Cardiopulmonary exercise testing in adolescence following extremely premature birth.

BACKGROUND: Although extremely premature birth disrupts lung development, adolescent survivors of extreme prematurity show good clinical and physiologic outcomes. Cardiopulmonary limitations may not be clinically evident at rest. Data regarding exercise limitation in adolescents following preterm birth in the postsurfactant era are limited. RESEARCH QUESTION: What are the long-term effects of bronchopulmonary dysplasia (BPD) and extreme prematurity (<29 weeks) on ventilatory response during exercise in adolescents in the postsurfactant era? STUDY DESIGN AND METHODS: We followed a longitudinally recruited cohort of children aged 13-19 years who were born at a gestational age of <29 weeks (study group - SG). We compared the cardiopulmonary exercise testing (CPET) results of those with and without BPD, to their own CPET results from elementary school age (mean 9.09 ± 1.05 years). RESULTS: Thirty-seven children aged 15.73 ± 1.31 years, mean gestational age 26 weeks ( ± 1.19), completed the study. CPET parameters in adolescence were within the normal range for age, including mean V̇O2 peak of 91% predicted. The BPD and non-BPD subgroups had similar results. In the longitudinal analysis of the SG, improvement was observed in adolescence, compared with elementary school age, in breathing reserve (36.37 ± 18.99 vs. 26.58 ± 17.92, p = 0.044), tidal volume as a fraction of vital capacity achieved at maximal load (0.51 ± 0.13 vs. 0.37 ± 0.08, p < 0.001), and respiratory exchange ratio at maximal load (1.18 ± 0.13 vs. 1.11 ± 0.10, p = 0.021). INTERPRETATION: In the current cohort, adolescents born extremely premature have essentially normal ventilatory response during exercise, unrelated to BPD diagnosis. CPET results in this population improve over time.

Pulmonary Evaluation in Children with Post-COVID-19 Condition Respiratory Symptoms: A Prospective Cohort Study.

Background: Studies on post-COVID-19 condition (PCC) in adults have shown deterioration in pulmonary function tests (PFTs), mainly a diffusion limitation. Among the pediatric population, data are scarce. Aim: To characterize PFTs in children with PCC, including changes over time. Methods: A prospective longitudinal study of children with defined PCC and respiratory complaints who were referred to a designated multidisciplinary clinic from 11/2020 to 12/2022. Results: Altogether, 184 children with a mean age of 12.4 years (SD 4.06) were included. A mild obstructive pattern was demonstrated in 19/170 (11%) at presentation, as indicated by spirometry and/or positive exercise challenge test and/or reversibility post bronchodilators, only three had a previous diagnosis of asthma. Lung volumes and diffusion were normal in all but one patient (1/134, 0.7%). Exhaled nitric oxide levels were elevated in 32/144 (22%). A total of 33 children who had repeated PFTs had normal or near-normal PFTs on follow-up testing, including seven (21.2%) who had mild obstructive PFTs at presentation. Multivariate analysis identified older age [OR 1.36 (95% CI:1.07-1.75)], specific imaging findings (prominent bronchovascular markings (OR 43.28 (95% CI: 4.50-416.49)), and hyperinflation (OR 28.42, 95% CI: 2.18-370.84)] as significant predictors of an obstructive pattern on PFTs. Conclusions: In children with PCC and respiratory symptoms, the most common impairment was a mild obstructive pattern; most were without a history of asthma. Improvement was witnessed in long-term follow-up. In contrast to the adult population, no diffusion limitation was found. Empirical periodic inhaler therapy may be considered in children with factors associated with PFT abnormalities.

Dynamic Hyperinflation While Exercising-A Potential Predictor of Pulmonary Deterioration in Cystic Fibrosis.

BACKGROUND: Lung function deterioration in cystic fibrosis (CF) is typically measured by a decline in the forced expiratory volume in one second (FEV1%), which is thought to be a late marker of lung disease. Dynamic hyperinflation (DH) is seen in obstructive lung diseases while exercising. Our aim was to assess whether DH could predict pulmonary deterioration in CF; a secondary measure was the peak VO2. METHODS: A retrospective study was conducted of people with CF who performed cardiopulmonary exercise tests (CPETs) during 2012-2018. The tests were classified as those demonstrating DH non-DH. Demographic, genetic, and clinical data until 12.2022 were extracted from patient charts. RESULTS: A total of 33 patients aged 10-61 years performed 41 valid CPETs with valid DH measurements; sixteen (39%) demonstrated DH. At the time of the CPETs, there was no difference in the FEV1% measurements between the DH and non-DH groups (median 83.5% vs. 87.6%, respectively; p = 0.174). The FEV1% trend over 4 years showed a decline in the DH group compared to the non-DH group (p = 0.009). A correlation was found between DH and the lung clearance index (LCI), as well as the FEV1% (r = 0.36 and p = 0.019 and r = -0.55 and p = 0.004, respectively). Intravenous (IV) antibiotic courses during the 4 years after the CPETs were significantly more frequent in the DH group (p = 0.046). The peak VO2 also correlated with the FEV1% and LCI (r = 0.36 and p = 0.02 and r = -0.46 and p = 0.014, respectively) as well as with the IV antibiotic courses (r = -0.46 and p = 0.014). CONCLUSIONS: In our cohort, the DH and peak VO2 were both associated with lung function deterioration and more frequent pulmonary exacerbations. DH may serve as a marker to predict pulmonary deterioration in people with CF.

Evaluation of sputum cultures in children with spinal Muscular atrophy.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder. Despite increased survival due to novel therapies, morbidity from respiratory complications still persists. We aim to describe these patients' sputum cultures as an expression of chronic infectious airway disease. METHODS: Retrospective review of medical records of all children with SMA followed at the multidisciplinary respiratory neuromuscular clinic at Schneider Childrens' Medical Center of Israel over a 16-year period. Sputum cultures were obtained during routine visits or pulmonary exacerbations. RESULTS: Sixty-one SMA patients, aged 1 month to 21 years, were included in this cohort. Of these, sputum cultures were collected from 41 patients. Overall, 288 sputum cultures were obtained, and 98 (34%) were negative for bacterial growth. For the first culture taken from each patient, 12 out of 41 (29%) were sterile. The most common bacteria were pseudomonas aeruginosa (PSA) (38%) and staphylococcus aureus (19.6%). PSA was found in SMA type I patients more frequently than in type II patients (15/26 = 58% vs 4/13 = 31%, p < 0.001). PSA infection was positively associated with noninvasive ventilation, recurrent atelectasis, recurrent pneumonias, swallowing difficulties, but no significant association was found with cough assist machine usage. The incidence of positive cultures did not differ between those treated with Onasemnogene abeparvovec or Nusinersen compared to those without treatment, but the age of first PSA isolation was slightly older with Nusinersen treatment (p = 0.01). CONCLUSIONS: Airway bacterial colonization is common in SMA type I patients and is not decreased by Onasemnogene abeparvovec or Nusinersen treatment.

Lactose-Containing Dry-Powder Inhalers for Patients with Cow's Milk Protein Allergy-The Conundrum; A National Survey of Pediatric Pulmonologists and Allergologists.

Introduction: Several dry-powder inhalers (DPIs) contain lactose which may be contaminated with milk proteins. Confusion exists pertaining to DPI use in patients with cow's milk protein allergy (CMPA). Methods: A computerized survey sent via e-mail to pediatric pulmonologists and allergologists. Results: A total of 77 out of 232 (33.2%) doctors replied, of whom 80.5% were pediatric pulmonologists. A total of 69 of 77 (89.6%) were specialists, 37.6% with more than 15 years of experience. The most commonly used DPIs were formoterol + budesonide and vilanterol + fluticasone. A total of 62 out of 77 (80.5%) responders knew these DPIs contained lactose. A total of 35 out of 77 (45.5%) doctors who replied did not know that DPI leaflets list CMPA as a contra-indication to DPI administration. Of these, 4 (11.4%) stated that they would instruct patients with CMPA to stop DPIs, and 7 (20%) would avoid recommending DPIs. A total of 42 out of 77 (54.5%) responders were aware of this warning, yet 13 of these 42 (30.9%) continued to recommend lactose-containing DPIs without hesitation and 18 of these 42 (42.8%) responders prescribed DPIs but considered allergy severity. Conclusions: Almost half of certified, experienced pediatric pulmonologists and allergologists were unaware of the warning to administer DPIs to patients with CMPA. Most doctors who do know of this warning still continue to prescribe these DPIs.

Effects of Wearing Facemasks During Brisk Walks: A COVID-19 Dilemma.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, wearing facemasks became obligatory worldwide. OBJECTIVES: The objective of this study was to evaluate the effects of facemasks on gas exchange. METHODS: Healthy adults were assessed at rest and during slow and brisk 5-minute walks, with and without masks. We monitored O2 saturation, end-tidal carbon dioxide (EtCO2), and heart and respiratory rates. Participants graded their subjective difficulty and completed individual sensations questionnaires. RESULTS: Twenty-one participants with a median age of 38 years (range, 29-57 years) were recruited. At rest, all vital signs remained normal, without and with masks. However, during slow and brisk walks, EtCO2 increased; the rise was significantly higher while wearing masks: slow walk, mean EtCO2 (mmHg) change +4.5 ± 2.4 versus +2.9 ± 2.3, P = .004; brisk walk EtCO2 change +8.4 ± 3.0 versus +6.2 ± 4.0, P = .009, with and without masks, respectively. Wearing masks was also associated with higher proportions of participant hypercarbia (EtCO2 range, 46-49 mmHg) compared with walking without masks, though this was only partially significant. Mean O2-saturation remained stable (98%) while walking without masks but decreased by 1.2 % ± 2.2 while walking briskly with a mask (P = .01). Mild desaturation (O2 range, 93% to 96%) was noted during brisk walks among 43% of participants with masks, compared with only 14% without masks (P = .08). Borg's scale significantly increased while walking with a mask, for both slow and brisk walks (P < .001). Sensations of difficulty breathing and shortness of breath were more common while walking with masks. CONCLUSION: While important to prevent viral spread, wearing facemasks during brisk 5-minute walks might be associated with mild hypercarbia and desaturation. The clinical significance of these minor gas exchange abnormalities is unclear and should be further investigated.

Low flow intermittent bronchoscopic oxygen insufflation to identify occult tracheo-esophageal fistulas.

BACKGROUND: Esophageal atresia and tracheo-esophageal fistula (TEF), a well described congenital anomaly of the aero-digestive tract, commonly presents with inability to swallow and feed immediately after birth. However, diagnosis of recurrent or isolated TEF can be challenging and requires a combination of endoscopic and contrast studies. We describe a hitherto unreported technique of low flow intermittent oxygen insufflation into the suspicious tract and examine its safety and diagnostic yield for identification of occult TEF. METHODS: A retrospective single center cohort study, analyzing case notes of patients with TEF who underwent bronchoscopic oxygen insufflation for suspected recurrent or isolated TEF between 2006 and 2019 at a tertiary pediatric hospital. RESULTS: One-hundred and seven patients with TEF underwent 142 bronchoscopies during the study period. Of these, 22 patients underwent 28 bronchoscopies with oxygen insufflation. Twelve (43%) open fistulas were identified; of these, 9 (75%) were found using oxygen insufflation, revealing the fistula in 4/9 (44%) cases that had not been apparent using simple bronchoscopic visualization alone. One fistula was missed with multiple investigations, including bronchography and found only using oxygen insufflation. No complications were encountered. CONCLUSIONS: Recurrent or isolated TEF may be missed using ordinary flexible bronchoscopy and imaging studies. Low flow oxygen insufflation can be applied safely and may detect otherwise occult TEF.

Risk factors for respiratory syncytial virus bronchiolitis hospitalizations in children with chronic diseases.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract disorder causing hospitalization in infants. Due to decreased hospitalization rates of premature infants following Palivizumab immune prophylaxis, the proportion of infants with chronic diseases not eligible for Palivizumab has increased. AIM: To characterize infants hospitalized during 2014-2018 with RSV bronchiolitis, to compare between those with and without chronic conditions, and to identify risk factors for severe disease. METHODS: This retrospective study analyzed demographic and clinical data of patients younger than 2 years admitted with bronchiolitis during four consecutive RSV seasons. RESULTS: Of 1124 hospitalizations due to RSV bronchiolitis, 244 (22%) were in infants with chronic diseases. Although 20/1124 qualified for RSV prophylaxis, only eight received immune prophylaxis. Compared to otherwise healthy infants, children with chronic diseases had longer hospitalizations, median 4.8 days (interquartile range [IQR]: 3.4-8.3) versus 3.7 days (IQR: 2.7-5.1), p < .001; and higher pediatric intensive care unit (PICU) and readmission rates (9% vs. 4.5%, p = .007% and 3% vs. 1%, p = .055, respectively). Children with Down's syndrome comprised 2% of all hospitalizations, but 8% of PICU admissions; their median length of hospitalization was 10.7 days (IQR: 6.6-17.6). Respiratory tract malformations were present in 2% of hospitalizations, and comprised 4% of PICU admissions. CONCLUSION: Among infants admitted with RSV bronchiolitis, those with chronic diseases had longer hospitalizations and higher rates of transfer to the PICU. Children with multiple comorbidities, and especially those with Down's syndrome, are at particularly high risk for severe hospitalization and may benefit from RSV immune prophylaxis.

Diagnostic value of sputum cultures in children under 2 years of age with chronic suppurative lung diseases.

BACKGROUND: Acquiring sputum cultures from infants is considered challenging. We describe their yield in infants with cystic fibrosis (CF) and other chronic suppurative lung diseases (CSLDs). METHODS: Retrospective medical record review over a 4-year period, for infants aged 0-2 years with ≥2 airway bacterial cultures acquired by deep suction or induced sputum ≥4 weeks apart. Data included demographics, culture results, and clinical status. RESULTS: A total of 98 infants (16 CF) were evaluated and 534 sputum cultures acquired, 201 in CF and 333 in CSLD. There were 12 (2-23), median (range) cultures/CF infant, and 3 (2-21)/CSLD infant. Age at first culture was 3.8 (1-19.5) months for CF and 10.4 (0.5-22) months for CSLD; p = .016. In total, 360 cultures (67%) were positive for any bacteria, with 170/234 (73%) positive during exacerbations, compared with 190/300 (63%) during routine visits; p = .05. More infants with CF than CSLD had cultures positive for Staphylococcus aureus (SA; 75% vs. 34%; p = .004) throughout the period. Pseudomonas aeruginosa (PA) was common in both CF and CSLD (56% and 44%, respectively; p = .42) and increased over time for CF but was high throughout for CSLD. The number of hospital days before PA acquisition was 6 (10.2) for CF and 28.8 (38.7) for CSLD (p = .003). No CF but 6/82 (7%) CSLD infants had chronic PA (p = .56). CONCLUSIONS: Sputum cultures showed that infection, in particular PA, is common in CF and CSLD whereas SA is more common in CF. Prospective studies are warranted to elucidate the role of active surveillance in guiding antibiotic therapy.

Palivizumab Following Extremely Premature Birth Does Not Affect Pulmonary Outcomes in Adolescence.

BACKGROUND: Prematurity is a risk factor for impaired lung function. We sought to assess the long-term effect of palivizumab immunization and extreme prematurity (<29 weeks gestation) on respiratory symptoms and pulmonary function in adolescence. RESEARCH QUESTION: What is the long-term effect of palivizumab immunization and extreme prematurity (<29 weeks) on respiratory symptoms and pulmonary function in adolescence? STUDY DESIGN AND METHODS: We examined survivors of extreme prematurity (<29 weeks gestation) at 13 to 18 years of age (study group). Study group babies who were born immediately before palivizumab immunization (nonpalivizumab group [NPG]) were compared with those babies who were born just after implementation (PG) and with a control group. For study group patients, lung function in adolescence was further compared longitudinally with that at primary school age. RESULTS: Sixty-four adolescents aged 15.76 ± 1.52 years were included: 46 in the study group (17 PG and 29 NPG) and 18 in the control group. For the study group, wheezing episodes, inhaler use, and hospitalizations were uncommon. For the study group compared with the control group, FEV1 percent predicted was 82.60% ± 13.54% vs 105.83% ± 13.12% (P < .001), and the lung clearance index was 7.67 ± 1.02 vs 7.46 ± 0.70 (P = .48), respectively. Study group adolescents with bronchopulmonary dysplasia had a higher lung clearance index than did adolescents with no bronchopulmonary dysplasia (7.94 ± 1.11 vs 7.20 ± 0.60; P = .002). PG and NPG adolescents were not significantly different. Comparing the study group in adolescence with primary school age, we found improvement in mean FEV1 percent predicted bronchodilator response (0.37% ± 9.98% vs 5.67% ± 9.87%; P = .036) and mean provocative concentration causing 20% decline in FEV1 (12.16 ± 4.71 mg/mL vs 4.14 ± 4.51 mg/mL, respectively; P < .001). INTERPRETATION: Palivizumab did not provide any discernable long-term protective effect. Nevertheless, adolescent survivors of extreme prematurity showed good clinical and physiologic outcomes, except for mildly raised lung clearance index in patients with bronchopulmonary dysplasia. Airway hyperreactivity detected at primary school age, decreased by adolescence.

Inspiromatic-safety and efficacy study of a new generation dry powder inhaler in asthmatic children.

BACKGROUND: Dry powder inhalers (DPI) are effective but forceful inhalation required to fluidize the powder may be difficult for children and patients with airway disease. Inspiromatic is a new generation active DPI that actively suspends drugs in synchrony with inhalation. We evaluated safety and efficacy of Formoterol delivery via Inspiromatic, compared to Aerolizer, a conventional DPI, in pediatric asthmatic subjects. METHODS: A phase I/II, randomized, single-center, double-blind, double-dummy, placebo-controlled, cross-over study. Subjects aged 8-18 years with FEV1 40-80% predicted were included. Patients were randomized to inhale Formoterol via the Inspiromatic, immediately followed by the placebo via the Aerolizer or vice versa, in a double-blind fashion. Spirometry, blood pressure, and heart rate were measured at baseline and 15, 30, and 60 min after drug administration. Capsule emptying, comfort of use, confidence in efficacy, and patient satisfaction were assessed. At a subsequent visit, three months later, patients inhaled the active drug via the other DPI. RESULTS: Twenty-nine patients, aged 12.6 (±2.3) years, mean (SD), completed the study. Baseline FEV1 was 69.1 (±6.7) % at visit one and 65.3 (±9) % at visit two. Maximal FEV1 increase was 16.6 (±7.1) % with Inspiromatic and 15.5 (±7.5) % with Aerolizer (P = 0.47). No differences in heart rate or blood pressure were observed; 24/28 capsules were emptied using the Inspiromatic and 19/28 with the Aerolizer (P = 0.5); 21/28 preferred the Inspiromatic and 7/28 the Aerolizer (P < 0.001). There were no adverse events. CONCLUSIONS: Formoterol inhalation via the Inspiromatic is safe and as efficacious as with the Aerolizer. The device is well accepted by asthmatic subjects.

Propranolol treatment for infantile hemangioma does not increase risk of childhood wheezing.

OBJECTIVE: Propranolol is the treatment of choice for infantile hemangiomas requiring medical intervention. Although contraindicated in asthma, its bronchoconstrictive effect in infants and children has not been extensively studied. We aimed to assess the incidence of wheezing episodes in infants and children treated with propranolol for infantile hemangiomas. STUDY DESIGN: A retrospective case-control study. SETTING: a tertiary pediatric hospital. PATIENTS: All Children followed for infantile hemangioma between 2009 and 2014. Children followed conservatively served as control group and were matched 1:1 for gender and month of birth by random matching to children treated with propranolol. INTERVENTIONS: All respiratory episodes (asthma, wheezing, stridor, and pneumonia) and respiratory associated hospitalizations were recorded from hospital records, from the primary care physician visits records and pharmacy prescriptions. The main outcome measure was the incidence of respiratory episodes in the treatment and the control groups. RESULTS: A total of 1828 clinic visits were reviewed for 683 children. In addition, primary care physician visits records were available in 80% of them. Two hundred and sixteen children were treated with propranolol. Incidence of respiratory episodes and recurrent respiratory episodes was similar in the propranolol and control groups (8.3% vs 12%, P = 0.265; 3.7% vs 6.5%, P = 0.274, respectively). Time to first episode was similar in the treatment and control groups (5.03 ± 3.32 vs 4.45 ± 3.21 months, respectively, P = 0.09). Respiratory hospital admission rate was similar in both groups. CONCLUSIONS: Propranolol treatment does not exacerbate wheezing episodes in infants and children.

Feasibility of multiple breath washout measurements in infants with bronchiolitis: A pilot study.

BACKGROUND: Lung clearance index (LCI) reflects ventilation inhomogeneity and is raised in obstructive airway disease. Feasibility of multiple breath washout (MBW) measurement during acute lung disease in infants is unknown. As a further measure of disease, exhaled nitric oxide (eNO) may paradoxically decrease in acute bronchiolitis. We hypothesized that MBW measurements were attainable in infants with bronchiolitis and that LCI was raised and eNO reduced, compared to normal controls. METHODS: Infants with acute bronchiolitis were tested with sulfur hexafluoride (SF6 ) MBW during hospitalization and compared to controls. Tidal breathing and eNO parameters were obtained. Measurements were performed during natural sleep. RESULTS: Twenty-nine infants with bronchiolitis aged 3.7 ± 2.3 months (mean ± SD) and 23 controls aged 4.2 ± 2.5 months (P = 0.07) were evaluated. Fifteen of 29 (52%) infants with bronchiolitis and 19/23 (83%) controls achieved ≥2 valid MBW measurements. Reasons for test failure included waking up during facemask application and an irregular respiratory pattern. LCI was 8.4 ± 0.8 in the study group and 7.3 ± 0.7 in controls (P < 0.001). ENO was 2.3 ± 2.7 ppb in the study group and 7.9 ± 6.9 ppb in controls (P = 0.004). CONCLUSION: MBW measurements during natural sleep are feasible but technically challenging in infants with acute bronchiolitis. LCI is raised compared to healthy controls. Larger trials, possibly using sedation protocols and shortened washout periods, are required to corroborate these findings. LCI can potentially serve as an objective indicator of severity and could be considered as a biomarker for future interventional trials.

Short- and Long-term Pulmonary Outcome of Palivizumab in Children Born Extremely Prematurely.

BACKGROUND: Palivizumab reduces the severity of respiratory syncytial virus infection in premature infants, but whether there is a protective effect beyond the preschool age is unknown. This study sought to assess the short- and long-term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born extremely prematurely. METHODS: Infants born before 29 weeks' gestation in 2000 to 2003 were assessed at school age by parental questionnaire, hospital chart review, and lung function tests. Children born immediately before the introduction of routine palivizumab prophylaxis were compared with age-matched children who received palivizumab prophylaxis during the first respiratory syncytial virus season. RESULTS: Sixty-three children with a mean age 8.9 years were included: 30 had received palivizumab and 33 had not (control subjects). The groups were similar in terms of gestational age, birth weight, need for mechanical ventilation, and oxygen supplementation. Fifty-three percent of the palivizumab group, compared with 39% of the control group, had bronchopulmonary dysplasia (P = .14). Wheezing occurred in the first 2 years of life in 27% of the palivizumab group and in 70% of control subjects (P = .008); respective hospitalization rates were 33% and 70% (P = .001). At school age, rates of hyperresponsiveness (provocative concentration leading to a 20% fall in FEV1 < 1 mg/mL) were 33% and 48%, respectively (P = .38). Spirometry, lung volumes, diffusion, and exhaled nitric oxide were within normal limits, with no significant differences between groups. CONCLUSION: Palivizumab prophylaxis was associated with reduced wheezing episodes and hospitalizations during the first 2 years of life in children born extremely prematurely. However, it did not affect pulmonary outcome at school age.

Clinical Impact of ß-Lactamase-producing Enterobacteriaceae in Sputum of Cystic Fibrosis Patients.

This case series describes 18 cystic fibrosis (CF) patients of a 135-patient CF center cohort with extended spectrum ß-lactamase-producing Enterobacteriaceae, from 2003 to 2012. Four had chronic infection. Prevalence increased annually from 0 to 6.35%. Risk factors compared with the 2010 CF center cohort included continuous inhaled antibiotics (P = 0.014) and courses of intravenous antibiotics during the year before first isolation (P = 0.009). Hospitalization rates were 1.05/year and 0.47/year preinfection and postinfection, respectively (P = 0.02). Slope of forced expiratory volume at 1 second% predicted remained unchanged during 12 months.

The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening.

BACKGROUND: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. METHODS: A retrospective review of governmental databanks, the national CF registry and CF centers. RESULTS: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. CONCLUSIONS: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.

The Spectrum of Nocardia Lung Disease in Cystic Fibrosis.

We reviewed all cases of Nocardia infection in cystic fibrosis patients at 2 centers. Eight of 200 patients had Nocardia in sputum. Four developed severe lung disease, including 3 with associated allergic bronchopulmonary aspergillosis; 4 remained clinically stable. Nocardia is often associated with significant lung disease in cystic fibrosis, possibly associated with allergic bronchopulmonary aspergillosis or steroids.

Increasing nontuberculous mycobacteria infection in cystic fibrosis.

BACKGROUND: Nontuberculous mycobacteria (NTM) are emerging infections in the CF population. AIMS: To assess NTM infection prevalence and associated features in our CF clinic population. METHODS: Patient records, 2002-2011, were reviewed for NTM infection. FEV1, pancreatic function, sputum microbiology, and serum cytokines were compared in patients with and without NTM infection. RESULTS: Incidence rate of NTM infection increased from 0 in 2002 to 8.7% in 2011 (p<0.001). NTM infection prevalence increased 3-fold from 5% (4/79) in 2003 to 14.5% (16/110) in 2011 (p=0.05). Prevalence of chronic NTM lung disease has decreased somewhat since a peak in 2009, with institution of aggressive triple therapy. Of NTM-infected compared to uninfected patients, 88.2% vs. 60.3% had a known 'severe' CFTR genotype (p=0.04), 88.2% vs. 58.9% were pancreatic insufficient (p=0.02); 70.6% vs. 43.8% had chronic Pseudomonas aeruginosa (p=0.06); 75% vs. 32% had Aspergillus infection (p=0.007) and 23.5% vs 2.7% had allergic bronchopulmonary aspergillosis (p=0.01). Patients infected with Mycobacterium abscessus had increased TGF-ß, TNF-α, IL-1ß, IL-2, IL-4 and IL-5 levels (p<0.05). There was no difference in cytokine levels for all NTM infected compared to uninfected patients. M. abscessus comprised 46% of all NTM infections. Comparing M. abscessus versus other NTM, duration was 10.5 (1-118) months versus 1 (1-70) month, median (range) (p=0.004); lung disease occurred in 69% versus 17% (p=0.0004), with sputum conversion in 4/11 versus 5/6, respectively (NS). CONCLUSIONS: NTM incidence and prevalence have increased dramatically in our CF clinic, associated with a severe CF genotype and phenotype. M. abscessus, the most prevalent NTM, caused prolonged infection despite therapy. There has been some decrease in the prevalence of NTM lung disease since 2009.

Effectiveness of long-term routine pulmonary function surveillance following pediatric hematopoietic stem cell transplantation.

INTRODUCTION: Pulmonary complications following hematopoietic stem cell transplantation (HSCT) are common and often subclinical. Thus, periodic pulmonary function testing (PFT) is mandatory. This study sought to evaluate the effectiveness of long-term PFT surveillance for children undergoing HSCT and identify potential risk factors. METHODS: We reviewed long-term PFT for HSCT patients at a tertiary pediatric center. Inclusion criteria were PFT prior to and at least once following HSCT. RESULTS: Fifty-seven patients performed 202 spirometry and 193 plethysmographic maneuvers; 41 were tested during the first year after HSCT, but only 29 were evaluated consistently long term (2-12 years). FVC and FEV(1) decreased gradually suggesting a restrictive ventilatory defect: FVC % predicted [mean ± SD] dropped from 91 ± 14% to 85 ± 17% after 0-24 months and 80 ± 19% beyond 2 years (P = 0.01) whereas FEV(1) dropped from 95 ± 16% to 88 ± 19% and 82 ± 20%, respectively (P = 0.002). A slight reduction in TLC was observed. Those undergoing allogeneic HSCT had a greater decline in FVC (P = 0.025) and FEV(1) (P = 0.025) as did those conditioned with radiation, regarding both FVC (P = 0.003) and FEV(1) (P = 0.002). Decline occurred earlier (≤2 years) after chemotherapy compared with radiation. Seven children had severe irreversible obstruction at >2 years despite therapeutic intervention. CONCLUSIONS: Most survivors of childhood HSCT maintain almost normal pulmonary function although mild restrictive lung disease may develop, particularly following allogeneic HSCT and conditioning with radiation. Severe airways obstruction developed in a small minority. The surveillance protocol for PFT needs to be followed more stringently to enable intervention possibly before early subclinical changes progress and become irreversible.

Encouraging pulmonary outcome for surviving, neurologically intact, extremely premature infants in the postsurfactant era.

OBJECTIVE: The aim of this study was to determine the long-term pulmonary outcome of extreme prematurity at a single tertiary-care center from 1997 to 2001 in the postsurfactant era. METHODS: We assessed symptoms, exhaled nitric oxide, spirometry, methacholine challenge (provocative concentration of methacholine required to decrease FEV1 by 20% [PC(20)]), lung volumes, diffusion, and cardiopulmonary exercise tolerance. RESULTS: Of 279 infants born, 192 survived to discharge, and 79 of these developed bronchopulmonary dysplasia (BPD) (65 mild, 12 moderate, two severe). We studied a subgroup of 53 neurologically intact preterm subjects aged 10 ± 1.5 years (28 with BPD [born, 26.2 ± 1.4 weeks; birth weight, 821 ± 164 g] and 25 without BPD [born, 27.2 ± 1 weeks; birth weight, 1,050 ± 181 g]) and compared them with 23 term control subjects. Of the BPD cases, 21 were mild, seven were moderate, and none was severe; 77.4% of subjects received antenatal steroids, and 83% received postnatal surfactant. Sixty percent of the preterm subjects wheezed at age < 2 years compared with 13% of the control subjects (P < .001), but only 13% wheezed in the past year compared with 0% of control subjects (not significant). For preterm and control subjects, respectively (mean ± SD), FEV1 % predicted was 85% ± 10% and 94% ± 10% (P < .001), with limited reversibility; residual volume/total lung capacity was 29.3% ± 5.5% and 25% ± 8% (P < .05); diffusing capacity/alveolar volume was 89.6% ± 9.2% and 97% ± 10% (P < .005); and PC(20) was 6.5 ± 5.8 mg/mL and 11.7 ± 5.5 mg/mL (P < .001). PC(20) was < 4 mg/mL in 49% of preterm subjects despite normal exhaled nitric oxide. Most measurements were similar in premature subjects with and without BPD. Peak oxygen consumption and breathing reserve were normal, but % predicted maximal load (measured in Watts) was 69% ± 15% for subjects with BPD compared with 88% ± 23% for subjects without and 86% ± 20% for control subjects (P < .01). CONCLUSIONS: Pulmonary outcome was encouraging at mid-childhood for neurologically intact survivors in the postsurfactant era. Despite mechanical ventilation and oxygen therapy, most had no or mild BPD. Changes found probably reflect the hypoplastic lungs of prematurity.