Growth Charts for Shwachman-Diamond Syndrome at Ages 0 to 18 Years.

Shwachman-Diamond syndrome (SDS) is one of the most common inherited bone marrow failure syndromes. SDS is characterized by hypocellular bone marrow, with a severe impairment of the myeloid lineage, resulting in neutropenia, thrombocytopenia, and, more rarely, anemia. Almost 15% of patients with SDS develop myelodysplastic syndrome or acute myeloid leukemia as early as childhood or young adulthood. Exocrine pancreatic insufficiency is another common feature of SDS. Almost all patients with SDS show failure to thrive, which is associated with skeletal abnormalities due to defective ossification. Considering these observations, it remains unfeasible to use the common growth charts already available for the general population. To address this issue, we report how we drew up growth charts of patients with SDS aged 0 to 18 years. We analyzed height, weight, and body max index (BMI) in 121 Italian patients with SDS. Results indicated that the 50th and 3rd percentiles of weight and height of the pediatric general population correspond to the 97th and 50th percentiles of patients with SDS aged 0-18 years, respectively. In addition, the percentage increment in weight of subjects aged 14-18 years was higher in patients with SDS than in the general population. SDS-specific growth charts, such as those described here, afford a new tool, which is potentially useful for both clinical and research purposes in SDS.

Relationship Between Lung Volumes and Heterogeneity in the Response to Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Lung Disease.

BACKGROUND: The effects of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory outcomes for people with cystic fibrosis (CF) were demonstrated by several clinical trials, mainly based on simple spirometry. However, gains in lung function may vary greatly between patients, and predictors of FEV1 change after treatment are still missing. RESEARCH QUESTION: Which ventilatory parameters are involved in the heterogeneity of FEV1 change after 12-month ETI treatment in people with CF with advanced lung disease? STUDY DESIGN AND METHODS: This was a multicenter, observational, prospective cohort study at two major CF centers in Italy. We enrolled 47 adults with CF and advanced lung disease (FEV1 < 40% or actively listed for lung transplant) who started ETI treatment between December 2019 and December 2021. At treatment initiation and after 12 months, patients underwent body plethysmography. Values were compared at the two time points. To assess the relationship between baseline plethysmography measurements and treatment-induced changes in FEV1, we used the Spearman rank correlation coefficient (r) and median quantile regressions. RESULTS: After 12 months of ETI treatment, there was a significant increase in FEV1 % predicted from a median value of 36.0 (25th-75th percentile, 33-39) to 52 (25th-75th percentile, 43-61) (P < .001). Inspiratory capacity/total lung capacity (TLC) ratio also increased from 32.0 (25th-75th percentile, 28.6-36.9) to 36.3 (25th-75th percentile, 33.4-41.3) (P < .001). Specific airway resistance decreased from 263 (25th-75th percentile, 182-405) to 207 (25th-75th percentile, 120-258) (P < .001). Functional residual capacity/TLC ratio decreased from 68.2 (25th-75th percentile, 63.3-71.9) to 63.9 (25th-75th percentile, 58.8-67.1) (P < .001), and residual volume (RV)/TLC ratio decreased from 53.1 (25th-75th percentile, 48.3-59.4) to 45.6 (25th-75th percentile, 39.4-49.8) (P < .001). Changes in FEV1 % predicted negatively correlated with baseline functional residual capacity/TLC ratio (r = -0.38, P = .009) and RV/TLC ratio (r= -0.42, P = .004). After adjustment for age at treatment initiation and cystic fibrosis transmembrane conductance regulator genotype, we estimated that for each 10-unit increase in baseline RV/TLC ratio, the expected median change in FEV1 decreased by 2.3 (95% CI, -5.8 to -0.8). INTERPRETATION: ETI was associated with improvements in both static and dynamic volumes in people with CF and advanced lung disease. Heterogeneity in FEV1 % predicted change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline.

Efficacy of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis.

PURPOSE: Our work aims to add evidence on the effectiveness of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis. MATERIALS AND METHODS: We conducted an observational retrospective cohort study at the Cystic Fibrosis Center of a tertiary care hospital to investigate the effect of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis patients, aged 12 or older. The study's endpoints were the change in the occurrence of acute exacerbations of chronic rhinosinusitis, and the variation of the endoscopic and radiologic findings scored using the Lund-Kennedy endoscopic scale, Lund-Mackay, and modified Lund-Mackay radiologic scales, in patients who underwent both pre-treatment and post-treatment examinations. RESULTS: The study population comprised 136 patients, of which 28 underwent both pre-treatment and post-treatment nasal endoscopy and 15 had pre- and post-treatment CT scans. Elexacaftor-Tezacaftor-Ivacaftor provided a significant improvement in chronic rhinosinusitis. The mean number of acute exacerbations of chronic rhinosinusitis per year in the pre-treatment time was 0.55 versus 0.35 during the treatment (p < 0.0021). The Lund-Kennedy scale had a pre-treatment average score of 4.21 points versus 1.5 points after the start of Elexacaftor-Tezacaftor-Ivacaftor (p < 0.0001). The average Lund-Mackay and modified Lund-Mackay scores in the pre-treatment time were respectively 14.6 and 16.45 points; and after the start of the therapy, they became 5.87 and 6.73 (p < 0.0001). CONCLUSION: Elexacaftor-Tezacaftor-Ivacaftor was associated with fewer acute exacerbations of chronic rhinosinusitis, and a significant improvement of chronic rhinosinusitis evaluated endoscopically and radiologically. To our knowledge, this is the first study investigating the change in the occurrence of acute exacerbation of chronic rhinosinusitis in patients affected by cystic fibrosis in therapy with Elexacaftor-Tezacaftor-Ivacaftor.

Inducing Cough Reflex by Capsaicin Spray Stimulation in Patients with Acquired Brain Injury: A Preliminary Test and Proof of Concept.

Individuals with acquired brain injuries (ABIs) may experience various complications related to poor coughing or impaired cough reflex (including risk of aspiration pneumonia or respiratory infections). For this reason, cough assessment is an important component in the clinical evaluation since patients with ABI are not able to cough voluntarily due to severe motor deficits. When voluntarily coughing is not possible, it is essential for clinical practices to find a quick and minimally invasive way to induce a cough reflex. In the present study, we evaluated the cough reflex in ABI patients using a new method based on a capsaicin spray stimulation test. In total, 150 healthy controls demographically matched with 50 ABI patients were included in this study. Clinical observations demonstrated robust cough response in both healthy controls and ABI patients, as well as the safety and tolerability of capsaicin spray stimulation. ABI patients with dysphagia were characterized by slower and delayed cough responses. Further studies are needed to validate this feasible, less-invasive, and simple-to-comprehend technique in inducing cough reflex. According to this preliminary evidence, we believe that this test might be translated into a simple and effective treatment to improve reflexive cough modulation in ABI patients.

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.

Primary ciliary dyskinesia: A multicenter survey on clinical practice and patient management in Italy.

INTRODUCTION: There are no recent data on primary ciliary dyskinesia (PCD) distribution, diagnosis and treatment in Italy. METHODS: A descriptive study based on a survey questionnaire. It consisted of three sections (patients, diagnosis, and treatment), and sent to all the Italian PCD Centers. RESULTS: Questionnaires obtained from 20/22 centers in 12/20 regions showed that the total number of PCD patients treated at the participating centers was of 416. Out of all centers, 55% follow <20 patients, two centers have >40 patients, and 75% follow both pediatric and adults. Age at diagnosis was between 4 and 8 years in 45% of the centers, <3 years in three centers. Nasal nitric oxide, transmission electron microscopy and ciliary high-speed video microscopy are performed in 75%, 90%, and 40% of centers, respectively. Immunofluorescence is available in five centers. Genetic analysis is offered in 55% of the centers, and in seven centers >50% of the patients have a known genetic profile. Patients treated at all centers receive inhaled saline solutions, corticosteroids and chest physiotherapy. Prophylactic antibiotics and mucolytics are prescribed in 95% and 50% of the centers, respectively. Pseudomonas infection is treated with oral or inhaled antibiotics. CONCLUSIONS: Many Italian centers care for a small number of pediatric and adult patients, and diagnosis is often delayed. We found a great variability in the available diagnostic procedures, as well in the prescribed therapies. Our study will help to uniform diagnostic algorithm and share treatments protocols for PCD in Italy and allowed to set specific national goals.

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.

State-of-the-art review of lung imaging in cystic fibrosis with recommendations for pulmonologists and radiologists from the "iMAging managEment of cySTic fibROsis" (MAESTRO) consortium.

OBJECTIVE: Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists. STUDY DESIGN: A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation. RESULTS: After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements. CONCLUSIONS: There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease.

Management of respiratory tract exacerbations in people with cystic fibrosis: Focus on imaging.

Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective "cut-offs" for clinical and lung function parameters. In particular, the latter shows a large variability, making the current 10% change in spirometry outcomes an unreliable threshold to detect exacerbation. Moreover, spirometry cannot be reliably performed in preschool children and new emerging tools, such as the forced oscillation technique, are still complementary and need more validation. Therefore, lung imaging is a key in providing respiratory tract exacerbation-related structural and functional information. However, imaging encompasses several diagnostic options, each with different advantages and limitations; for instance, conventional chest radiography, the most used radiological technique, may lack sensitivity and specificity in respiratory tract exacerbations diagnosis. Other methods, including computed tomography, positron emission tomography and magnetic resonance imaging, are limited by either radiation safety issues or the need for anesthesia in uncooperative patients. Finally, lung ultrasound has been proposed as a safe bedside option but it is highly operator-dependent and there is no strong evidence of its possible use during respiratory tract exacerbation. This review summarizes the clinical challenges of respiratory tract exacerbations in patients with cystic fibrosis with a special focus on imaging. Firstly, the definition of respiratory tract exacerbation is examined, while diagnostic and monitoring tools are briefly described to set the scene. This is followed by advantages and disadvantages of each imaging technique, concluding with a diagnostic imaging algorithm for disease monitoring during respiratory tract exacerbation in the cystic fibrosis patient.

Clinical course and risk factors for severe COVID-19 among Italian patients with cystic fibrosis: a study within the Italian Cystic Fibrosis Society.

PURPOSE: To describe the clinical course of COVID-19 in patients with cystic fibrosis (CF) and to identify risk factors for severe COVID-19. METHODS: We conducted a prospective study within the Italian CF Society. CF centers collected baseline and follow-up data of patients with virologically confirmed SARS-CoV-2 infection between March 2020 and June 2021. Odds ratios (ORs) for severe SARS-CoV-2 (as defined by hospital admission) were estimated by logistic regression models. RESULTS: The study included 236 patients with positive molecular test for SARS-CoV-2. Six patients died, 43 patients were admitted to hospital, 4 admitted to intensive care unit. Pancreatic insufficiency was associated with increased risk of severe COVID-19 (OR 4.04, 95% CI 1.52; 10.8). After adjusting for age and pancreatic insufficiency, forced expiratory volume in one second (FEVp) < 40% (OR 4.54, 95% CI 1.56; 13.2), oxygen therapy (OR 12.3, 95% CI 2.91-51.7), underweight (OR 2.92, 95% CI 1.12; 7.57), organ transplantation (OR 7.31, 95% CI 2.59; 20.7), diabetes (OR 2.67, 95% CI 1.23; 5.80) and liver disease (OR 3.67, 95% CI 1.77; 7.59) were associated with increased risk of severe COVID-19, while use of dornase alfa was associated with a reduced risk (OR 0.34, 95% CI 0.13-0.88). No significant changes were observed in FEVp from baseline to a median follow-up of 2 months (median difference: 0, interquartile range: - 4; 5, P = 0.62). CONCLUSION: Clinical features indicative of severe form of CF are associated with increased risk of COVID-19 hospitalization. SARS-CoV-2 infected patients do not experience a deterioration of respiratory function.

Does cystic fibrosis constitute an advantage in COVID-19 infection?

The Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.

Antibiotic resistance evolution of Pseudomonas aeruginosa in cystic fibrosis patients (2010-2013).

INTRODUCTION: Pseudomonas aeruginosa is the predominant pathogen responsible of chronic colonization of the airways in cystic fibrosis (CF) patients. There are few European data about antibiotic susceptibility evolution of P aeruginosa in CF patients. OBJECTIVES: The aim of this study is to evaluate the evolution of antibiotic resistance in the period 2010-2013 in CF patients chronically colonized by P aeruginosa and to highlight the characteristics of this evolution in patients younger than 20 years. METHODS: Clinical and microbiological data were extracted from two electronic databases and analyzed. Antibiotic resistance was defined according to European Committee of Antimicrobial Susceptibility Testing for levofloxacin, ciprofloxacin, meropenem, amikacin and ceftazidime. The between-group comparison was drawn with the Chi-square test for proportions, with the T-test for unpaired samples for normally distributed data and with Mann-Whitney test for non-normally distributed data. Significancy was defined by P < .05. RESULTS: Fifty-seven CF patients, including thirteen subjects aged less than 20 years, were enrolled. P.. aeruginosa antibiotic sensitivity decreased significantly for fluoroquinolones, mainly in patients aged <20 years, while it increased for amikacin and colistin. The analysis of minimum inhibitory concentration confirmed these trends. In pediatric patients treated with more than three antibiotic cycles per year, greater resistance was found, except for amikacin and colistin. CONCLUSION: An evolution in P aeruginosa antibiotic resistances is observed in the 4-year period studied. Responsible and informed use of antibiotics is mandatory in CF.

Asymmetric dimethylarginine and related metabolites in exhaled breath condensate of children with cystic fibrosis.

INTRODUCTION: Asymmetric dimethylarginine (ADMA) competitively inhibits nitric oxide synthase (NOS). Its levels in specimens from murine models and asthmatic patients are related to inflammation and oxidative stress. Patients with cystic fibrosis(CF) reportedly have higher arginase activity, lower NO production and NOS expression than healthy controls. OBJECTIVE: The objective was to assess the role of ADMA and related metabolites as disease biomarkers in exhaled breath condensate (EBC) of pediatric CF patients, compared with age-matched healthy controls (HC). METHODS: A longitudinal design was conceived and 34 CF patients (21 stable, 13 at the onset of exacerbation) and 16 HC were enrolled. All CF patients underwent clinical examination, spirometry and EBC collection at enrolment; the same tests were performed also after an antibiotic course in those patients with exacerbation. Metabolites levels in EBC were measured with an ultra-performance liquid chromatography and tandem mass spectrometry technique. RESULTS: All CF patients had ADMA levels (expressed as ratio to tyrosine) similar to those in HC (median 0.0112, IQR 0.0103-0.0120 and median 0.0114, IQR 0.0090-0.0128, respectively; P = 0.983), while a significant increase in the citrulline/tyrosine ratio was found in CF patients (median 0.6419, IQR 0.5738-0.6899 in CF vs median 0.4176, IQR 0.2986-0.5082 in HC; P = 0.00003). No differences in ADMA levels emerged between stable patients and those with exacerbation. CONCLUSION: ADMA and related aminoacids were measured simultaneously for the first time in EBC from CF patients. Higher citrulline/tyrosine ratios were found in CF children with normal ADMA levels, suggesting a dysregulated ADMA metabolism in these patients.

Short stature: an ordinary sign for an unordinary diagnosis.

BACKGROUND: Short stature (SS) is a relatively early sign of poor health. Only in 5% of cases we can explain it through the presence of endocrinological pathologies. Therefore, if SS is present since the first months of life, it is necessary to investigate all systemic disorders with secondary effects on growth. CASE PRESENTATION: We report the case of a 16-months-old male infant with severe SS apparently not associated with other clinical signs or symptoms. The patient arrived to our attention after he was hospitalized for an Echovirus enteritis, associated to moderate neutropenia (800/mm3) and hypertransaminasemia (AST 116 U/L, ALT 88 U/L) at the age of 13 months. SS was detected in that occasion. Since SS persisted even after the complete resolution of enteritis symptoms, he was taken care by our unit. CONCLUSIONS: SS appeared in the first months of life and associated with moderate neutropenia and hypertransaminasemia led us to the diagnosis of Shwachmann-Diamond syndrome. We recommend paying further attention to this condition during the differential diagnosis of children with severe SS.

Detection and monitoring of lung inflammation in cystic fibrosis during respiratory tract exacerbation using diffusion-weighted magnetic resonance imaging.

The aim was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects and monitors inflammatory and lung function changes during respiratory tract exacerbations (RTE) treatment in patients with cystic fibrosis (CF).29 patients with RTE underwent DWI pre- and post-antibiotic treatment. A control group of 27 stable patients, matched for age and sex, underwent DWI with the same time gap as those undergoing RTE treatment. Clinical status and lung function were assessed at each DWI time point. The CF-MRI scoring system was used to assess structural lung changes in both CF groups.Significant reduction in the DWI score over the course of antibiotic treatment (p<0.0001) was observed in patients with RTE, but not in the control group. DWI score had a strong inverse correlation with clinical status (r=-0.504, p<0.0001) and lung function (r=-0.635, p<0.0001) in patients with RTE. Interestingly, there were persistent significant differences in the CF-MRI score between the RTE and control group at both baseline and follow-up (p<0.001), while the differences in DWI score were only observed at baseline (p<0.001).DWI is a promising imaging method for noninvasive detection of pulmonary inflammation during RTE, and may be used to monitor treatment efficacy of anti-inflammatory treatment.

Hyaluronic acid improves the tolerability of hypertonic saline in the chronic treatment of cystic fibrosis patients: a multicenter, randomized, controlled clinical trial.

UNLABELLED: TRIAL DESIGN AND METHODS: Between December 2009 and July 2011, four cystic fibrosis (CF) centers in Italy participated in a randomized, double-blind, controlled clinical trial to test whether 7% hypertonic saline (HS) administered together with 0.1% hyaluronic acid (HA) was better tolerated by patients who previously did not tolerate HS well on its own. Participants were CF patients at least 8 years old, in clinically stable conditions, with forced expiratory volume in 1 sec (FEV1) at least 50% predicted. Forty patients were recruited and randomized to receive either HS or HS plus HA (5 mL to be inhaled over 15 min, twice daily for 28 days). Primary endpoints were cough, throat irritation, salty taste, and overall acceptability, as assessed by each patient on a semiquantitative scale on a diary card. Secondary endpoint was FEV1 change at the end of treatment. Patients were randomized into randomly permuted blocks. The first and last doses were administered in hospital. In between, patients were treated at home. Patients, all caregivers, and the statistician who conducted the analysis (different from the one who generated the random list) were blinded to group assignment. RESULTS: Severity of cough, throat irritation, and saltiness were more severe in patients treated with HS alone, both after the first inhalation and over the entire treatment period. Overall pleasantness was rated higher by patients treated with the combination product. All differences were highly significant. There were no changes in FEV1 between the first and last administrations. Five patients did not complete the study. Four patients (two from each group) withdrew because of cough or throat irritation. One more patient from the HS group withdrew because of a respiratory exacerbation at week 3. CONCLUSIONS: HS is currently a cornerstone in the treatment of CF patients. The addition of HA to HS reduces the prevalence and severity of cough, throat irritation, and saltiness and may improve compliance in patients who previously did not tolerate HS well on its own. Longer-term studies could further assess the benefit of chronic treatment.