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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.

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

Background: Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract disorder causing hospitalization in infants. Palivizumab has shifted the profile of the hospitalized population away from premature infants and towards those with chronic morbidities who are not eligible for prophylaxis. Aim: To characterize RSV bronchiolitis hospitalizations in infants with chronic diseases, compared to otherwise healthy infants. Methods: A four consecutive RSV season retrospective analysis of patients younger than two years admitted with bronchiolitis. Background demographic and clinical data, including vital sign measurements, laboratory tests, and pediatric intensive care unit (PICU) admissions during hospitalization, were analyzed. Results: Of 1124 hospitalizations due to RSV bronchiolitis, 244 (22%) were in infants with chronic diseases. Although 20/1124 qualified for RSV prophylaxis, only 8 had been vaccinated. Compared to otherwise healthy infants, children with chronic diseases had longer hospitalizations, median 4 days (IQR 4-7) vs 3 days (2-5), p

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.

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.

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

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.

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

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.What is the long-term effect of palivizumab immunization and extreme prematurity (29 weeks) on respiratory symptoms and pulmonary function in adolescence?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.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, FEVPalivizumab 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.

Background: In children with suspected aspiration, clinical swallow assessment (CSA) may be supplemented with video-fluoroscopic swallow studies (VFSS) to inform feeding management. Aim: To assess the diagnostic accuracy of CSA, compared to VFSS and evaluate the impact of VFSS on feeding management and clinical status. Method: Retrospective case review of children who underwent CSA, followed by VFSS in a tertiary centre. Results: 113 children underwent VFSS at age 2.2 (0.1-17.9) years, median (range). Diagnoses were syndromic entities (38, 34%), CNS dysfunction (28, 25%), anatomic abnormalities (18, 16%), CNS malformation (7, 6%), neuromuscular disease (6, 5%) and other (16, 14%). 62% had laryngeal penetration or aspiration per CSA, compared to 38% per VFSS, p VFSS based feeding route recommendations differed significantly from those based on prior CSA, p=0.04. Following VFSS, the rate of orally fed children rose from 66% to 78%, p=0.006. However, exclusive gastrostomy feeding also increased, from 7% to 12%, p=0.005. In the year after VFSS, compared to the year prior, total hospital admissions fell from 364 to 252, p Conclusion: CSA overestimated the presence of overall swallowing abnormalities, but underestimated silent aspirations. VFSS led to change in feeding route and advice, which was associated with clinical improvement.

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.

Summary 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 FEV1 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 FEV1 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 FEV1 (P = 0.025) as did those conditioned with radiation, regarding both FVC (P = 0.003) and FEV1 (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. Pediatr Pulmonol. 2014; 49:1124–1132. © 2013 Wiley Periodicals, Inc.

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.Infants with acute bronchiolitis were tested with sulfur hexafluoride (SFTwenty-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).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.

The killing of natural killer (NK) cells is regulated by activating and inhibitory NK receptors that recognize mainly class I major histocompatibility complex (MHC) proteins. In transporter associated with antigen processing (TAP2)-deficient patients, killing of autologous cells by NK cells is therefore expected. However, none of the TAP2-deficient patients studied so far have suffered from immediate NK-mediated autoimmune manifestations. We have previously demonstrated the existence of a novel class I MHC-independent inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) interactions. Here, we identified 3 new siblings suffering from TAP2 deficiency. NK cells derived from these patients express unusually high levels of the various killer cell inhibitory receptors (KIRs) and the CEACAM1 protein. Importantly, the patients' NK cells use the CEACAM1 protein to inhibit the killing of tumor and autologous cells. Finally, we show that the function of the main NK lysis receptor, NKp46, is impaired in these patients. These results indicate that NK cells in TAP2-deficient patients have developed unique mechanisms to reduce NK killing activity and to compensate for the lack of class I MHC-mediated inhibition. These mechanisms prevent the attack of self-cells by the autologous NK cells and explain why TAP2-deficient patients do not suffer from autoimmune manifestations in early stages of life.

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.

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.

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.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.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 FEV11 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.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.

Chemokines play a pivotal role in homeostatic and inflammatory migration of naive and activated natural killer (NK) subsets. Recent studies have shown that aberrant chemokine receptor expression on certain immune cells underlies the pathogenesis of clinical conditions in which recruitment of such cells is altered. Progressive accumulation of activated NK cells, subsequently resulting in the formation of chronic granulomatous lesions in the respiratory tract and the skin, has been described in a number of patients with transporter associated with antigen processing 2 (TAP-2) deficiency in the later stages of disease. Therefore, the goal of the present study was to elucidate whether the dysregulation of chemoattracting receptor expression on NK cells could explain abnormal navigation of these cells in TAP-2 deficiency. High-throughput proteomic comparison, followed by verification with flow cytometry, revealed that chronically activated NK cells derived from 3 newly identified patients with TAP-2 deficiency consistently expressed aberrant levels of CC chemokine receptor 2 (CCR2) chemokine receptor in vitro and in vivo. This expression pattern translated into specific responsiveness of chronically activated NK cells derived from patients with TAP-2 deficiency to multiple ligands of CCR2. Moreover, the in vivo elevated levels of interleukin-2 (IL-2) and monocyte chemoattractant protein-1 (MCP-1) detected in serum and bronchoalveolar lavage samples derived from these patients highlight the potential involvement of the CCR2 pathway in aberrant NK-cell retention at chronic inflammatory sites.

We previously demonstrated that the quinolone moxifloxacin prevents Candida albicans pneumonitis and epithelial nuclear factor kappaB (NF-kappaB) nuclear translocation in immunosuppressed mice.To explore the anti-inflammatory effects of moxifloxacin directly on a lung epithelial cell line.We studied the effect of clinically relevant concentrations of moxifloxacin (2.5-10 mg/L) on cytokine-induced activation of nitric oxide (NO) secretion, inducible NO synthase (iNOS) expression and the activation of signal transduction pathways of inflammation, NF-kappaB and the mitogen-activated protein kinases [extracellular signal-regulated kinases (ERK1/2) and C-Jun N-terminal kinase (JNK)], in the A549 lung epithelial cell line.Stimulation with the cytokines interleukin-1beta(IL-1beta)/interferon-gamma (IFN-gamma) increased NO up to 3.3-fold and moxifloxacin inhibited this up to 68% (P0.05). Similarly, the increase in iNOS levels was inhibited in cells pre-treated with moxifloxacin by up to 62%. IL-1beta stimulated a rapid increase in the activities of early intracellular signalling molecules, ERK1/2 and JNK. Moxifloxacin inhibited ERK1/2 by up to 100% and p-JNK activation by 100%. NF-kappaB, as measured by electrophoretic mobility shift assay, was inhibited up to 72% by moxifloxacin. Western-blot analysis revealed that IL-1beta enhanced NF-kappaB p65 and p50 proteins by 1.7- and 3.6-fold, respectively, whereas moxifloxacin inhibited the proteins by up to 60%.Moxifloxacin inhibits intracellular signalling, iNOS expression and NO secretion in a lung epithelial cell line. Future studies may uncover a primary site of quinolone immunomodulation, either upstream or at the cell membrane. Eventually, this quinolone might become an important therapy for inflammatory lung diseases.

BackgroundNontuberculous mycobacteria (NTM) are emerging infections in the CF population.AimsTo assess NTM infection prevalence and associated features in our CF clinic population.MethodsPatient 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.ResultsIncidence rate of NTM infection increased from 0 in 2002 to 8.7% in 2011 (p

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.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.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 at2 years despite therapeutic intervention.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.

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.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.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 age2 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) was4 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).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.

The forced oscillation technique is a noninvasive and effort-independent technique that is well suited for lung function measurement in young children. FOT employs small-amplitude pressure oscillations superimposed on normal breathing. Therefore, it has the advantage over conventional lung function techniques in that it does not require patient cooperation for conducting respiratory maneuvers.To test the feasibility of the FOT test in preschool children and to compare the results to the commonly used spirometry before and after the administration of bronchodilator therapy.Forty-six children (median age 4.9 years, range 1.8-18.3) attending the pulmonary clinic at Schneider Children's Medical Center tried to perform FOT and routine spirometry. Results were retrospectively analyzed.Of the 46 children 40 succeeded in performing FOT and only 29 succeeded in performing simple spirometry. All but one of the 32 children aged 4 years and above (97%) could perform both tests. Nine of 14 children (64%) aged 4 and less could perform the FOT but only 3 (21%) could perform spirometry. Baseline values of respiratory resistance measured at 6 Hz (R6) negatively correlated with body length (r2 = 0.68, P0.005). Twenty-four children performed both tests before and after bronchodilator therapy. A significant concordance was found between the measured responses to bronchodilators by FOT and spirometry (P0.01). Only one child had a negative response by FOT but a positive response by spirometry.The FOT is a simple, non-invasive technique that does not require subject cooperation and thus can be utilized for measuring lung function in children as young as 2 years old. Furthermore, the FOT was shown to reliably measure response to bronchodilator therapy.

Neonatal hyperthyroidism, a rare and serious disorder, occurs in two forms. An autoimmune form associated with maternal Graves' disease, resulting from transplacental passage of maternal thyroid-stimulating antibodies, and a non-autoimmune form, resulting from mutations in the stimulatory G protein or the thyrotropin receptor (TSHR) causing constitutive activation of intracellular signaling cascades. To date, 29 separate cases of thyrotoxicosis caused by germline mutations of the TSHR have been documented. These cases have expressed themselves in a range of clinical consequences. This report describes a new case of a newborn with non-autoimmune hyperthyroidism secondary to a constitutively active TSHR mutation (S281N) whose clinical course was complicated by severe respiratory compromise. Typical clinical findings in this disorder are discussed by a review of all previously published cases.

Interactions of natural killer (NK) cells with MHC class I proteins provide the main inhibitory signals controlling NK killing activity. It is therefore surprising to learn that TAP2-deficient patients suffer from autoimmune manifestations only occasionally in later stages of life. We have previously described that the CEACAM1-mediated inhibitory mechanism of NK cytotoxicity plays a major role in controlling NK autoreactivity in three newly identified TAP2-deficient siblings. This novel mechanism probably compensates for the lack of MHC class I-mediated inhibition. The CEACAM1 protein can also be present in a soluble form and the biological function of the soluble form of CEACAM1 with regard to NK cells has not been investigated. Here we show that the homophilic CEACAM1 interactions are abrogated in the presence of soluble CEACAM1 protein in a dose-dependent manner. Importantly, the amounts of soluble CEACAM1 protein detected in sera derived from the TAP2-deficient patients were dramatically reduced as compared to healthy controls. This dramatic reduction does not depend on the membrane-bound metalloproteinase activity. Thus, the expression of CEACAM1 and the absence of soluble CEACAM1 observed in the TAP2-deficient patients practically maximize the inhibitory effect and probably help to minimize autoimmunity in these patients.