cohort of 29,476 individuals from the U.S. CF Foundation Patient Registry (2011–2018). The FIES marker was defined for each clinical encounter using relative drops in lung function, measured as forced expiratory volume in 1 s of % predicted (FEV1pp). We formed predictive probabilities for each FIES event via a target function for a predictive algorithm of FEV1pp. Models were trained using 2 year data windows with prediction performance tested on subsequent years.ResultsYear-over-year FIES event discrimination remained consistent (area under the receiver-operator characteristic curve, AUC > 80%). Annual drift was < 1% with actual drop in AUC ~ 3% in 6 years. The model performed best in individuals with moderate-to-low baseline FEV1pp (AUC range: 84–85%). For relatively higher FEV1pp levels, discrimination was slightly lower with higher AUC variability.ConclusionWhile model fit improved by accounting for modulator therapy, prediction performance was similar. Most impactful model drifts occurred after 2012 coinciding with increased ivacaftor modulator use. Additional evaluation will be necessary given recent, broad uptake of highly effective modulators.

Dynamics of inflammatory markers in patients with normal and impaired glucose metabolism during lung exacerbation treatment

Cystic fibrosis (CF) is one of the most common autosomal-recessive inherited diseases. The primary genetic defect in CF is aligned CFTR gene mutation which encodes a membrane protein functioning as cAMP-depended chloride channel. Classic phenotypical manifestations of CF include chronic obstructive pulmonary disease with bronchiectasis, persisting infection (St. aureus, Ps. aeruginosa, B. cepacia) and aberrant inflammatory response, as well as exocrine pancreatic insufficiency with malabsorption, hypotrophy and growth retardation. CFTR deficiency is also accompanied by β-cell pancreatic dysfunction, causing glucose metabolism disturbances and CF-related diabetes. The aim of the study was the comparison of inflammatory markers dynamics in patients with normal and disturbed glucose metabolism during pulmonary exacerbation treatment. The study included 10 patients with impaired glucose tolerance (Group 1) and 24 patients with normal carbohydrate metabolism (Group 2). Patients of the two groups did not significantly differ in demographic characteristics, pulmonary function test and body mass index parameters, as well as in the number of F508del mutation carriers and in the number of those who were infected with Ps. aeruginosa and B. cepacia complex. Blood sampling was performed twice: before and after a routine course of antibiotic therapy. Plasma levels of biomarkers including the antibodies to single- and double-stranded DNA (ss-DNA-IgG, ds-DNA-IgG, respectively), the hormones (dehydroepiandrosterone (DHEA) and DHEA sulfate), C-reactive protein (CRP), Mn-dependent superoxide dismutase (Mn-SOD), and the cytokines (tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), IFNα, tissue growth factor-β1 (TGF-β1), interleukin-4 (IL-4), IL-6, IL-10, IL-17A) were assessed using commercial immunoassay kits. Our study shows that antibiotic treatment did not have a sufficient influence on levels of inflammatory markers in patients with disturbances of glucose metabolism while patients with normal glucose tolerance demonstrated a significant reduction in inflammatory marker values after the therapy. The data may suggest both impaired effectivity of antibiotic treatment and aberrant inflammatory response in patients with glucose intolerance.

The Association between Aminoglycoside Exposure and Ototoxicity in Children with Cystic Fibrosis

Introduction: Pulmonary exacerbations increase the requirement of aminoglycoside (AG) antibiotics in people with cystic fibrosis (pwCF). Several studies have shown that AGs have a cumulative effect on ototoxicity. We aimed to investigate the relationship between AG exposure and ototoxicity by using 3 different methods in patients with CF. Materials/Methods: The multicenter study included 121 pwCF aged between 5 and 18 years with a history of parenteral AG exposure. Standard pure-tone audiometry, extended high-frequency pure-tone audiometry (EHF-PTA), and distortion-product otoacoustic emissions (DPOAE) tests were performed. Mitochondrial mutation analysis for m1555G>A was performed in 61 patients. Results: Median age was 12.85 years and 52.1% (n = 63) were male. 18.2% (n = 22) of the patients had received parenteral AGs more than 5 courses/lifetime. Ototoxicity was detected in at least one of the tests in 56.2% (n = 68) of the patients. Only 10.7% (n = 13) of the patients had reported a symptom indicating ototoxicity. 30.3% (n = 30) of the patients had ototoxicity in the low exposure group, while it was 45.5% (n = 10) in the high exposure group according to EHF-PTA (p > 0.05). Median number of parenteral amikacin courses was significantly higher in the ototoxic group (2 [1.25–5.75] vs. 2 [1–3]; p = 0.045). No m1555A>G mutation was detected in 61 patients who screened for mitochondrial mutation analysis. Conclusion: As AG ototoxicity occurs primarily at high frequencies, EHF-PTA is important in early detecting ototoxicity. EHF-PTA and DPOAE detected ototoxicity in some patients with normal PTA results. All pwCF with a history of AG exposure should be evaluated for hearing loss since symptoms may only be noticed in the late period.

Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis

BackgroundIvacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of...

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis

BackgroundIvacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied.MethodsWe...

Elexacaftor/tezacaftor/ivacaftor, a game-changer in cystic fibrosis: The Portuguese experience

BackgroundPhase 3 trials of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) combination treatment in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele showed profound short-term effects on lung function, weight, and pulmonary exacerbations (PEx). The authors conducted a 12-month study to add evidence on the real-world long-term effectiveness and safety of CFTR modulator therapy with ELX/TEZ/IVA in Portuguese CF adult population. MethodsAmbispective, multicentre, observational, real-life study involving all the Portuguese CF Reference Centres. Adult patients on treatment with ELX/TEZ/IVA combination outside clinical trials were included. Demographics, efficacy, and safety variables on the first 12 months of treatment were compared with the pre-treatment year. Results132 adult people with CF were included, of which 119 completed 12 months treatment (mean duration of treatment 21.5 months). Mean age was 31.7 ± 11.0 years, 53 % patients were homozygous for the F508del variant, baseline sweat chloride was 86.7 ± 25.9 mmol/L and pre-treatment percent-predicted FEV1 was 77.9 ± 19.7 %. At 1 year, mean absolute change from baseline in FEV1 was +0.46L (95 % CI: 0.37, 0.55; p < 0.001) and +13.9 percentage points (95 % CI: 11.5, 16.2; p < 0.001). PEx episodes decreased by 78 % (p < 0.001) and hospitalizations for PEx decreased by 91.4 % (p < 0.001). Body mass index (BMI) increased 1.2 kg/m2 (95 % CI: 0.9, 1.5; p < 0.001). Mean sweat chloride variation was −44.5 mmol/L (95 % CI: −49.8, −39.2; p < 0.001). No correlation was found between sweat chloride and lung function (r = −0.116, p = 0.335). There were no major safety concerns. Of note, headache was reported in 7.6 % and neuropsychiatric manifestations occurred in 12.6 % treated patients, being anxiety and depressive disorders the most common. ConclusionsELX/TEZ/IVA treatment in Portuguese adults with CF was associated with significant improvement in lung function, a drop in PEx and PEx-related hospitalizations and increase in BMI at 12 months and was well tolerated. These results add knowledge to our understanding of clinical benefits and tolerability of ELX/TEZ/IVA. Careful evaluation of adverse effects of ELX/TEZ/IVA therapy and its determinants, mainly concerning mental health, are a research priority.

The Impact of Age of Diagnosis in Children with Primary Ciliary Dyskinesia.

The typical symptoms for primary ciliary dyskinesia (PCD) manifest after birth and in early infancy, however diagnosis is often not confirmed during infancy. There is currently a lack of evidence in PCD regarding the impact of the age of diagnosis on clinical outcomes. To determine whether early diagnosis is related to improved long-term outcomes. This was a retrospective study of patients diagnosed with PCD between 2000 to 2022. We divided our cohort to three groups according to the age of diagnosis. 1) early diagnosis (<1 year); typical diagnosis (1-7 years) and late diagnosis (8-14 years). We compared various clinical long-term outcomes between the groups. Over the study period, 110 patients were included in the analysis, with 41 patients in the early diagnosis group, 35 in the typical diagnosis group and 34 patients in the late diagnosis group. The presence of unexplained neonatal respiratory distress (NRDS) and organ laterality defect were higher in the early diagnosis group with rates between the early, typical, and late diagnosis groups for NRDS (80% vs 53% vs 61%, p=0.045) and laterality defect (64% vs 50% vs 18%, p<0.001). At the end of the first decade of life, patients in the early diagnosis and the typical age of diagnosis had better forced expiratory volume in 1 second (FEV1), compared to the late diagnosis group (93.5% and 93.1% vs 80.2%, P=0.002), respectively, but there was no significant change in the annual rate of decline between the groups once diagnosis was confirmed. Patient diagnosed late had significantly higher rates of pulmonary exacerbations (Pex) compared to typical age (1.95 vs 0.75 Pex/year, p<0.01) Conclusion: Late diagnosis (>8 years) was associated with lower FEV1 throughout childhood, although once diagnosed, the annual rate of decline was not different. These findings demonstrate the negative effect of delayed diagnosis in pediatric PCD.