Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study.

BACKGROUND: The prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF. METHODS: This retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment. RESULTS: Fifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05). CONCLUSIONS: For the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

The new face of cystic fibrosis in the era of population genetic carrier screening.

BACKGROUND: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features. METHODS: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected. RESULTS: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p=  0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04). CONCLUSIONS: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF.

Exhaled Breath Condensate and Respiratory Sequelae in Children Post-COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an acute respiratory illness. A substantial proportion of adults experience persistent symptoms. There is a paucity of data on respiratory sequelae in children. Exhaled breath condensate (EBC) is a non-invasive tool used to assess airway inflammation. OBJECTIVES: This study aimed to evaluate EBC parameters, respiratory, mental and physical ability among children post COVID-19 infection. METHODS: Observational study of confirmed SARS-CoV-2 infection cases among children, aged 5-18 years, evaluated once, 1-6 months post positive SARS-CoV-2 PCR testing. All subjects performed spirometry, 6-min walk test (6MWT), EBC (pH, interleukin-6), and completed medical history questionnaires, Depression, Anxiety, and Stress Scale (DASS-21), and physical activity scores. Severity of COVID-19 disease was classified according to WHO criteria. RESULTS: Fifty-eight children were included and classified asymptomatic (n = 14), mild (n = 37), and moderate (n = 7) disease. The asymptomatic group included younger patients compared to the mild and moderate groups (8.9 ± 2.5y vs. 12.3 ± 3.6y and 14.6 ± 2.5y, respectively, p = 0.001), as well as lower DASS-21 total scores (3.4 ± 4 vs. 8.7 ± 9.4 and 8.7 ± 0.6 respectively, p = 0.056), with higher scores in proximity to positive PCR (p = 0.011). No differences were found between the 3 groups regarding EBC, 6MWT, spirometry, body mass index percentile, and activity scores. CONCLUSIONS: COVID-19 is an asymptomatic-mild disease in most young healthy children, with gradually diminishing emotional symptoms. Children without prolonged respiratory symptoms revealed no significant pulmonary sequelae as evaluated by EBC markers, spirometry, 6MWT, and activity scores. Larger studies are required to assess long-term pediatric consequences of post SARS-CoV-2 infection, to assess the need for pulmonology surveillance.

Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA. METHODS: Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment. RESULTS: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity. CONCLUSIONS: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

Phenotypic Alteration of an Established Human Airway Cell Line by Media Selection.

Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride/bicarbonate channel. Many studies utilize human airway cell models (cell lines and primary cells) to study different aspects of CFTR biology. Media selection can alter the growth and differentiation of primary cells, yet the impact on stable airway cell lines is unclear. To determine the impact of media and growth conditions on CFBE41o- cells stably transduced with wild-type or F508del CFTR, we examined four commonly used growth media, measuring epithelial and mesenchymal markers, as well as CFTR expression, maturation, and function. The selection of growth media altered the expression of epithelial and mesenchymal markers in the cell lines, and significantly impacted CFTR expression and subsequent function. These results highlight the importance of media selection to CFTR and cell line behavior and should be considered in both studies of primary human airway cells and stable cell lines.

Treatment effects of Elexacaftor/Tezacaftor/Ivacaftor in people with CF carrying non-F508del mutations.

BACKGROUND: In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations. METHODS: We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI. RESULTS: We included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the "naïve" group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEV1% changed from 66.3±25 to 72.4±29 % (mean ± SD, p=0.058). In the group of patients previously treated with Ivacaftor or Tezacaftor/Ivacaftor, we didn't observe significant improvements in any of the parameters. CONCLUSIONS: We demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

Optimizing CFTR modulator therapy management for cystic fibrosis through the ReX platform.

Background: Cystic fibrosis (CF) is a chronic multi-systemic disease that requires a complex daily treatment regimen. Therefore, there is sub-optimal adherence to CF therapies, and it was shown to impact its clinical and economic burden. Cystic fibrosis transmembrane conductance regulator modulators (CFTRm) are high-cost medications that demonstrated significant benefit in clinical trials. The aim of this study was to evaluate the safety, usability, and efficacy of the ReX platform in medication management of CFTRm for the treatment of people with CF (pwCF). Methods: ReX is a patient engagement platform consisting of a cloud-based management system and a cell-enabled handheld device intended to dispense oral medication into the patient's mouth, following a pre-programmed treatment protocol. It provides real-time adherence data to caregivers and timely, personalized reminders to patients. This is a prospective multi-center open study for pwCFs older than 12 years, who had been prescribed CFTRm [elexacaftor/tezacaftor/ivacaftor (ETI) or tezacaftor/ivacaftor (TI)], and provided consent to use ReX platform to receive CFTRm and record their health condition. Study duration was 12-24 months, with clinic visits where physical examination, body mass index (BMI), and pulmonary function tests were performed, and user experience questionnaires were filled in. Results: Ten pwCFs from two CF centers in Israel were included. The mean age was 31.5 years (range 15-74 years); eight were taking ETI and two TI. Median adherence to CFTRm was 97.5% (range 70%-100%) in the first year and 94% (range 84%-99%) in the second year, which is higher than the previously reported CFTRm adherence of ∼80%. No adverse events related to the use of the platform were reported. Patients reported ReX to be valuable to their treatment management and user friendly. Estimated mean forced expiratory volume in 1 s (FEV1%) increased from 74.4% to 80.8% (p = 0.004) over 2 years. Similarly, estimated BMI percentile increased from 53.5 to 59.0 (p < 0.001). Conclusions: Using the ReX platform in medication management of pwCF treated by CFTRm is safe, easy to use, and effective in improving the adherence to treatment and the clinical outcomes. Consequently, this device may potentially reduce costs to healthcare providers. Further larger and long-term studies are required to examine the clinical benefits of the ReX platform.

Pneumonia in the presentation of Kawasaki disease: The syndrome or a sequence of two diseases?

Two cases of Kawasaki disease (KD) presented as persistent lung consolidation associated with Group A Streptococcus and Influenza A co-infection, which resolved following intravenous immunoglobulin. Thus, pediatricians should consider the diagnosis of KD in the presence of pneumonia that is nonresponsive to antibiotic therapy with prolonged fever and inflammatory reactions.

Respiratory healthcare professionals' views on long-term recommendations of interventions to prevent acute respiratory illnesses after the COVID-19 pandemic.

Respiratory professionals support the continuing use of protective measures for respiratory patients following the #COVID19 pandemic. The optimal use of these measures should be considered in clinical guidelines and public health recommendations. https://bit.ly/3IVL2pQ.

Real life evaluation of the multi-organ effects of Lumacaftor/Ivacaftor on F508del homozygous cystic fibrosis patients.

BACKGROUND: Lumacaftor/Ivacaftor (LUM-IVA), a cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector-potentiator combination, improves lung function and reduces pulmonary exacerbations (PEx) in F508del homozygous CF patients. However, the systemic effects of LUM-IVA outside the respiratory system have not yet been thoroughly investigated. METHODS: A prospective, real-world, yearlong study was performed on F508del homozygous adult CF patients who commenced treatment with LUM-IVA. Pancreatic function, bone metabolism, fertility status, nutritional and pulmonary factors were evaluated. RESULTS: Twelve patients, mean age 28.3 years (18.6-43.9) were recruited. Following 12 months of treatment, no changes were detected in glucose, insulin, c-peptide or BMI values. A significant relative decrease in mean alkaline-phosphatase levels (122.8 U/L vs 89.4, p = 0.002) and a trend toward an increase in calcium levels (9.5 vs 9.9 mg/dL, p = 0.074) were observed. A non-significant improvement in mean DEXA spine t-score after a year of treatment (-2.1 vs -1.6, n = 4, p = 0.11) was detected. Sweat chloride concentrations decreased significantly (-21.4 mEq/L; p = 0.003). Pulmonary outcome revealed improvement in spirometry values during the first three months (FEV1 by 5.7% p = 0.009, FEF25-75 by 4.3% p = 0.001) with no change in chest CT Bhalla score and CFQR after one year. There was also a significant decrease in parenteral antibiotic events (17 vs 8, p = 0.039) with shift from IV to oral antibiotics for PEx treatment. CONCLUSIONS: After one year of treatment, stabilization was observed in the pancreatic indices, nutritional status, structure and function of the lungs, with a beneficial effect on bone mineral metabolism and CFTR function. Additional studies should investigate the effect of CFTR modulators on extra-pulmonary manifestations.

4-week daily airway clearance using oscillating positive-end expiratory pressure versus autogenic drainage in bronchiectasis patients: a randomised controlled trial.

BACKGROUND: Airway clearance is a fundamental component of bronchiectasis care. Lung clearance index (LCI) is a measurement of ventilation inhomogeneity. Its responsiveness to long-term airway clearance is unknown. We aimed to compare two methods of daily airway clearance over 4 weeks: autogenic drainage (AD) and oscillating positive airway pressure (oPEP), and to determine effects of airway clearance on LCI and clinical outcomes. METHODS: Adults with bronchiectasis naive to airway clearance were randomised to daily airway clearance with either AD or oPEP. Difference in LCI as primary outcome, spirometry, sputum volume and purulence, and quality of life were at randomisation and after 4 weeks of airway clearance. RESULTS: 51 patients (32 women and 19 men, mean age 66.2±12.8 years) were randomised and 49 completed the study (25 AD and 24 oPEP). The LCI and forced expiratory volume in 1 s did not change between visits between groups (difference between groups 0.02), nor between visits in either group. Sputum quantity decreased in 12 out of 24 (50%) of the oPEP group, and in six out of 25 (24%) of the AD group (p=0.044). The "treatment burden" worsened or was unchanged in 70% of participants randomised to AD and 55% randomised to oPEP (p=0.038). CONCLUSION: Sputum quantity decreased in more participants randomised to oPEP group after 1 month of daily airway clearance, with a better treatment burden. The effects of 4 weeks of airway clearance on LCI were not significant in either treatment group.

Improvement in BMI z-score following adenotonsillectomy in adolescents aged 12-18 years: a retrospective cohort study.

BACKGROUND: Characteristics of obstructive sleep apnea (OSA) changes with age. Infants, toddlers and prepubertal children with OSA are usually underweight and may suffer from failure to thrive (FTT). Adenotonsillectomy (T&A) is the first line of treatment for OSA in childhood. In adults OSA is commonly associated with obesity and the metabolic syndrome. The change in body mass index (BMI) in adolescents with OSA following T&A was only sporadically studied. Thus, we peruse to examine the BMI z-score change following T&A in adolescents. METHODS: Clalit Health Services is the largest health care organization in Israel with the largest patient registry (more than 50% of the population). Two hundred and forty two adolescents aged 12-18 who underwent T&A between 2006 and 2015 were identified in the Clalit registry and their characteristics including height and weight were retrieved. The BMI z-score of these adolescents at baseline (up to 3 months prior to T&A) and during the consecutive 3 years after T&A were analyzed and compared. RESULTS: Changes in BMI Z-score were observed to all directions following T&A with overall small increase, not statistically significant (P = 0.26) from a median of 0.79 prior to T&A to a median of 0.835 after it. There was a minimal trend toward BMI z-score reduction in overweight children (n = 74) from 1.508 to 1.48 following T&A (p = NS), and in obese children (n = 33) from 2.288 to 2.000 (P = 0.06, 2 tailed). Interestingly thin individuals (n = 6) increased their BMI z-score following T&A from - 2.4 to - 0.59 (p = 0.046). CONCLUSIONS: Adolescents show variable changes in their BMI z-score following T&A. In this aspect their BMI z-score change is closer to the change seen in adults treated for OSA and not that of young children. The changes observed show a trend toward normalization of the BMI z-score such that overweight children tend to decrease their BMI z-score while thin individuals tend to increase it.

Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression.

BACKGROUND: With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. AIM: To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. METHODS: A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. RESULTS: Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. CONCLUSION: Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

Exercise capacity in patients with cystic fibrosis vs. non-cystic fibrosis bronchiectasis.

BACKGROUND: Bronchiectasis is associated with morbidity, low exercise capacity and poor quality of life. There is a paucity of data on exercise capacity using cardiopulmonary exercise test (CPET) in non-cystic fibrosis (CF) bronchiectasis. Our aim was to compare exercise capacity using CPET in CF and non-CF bronchiectasis patients. METHODS: Cross-sectional retrospective/prospective controlled study assessing CPET using cycle ergometer. Exercise parameters and computed tomography (CT) findings were compared. Results: Hundred two patients with bronchiectasis and 88 controls were evaluated; 49 CF (age 19.7 ± 9.7 y/o, FEV1%predicted 70.9 ± 20.5%) and 53 non-CF (18.6 ± 10.6 y/o, FEV1%predicted 68.7 ± 21.5%). Peak oxygen uptake (peak [Formula: see text]) was similar and relatively preserved in both groups (CF 1915.5±702.0; non-CF 1740±568; control 2111.0±748.3 mL/min). Breathing limitation was found in the two groups vs. control; low breathing reserve (49% in CF; 43% non-CF; 5% control) and increased [Formula: see text] (CF 31.4±4.1, non-CF 31.7±4.1 and control 27.2 ± 2.8). Oxygen pulse was lower in the non-CF; whereas a linear relationship between peak [Formula: see text] vs. FEV1 and vs. FVC was found only for CF. CT score correlated with [Formula: see text] and negatively correlated with [Formula: see text] and post exercise oxygen saturation (SpO2). CONCLUSIONS: CPET parameters may differ between CF and non-CF bronchiectasis. However, normal exercise capacity may be found unrelated to the etiology of the bronchiectasis. Anatomical changes in CT are associated with functional finding of increased [Formula: see text] and decreased SpO2. Larger longitudinal studies including cardiac assessment are needed to better study exercise capacity in different etiologies of non-CF bronchiectasis. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT03147651.

Decreased Fecal Calprotectin Levels in Cystic Fibrosis Patients After Antibiotic Treatment for Respiratory Exacerbation.

OBJECTIVES: In all patients with cystic fibrosis (CF), gastrointestinal (GI) tract CF transmembrane conductance regulator dysfunction occurs early in life. The identical pathophysiological triad of obstruction, infection, and inflammation causes disease of the airways and in the intestinal tract (CF enteropathy). Mucus accumulation within GI tract is a niche for abnormal microbial colonization, leading to dysbiosis. Fecal calprotectin (FC) is a neutrophil cytosolic protein released during apoptosis and necrosis and reflects inflammatory status. Systemic antibiotic treatment for pulmonary exacerbations has been shown to improve systemic inflammatory markers and serum and sputum calprotectin. Antibiotic treatment aimed at pulmonary complaints may improve GI tract inflammatory status. We hypothesized that high levels of FC present during pulmonary exacerbation are due, in part, to multiorgan dysbiosis and thus should diminish with systemic antibiotic treatment. METHODS: This prospective pilot study enrolled 14 patients with CF, with no current GI symptoms. FC levels and lung function were measured at the beginning and end of systemic antibiotic treatment. RESULTS: Compared to preantibiotic treatment baseline values, end of treatment FC levels declined significantly after antibiotic treatment, P = 0.004 and similarly, there was significant improvement in forced expiratory volume in 1 second, P = 0.002. CONCLUSIONS: High levels of FC during respiratory exacerbation may reflect a systemic exacerbation rather than solely pulmonary. Antibiotic treatment lowered the FC levels possibly by its impact on the intestinal microbiome.

Failure to conceive in women with CF is associated with pancreatic insufficiency and advancing age.

OBJECTIVE: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. METHODS: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. RESULTS: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03-3.5], p = .04) and older age (OR 3.9 [2.1-7.3] p < .0001) were associated with subfertility. Lung function, BMI, CFRD, Presence of two class I-III mutations and number of exacerbations in the year prior to fertility attempts were not associated with subfertility. CONCLUSIONS: The prevalence of subfertility among women with CF (35%) is higher than the expected 5-15% subfertility in the general population. Older age and pancreatic insufficiency are associated with subfertility in women with CF.

Ivacaftor for the p.Ser549Arg (S549R) gating mutation - The Israeli experience.

BACKGROUND: Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse. AIM: Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation. METHODS: Data obtained from CF patients receiving ivacaftor for one year. RESULTS: Eight CF patients, mean age 21 ± 10 years, received ivacaftor. After one year, significant improvement was found in FEV1, increasing from 74% to 88% (p < 0.001), FVC, 89% to 101% (p = 0.019), and FEF25-75, 59%-76% (p = 0.019). Sweat chloride concentration decreased from 116 ± 8 mmol/L to 51 ± 17 mmol/L (p < 0.001), and BMI increased from 20 ± 3 to 22 ± 4 (p = 0.003). Glucose tolerance improved in five patients. There was no significant change in bacterial colonization. CONCLUSIONS: Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Clinical impact of Pseudomonas aeruginosa colonization in patients with Primary Ciliary Dyskinesia.

BACKGROUND: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD. METHODS: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters. RESULTS: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV1) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results. CONCLUSIONS: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients.