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.

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.

Effect of late preterm birth on lung clearance index and respiratory physiology in school-age children.

BACKGROUND: We hypothesized that former late preterm (LP) children have abnormal pulmonary physiology parameters, including uneven ventilation distribution, due to premature disruption of normal lung development. METHODS: A cross-sectional study evaluating former LP children at the age of 6 to 12 years as compared to term controls. Demographics and child's and family history of asthma/atopy/smoking were recorded. The outcome parameters were spirometry, multiple breath washout (MBW) measurement by lung clearance index (LCI), 6-minute walk test (6MWT), symptoms related to asthma and allergy, and Godin Leisure-Time Exercise Questionnaire. RESULTS: Twenty-nine former LP were compared to 30 term-control children (mean age, 8.2 ± 1.7 and 8.8 ± 1.8 years, respectively). LP had reduced forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) compared to term controls (FEV1 1.59 ± 0.48 vs 1.80 ± 0.39 L, P = 0.005 and FVC 1.73 ± 0.45 vs 1.99 ± 0.49 L, P = 0.009). There were no differences between the two groups regarding FEV1/FVC, forced expiratory flow between 25 and 75 (FEF25-75), LCI (7.10 ± 0.79 vs 6.96 ± 0.75, P = 0.50), 6MW distance, and weekly leisure-activity score. Former LP children had more episodes of wheezing and greater use of asthma medication. CONCLUSIONS: This pilot study suggests that LP have lower pulmonary function tests (PFTs) but not ventilation inhomogeneity measured by LCI or functional disturbance. It is unclear if the differences in PFTs are due to late prematurity by itself or are the consequence of maternal and neonatal factors associated with LP. Further larger studies are required to assess the long-term respiratory consequences of LP birth.

Compassionate Nitric Oxide Adjuvant Treatment of Persistent Mycobacterium Infection in Cystic Fibrosis Patients.

BACKGROUND: Mycobacterium abscessus is one of the most antibiotic-resistant pathogens in cystic fibrosis (CF) patients. Nitric oxide (NO) has broad-spectrum antimicrobial activity. Clinical studies indicated that it is safe and tolerable when given as 160 ppm intermittent inhalations. METHODS: A prospective compassionate adjunctive inhaled NO therapy in 2 CF patients with persistent Mycobacterium abscessus infection. RESULTS: No adverse events were reported. Both subjects showed significant reduction in quantitative polymerase chain reaction results for Mycobacterium abscessus load in sputum during treatment; estimated colony forming unit decreased from 7000 to 550 and from 3000 to 0 for patient 1 and patient 2, respectively. CONCLUSIONS: Intermittent inhalations with 160 ppm NO are well tolerated, safe and result in significant reduction of Mycobacterium abscessus load. It may constitute an adjuvant therapeutic approach for CF patients with Mycobacterium abscessus lung disease. Further studies are needed to define dosing, duration and long-term clinical outcome.

Legionella pneumophila Pneumonia in Two Infants Treated with Adrenocorticotropic Hormone.

Patients with infantile spasms, an intractable epileptic disorder, often are treated with adrenocorticotropic hormone. Legionella pneumophila is a rare cause of pneumonia in children. We describe 2 infants with Legionella pneumonia whose infection occurred within 1 month after starting adrenocorticotropic hormone.

Lung Clearance Index (LCI) in Patients with Bronchiolitis Obliterans: A Preliminary Report and Comparison to Cystic Fibrosis Patients.

INTRODUCTION: Bronchiolitis obliterans (BO) is a chronic airway disease following an insult to the lower respiratory tract. Lung clearance index (LCI) measures ventilation inhomogeneity and has been studied in cystic fibrosis (CF). We aimed to evaluate LCI in BO and to compare it to LCI in CF patients. METHODS: LCI was measured in BO patients, compared to CF patients, and correlated with spirometry and CT findings. RESULTS: Twenty BO patients and 26 CF patients (with similar mean age and BMI) underwent evaluation. FEV1 % and FEF25-75 % predicted were significantly lower in the BO group (60.5 ± 17.8 vs. 72.7 ± 20.7, p = 0.041, and 42.8 ± 22.8 vs. 66.4 ± 37.4, p = 0.017, respectively). In both groups, LCI was inversely correlated with FVC %, FEV1 %, and FEF25-75 % predicted. LCI  % was slightly higher (190.4 ± 63.5 vs. 164.9 ± 39.4, p = 0.1) and FRC gas % (measured by multiple breath washout) was significantly higher in the BO group (92.5 ± 35.9 vs. 71.3 ± 18, p = 0.014). The strength of statistical association between the lower FEF25-75 % values and the higher LCI values was stronger in BO patients. CONCLUSIONS: Similar to CF, LCI may provide estimation of ventilation inhomogeneity in BO. The results indicate greater small airway involvement and air trapping in BO. Further prospective longitudinal studies evaluating the correlation of LCI measurements with multiple clinical and physiological parameters should be performed to assess the clinical benefit of LCI measurement in BO.

"I sit to sleep"-Spirometry as a clue to diagnosis.

A 15-year-old patient presented with a 4-month history of choking while sleeping that necessitated sleeping in a sitting position. Flow-volume curve demonstrating fixed upper airway obstruction led to further workup and to the diagnosis of childhood achalasia as a cause of unusual symptoms and fixed upper airway obstruction. Pediatr Pulmonol. 2016;51:E13-E15. © 2015 Wiley Periodicals, Inc.

Elevated serum B-cell activating factor in patients with chronic urticaria.

The B and T cells abnormalities that have been described among CU patients, lend support to its regard as an autoimmune disease. In this study we compared serum B-cell activation factor (BAFF) levels in 46 CU patients to 24 healthy controls and evaluated a possible association between elevated serum BAFF in CU patients and the presence of autologous serum skin test, anti-thyroid antibodies, antinuclear antibodies, high total IGE levels, and urticaria disease severity. We found that serum BAFF levels is elevated statistically significant in CU patients compared to healthy control (1228±342 pg/ml vs. 758±313 pg/ml, P<0.0001). CU patients with severe disease activity had significantly higher serum BAFF levels compared to patients with mild CU (1394.6±299.6 vs. 1097.6±221.3, P=0.0008). No association was found between the presence of positive autologous serum skin test, anti-thyroid antibodies or antinuclear antibodies or high levels of total IgE and serum BAFF levels in CU Patients. We conclude that CU patients have higher levels of serum BAFF which associate with disease severity.