DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Pulmonary function tests for evaluating the severity of Duchenne muscular dystrophy disease.

AIM: In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity. METHODS: This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment. RESULTS: Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r = 0.55, p = 0.02). CONCLUSION: Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms.

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.

Efficacy of Problem-Solving Intervention to Improve Adherence in Adolescents and Adults with Cystic Fibrosis.

BACKGROUND: Adherence to treatment by adolescents and adults with cystic fibrosis (CF) is often poor. OBJECTIVES: To assess the impact of a focused clinical intervention on adherence in individual patients, including help in problem-solving key barriers to adherence. To implement a patient-centered problem-solving intervention using CF My Way tools. To identify and overcome a selected barrier to adherence. METHODS: Medication possession ratios (MPRs), number of airway clearance sessions, forced expiratory volume (FEV1), body mass index (BMI), and health-related quality of life (HRQoL) were measured before and after the intervention. RESULTS: Sixteen patients with CF, aged 23.4 ± 6.7 years, participated. MPR increased for colistimethate sodium and tobramycin inhalations from a median of 21 (range 0-100) to 56 (range 0-100), P = 0.04 and 20 (range 0-100) to 33.3 (range 25-100), P = 0.03, respectively. BMI standard deviation score rose from -0.37 to -0.21, P = 0.05. No significant improvements were found in FEV1, airway clearance, or HRQoL scores. CONCLUSIONS: The CF My Way problem-solving intervention increased adherence to medical treatments by removing barriers directly related to the needs and goals of young adults with CF.

Lung transplantation in cystic fibrosis patients in Israel: The importance of ethnicity and nutritional status.

OBJECTIVES: To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF). METHODS: We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996 and 2014 at Rabin Medical Center, Israel. RESULTS: Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62%, and 39% at 1, 3, 5, and 10 years, respectively. Better survival correlated with: BMI at 6 months and 1 year after transplantation (P = .002 and P = .003, respectively), ischemic time of less than 300 minutes (P = .023), absence of liver disease (P = .012), and Jewish compared to Arab ethnicity (P = .007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75%, and 72% at 1, 3, and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (P = .012, P = .007). Additionally, prolonged time free of BOS correlated with male gender (P = .039), older age (P < .001), absence of liver disease (P = .012), and higher BMI 1 year after transplantation (P < .001). CONCLUSIONS: Clinically important determinants for survival include BMI pre- and 1-year post-transplantation and improved freedom from BOS. Arab ethnicity correlated with higher incidence and earlier onset of BOS compared to Jewish ethnicity in Israel.

A Homozygous Nme7 Mutation Is Associated with Situs Inversus Totalis.

We investigated the cause of situs inversus totalis (SIT) in two siblings from a consanguineous family. Genotyping and whole-exome analysis revealed a homozygous change in NME7, resulting in deletion of an exon causing an in-frame deletion of 34 amino acids located in the second NDK domain of the protein and segregated with the defective lateralization in the family. NME7 is an important developmental gene, and NME7 protein is a component of the γ-tubulin ring complex. This mutation is predicted to affect the interaction of NME7 protein with this complex as it deletes the amino acids crucial for the binding. SIT associated with homozygous deletion in our patients is in line with Nme7(-/-) mutant mice phenotypes consisting of congenital hydrocephalus and SIT, indicating a novel human laterality patterning role for NME7. Further cases are required to elaborate the full human phenotype associated with NME7 mutations.

Systematic Analysis of CCNO Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis.

Reduced generation of multiple motile cilia (RGMC) is a novel chronic destructive airway disease within the group of mucociliary clearance disorders with only few cases reported. Mutations in two genes, CCNO and MCIDAS, have been identified as a cause of this disease, both leading to a greatly reduced number of cilia and causing impaired mucociliary clearance. This study was designed to identify the prevalence of CCNO mutations in Israel and further delineate the clinical characteristics of RGMC. We analyzed 170 families with mucociliary clearance disorders originating from Israel for mutations in CCNO and identified two novel mutations (c.165delC, p.Gly56Alafs*38; c.638T>C, p.Leu213Pro) and two known mutations in 15 individuals from 10 families (6% prevalence). Pathogenicity of the missense mutation (c.638T>C, p.Leu213Pro) was demonstrated by functional analyses in Xenopus. Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%). Consistent with these findings, we demonstrate that CCNO expression is present in murine ependyma and fallopian tubes. CCNO is mutated more frequently than expected from the rare previous clinical case reports, leads to severe clinical manifestations, and should therefore be considered an important differential diagnosis of mucociliary clearance disorders.

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.

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.

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.

The association between Attention-Deficit-Hyperactivity-Disorder (ADHD) symptoms and disease severity in people with Cystic Fibrosis (pwCF).

BACKGROUND: The hallmarks of Cystic fibrosis (CF), chronic infection and inflammation, require intensive daily treatment to maintain and improve quality of life and outcome. The incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is increased in chronic inflammatory diseases. Previous studies suggested that the prevalence of ADHD in people with CF (pwCF) is higher than in the general population. The objective of this study was to evaluate the association between ADHD symptoms and parameters of CF disease severity, measured by demographic and clinical data. METHODS: Based on our previous study, the results of ADHD questionnaires and the MOXOCPT (continuous performance task) from 143 pwCF (7-68 years old) were analyzed and linked to patient data such as forced expiratory volume in 1 second (FEV1)%predicted, body mass index (BMI), number of pulmonary exacerbations, days of antibiotic (Abx) treatment and serum inflammatory markers. RESULTS: A positive correlation between FEV1 and ADHD questionnaire's score (p = 0.046) was observed in the children's group. Furthermore, BMI, white blood cells (WBC) count, and days of Abx treatment showed a positive correlation with some of the MOXOCPT parameters. CONCLUSION: There is an association between ADHD symptoms and some parameters of CF disease severity. These results highlight the need for an early diagnosis of ADHD in pwCF, which have the potential to improve their ability to deal with the burden of their disease and consequently their quality of life. Additional research is needed to understand the full spectrum of ADHD pathophysiology and the relationship with chronic inflammatory diseases such as CF.

Reversible Bronchial Obstruction in Primary Ciliary Dyskinesia.

BACKGROUND: Inhaled bronchodilators are frequently used among patients with primary ciliary dyskinesia (PCD), although neither the effectiveness nor the prevalence of their use is known, due to the paucity of relevant studies. METHODS: This is a retrospective analysis of pre- and post-bronchodilator spirometry results, of patients with PCD from two centers. Correlations were examined of bronchodilator response, with asthma and atopy markers. RESULTS: Of 115 patients, 46 (40%) completed spirometry pre- and post-bronchodilation. Of these, 26 (56.5%) demonstrated reversible airway obstruction (increase in %FEV1 predicted ≥ 10%). Obstruction reversibility was not found to be associated with a family history of asthma, blood eosinophil level, elevated IgE, or atopy symptoms. Of the 46 patients who completed bronchodilator spirometry, 29 (63%) were regularly using bronchodilators and inhaled corticosteroids. CONCLUSIONS: More than half of patients with PCD presented with reversible airway obstruction, without any correlation to markers of personal or familial atopy. Inhaled bronchodilators and corticosteroid therapies are commonly used for treating PCD. Evaluating bronchodilator response should be considered, and its effectiveness should be further studied.

DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G > A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes.

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.

International BEAT-PCD consensus statement for infection prevention and control for primary ciliary dyskinesia in collaboration with ERN-LUNG PCD Core Network and patient representatives.

INTRODUCTION: In primary ciliary dyskinesia (PCD) impaired mucociliary clearance leads to recurrent airway infections and progressive lung destruction, and concern over chronic airway infection and patient-to-patient transmission is considerable. So far, there has been no defined consensus on how to control infection across centres caring for patients with PCD. Within the BEAT-PCD network, COST Action and ERS CRC together with the ERN-Lung PCD core a first initiative has now been taken towards creating such a consensus statement. METHODS: A multidisciplinary international PCD expert panel was set up to create a consensus statement for infection prevention and control (IP&C) for PCD, covering diagnostic microbiology, infection prevention for specific pathogens considered indicated for treatment and segregation aspects. Using a modified Delphi process, consensus to a statement demanded at least 80% agreement within the PCD expert panel group. Patient organisation representatives were involved throughout the process. RESULTS: We present a consensus statement on 20 IP&C statements for PCD including suggested actions for microbiological identification, indications for treatment of Pseudomonas aeruginosa, Burkholderia cepacia and nontuberculous mycobacteria and suggested segregation aspects aimed to minimise patient-to-patient transmission of infections whether in-hospital, in PCD clinics or wards, or out of hospital at meetings between people with PCD. The statement also includes segregation aspects adapted to the current coronavirus disease 2019 (COVID-19) pandemic. CONCLUSION: The first ever international consensus statement on IP&C intended specifically for PCD is presented and is targeted at clinicians managing paediatric and adult patients with PCD, microbiologists, patient organisations and not least the patients and their families.

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.

Evidence of intestinal inflammation in patients with cystic fibrosis.

OBJECTIVES: Treatment with pancreatic enzymes fails to completely correct malabsorption and gastrointestinal symptoms in patients with cystic fibrosis (CF). The aim of the present study was to examine the small intestine of patients with CF without overt evidence of gastrointestinal disease using capsule endoscopy (CE). METHODS: Patients with CF received the agile patency capsule and, depending on the result of that procedure, then underwent standard CE using the PillCam SB capsule (Given Imaging, Yokneam, Israel). A stool specimen was taken on the same day as the CE for determination of the calprotectin level. RESULTS: Forty-two patients with CF ages 10 to 36 years were included; 29 had pancreatic insufficiency. One patient failed to excrete the patency capsule after 36 hours and was withdrawn from the study. Pulmonary function was mild to moderate with FEV1 68.5% +/- 16% predicted. Review of the CE videos showed that most of the patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including edema, erythema, mucosal breaks, and frank ulcerations. There were no adverse events. Fecal calprotectin levels were markedly high in patients with pancreatic insufficiency, 258 microg/g (normal <50). CONCLUSIONS: Small bowel mucosal pathology may be detected using CE in most of the patients with CF. The high fecal calprotectin levels found are suggestive of mucosal inflammation, which may correlate with the CE findings. Additional study is required to examine the possible relation of these mucosal lesions, which may be part of a newly identified enteropathy associated with CF, with persistent intestinal malabsorption in many of these patients.

Impact of a national population-based carrier-screening program on spinal muscular atrophy births.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services' insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA. All cases of prenatal and postnatal diagnosis of SMA in 2008-2017 were identified from databases of relevant government organizations, genetic laboratories in medical centers, and health care systems in Israel. Since 2013, screening was performed in 309,352 individuals, of whom 5741 were found to be carriers (carrier rate 1:54). Given an average of 180,000 live births annually, the predicted rate of SMA diagnosis was 15 cases per year. Prior to 2013, the average rate of prenatally diagnosed SMA was 4.66 cases per year, compared with 7.75 cases per year following population-wide provision of screening. The annual rate of postnatally diagnosed cases remained steady since 2008, with an average of 7- 7.25 cases per year. Screening has been effective in increasing prenatal detection of SMA but has had no effect on the rate of confirmed postnatal diagnoses. We speculate that screening rates may be affected by social, cultural, and religious factors.

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.

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.