Oded Breuer

CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation.

OBJECTIVE To investigate the effect of treatment with ivacaftor on insulin secretion in patients with cystic fibrosis (CF) (ΔF508\S549R) having CFRD/impaired insulin secretion. METHODS A standard OGTT was performed before and after 16weeks of treatment with ivacaftor in 2 sibling patients with CF carrying the S549R gating mutation. The area under the curve (AUC) for glucose and insulin was calculated using the trapezoidal estimation. RESULTS Before treatment, the OGTT of case 1 showed indeterminate glycemia; the OGTT of case 2 indicated CFRD. After ivacaftor treatment the OGTT demonstrated improved insulin secretion pattern mainly by increased first phase early insulin secretion, resulting in reduction of the AUC of glucose in both cases. CONCLUSIONS The treatment with ivacaftor in patients with CF carrying gating mutation can ameliorate impaired insulin secretion. Further studies and larger cohorts are needed to evaluate the impact of ivacaftor on insulin secretion in patients with CF carrying gating or other mutations.

Complicated community acquired pneumonia in childhood: Different types, clinical course, and outcome

The incidence of pediatric community acquired complicated pneumonia (PCACP) is increasing. Questions addressed: Are different types of PCACP one disease? How do different treatment protocols affect the outcome? Methods: Retrospective analysis of medical records of PCACP hospitalizations in the three major hospitals in Jerusalem in the years 2001–2010 for demographics, clinical presentation, management, and outcome. Results: Of the 144 children (51% aged 1–4 years), 91% of Jewish origin; 40% had para‐pneumonic effusion (PPE), 40% empyema (EMP), and 20% necrotizing pneumonia (NP). Bacterial origin was identified in 42% (empyema 79%, P = 0.009), most common S. pneumoniae (32%), group A streptococcus (9%). Patients with EMP, compared to PPE and NP, were less likely to receive prior antibiotic treatment (35% vs. 57% and 59%, respectively, P = 0.04). Mean hospitalization was longer in patients with NP followed by EMP and PPE (16.4 ± 10.6, 15.2 ± 7.9, and 12.7 ± 4.7 days, respectively), use of fibrinolysis was not associated with the outcome. All children had recovered to discharge regardless of antibiotic therapy or fibrinolysis. Answer: NP is a more severe disease with prolonged morbidity and hospitalization in spite of prior antibiotic treatment. All types had favorable outcome regardless of treatment‐protocol. Complicated pneumonia has an ethnic predominance. Pediatr Pulmonol. 2017;52:247–254.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

Neurological complications and pandemic influenza A (H1N1) virus infection

Aim:  To report on a different clinical course of pandemic influenza A (H1N1) infection among children who were neurologically impaired before the acute onset of the disease, in comparison with children who were neurologically intact.

Reversible airway obstruction in cystic fibrosis: Common, but not associated with characteristics of asthma.

BACKGROUND As asthma-like symptoms are common in CF, we evaluated reversible airway obstruction and associated characteristics. METHODS Retrospective analysis of charts including spirometry and bronchodilator response. RESULTS Of 190 CF patients (103 at Schneiders, 87 at Hadassah), aged 14.4 (4-76) years, median (range), 39% had reversible obstruction (ΔFEV1% predicted ≥12%), associated with younger age (p=0.01) and severe genotype (p=0.02). There was no association with family history of asthma, serum IgE, blood eosinophils, pancreatic status, FEV1<40% predicted, Aspergillus or pseudomonas infection. Of patients with reversible obstruction, 74% were on bronchodilator and 68% on inhaled corticosteroid therapy but 54% and 57% respectively receiving these therapies did not have reversible obstruction. CONCLUSIONS Reversible airway obstruction is common in CF, more frequent in younger patients and with severe genotype, with no correlation to markers of atopy or CF clinical severity. Bronchodilator and inhaled corticosteroid therapies are commonly prescribed even without reversible obstruction.

Antibiotic treatment for children hospitalized with community-acquired pneumonia after oral therapy

To compare the outcome of treatment with narrow spectrum versus broad spectrum antibiotics in children hospitalized with community‐acquired pneumonia (CAP) who received oral antibiotic treatment prior to their hospitalization.

Variable phenotypic presentation of a novel FOXF1 missense mutation in a single family.

Heterozygous mutations in the FOXF1 transcription factor gene are implicated in alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a developmental disorder of the lungs classically presenting with pulmonary hypertension and early demise. Evidence has suggested haploinsufficiency and partial paternal imprinting. We present a family with several affected members with an extremely variable phenotype.

Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis

BACKGROUND In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown. OBJECTIVE To investigate the cause and mechanism predisposing a patient to severe bronchiectasis. METHODS A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping. RESULTS The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen. CONCLUSIONS Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.

Hepatopulmonary Syndrome in Patients With Cystic Fibrosis and Liver Disease

Hepatopulmonary syndrome (HPS) is a liver-induced lung disorder defined as a triad of liver disease, pulmonary vascular dilatation, and a defect in oxygenation. It can complicate chronic liver disease of any etiology, but is most commonly associated with portal hypertension. Severe liver disease with portal hypertension is present in 2% to 8% of patients with cystic fibrosis (CF), but to date, to our knowledge, only one patient with CF has been reported to suffer from HPS. Here, we describe two patients with CF diagnosed with HPS, one subsequent to unresolved hypoxemia and the other following screening for HPS performed in our center. We speculate that HPS is underdiagnosed in patients with CF because of their coexisting respiratory morbidity, and we advocate routine screening for every patient with CF who has liver disease and portal hypertension.

The clinical significance of oropharyngeal cultures in young children with cystic fibrosis

In children with cystic fibrosis (CF) the associations between oropharyngeal swabs (OPSs) for detection of Pseudomonas and lung disease have not been evaluated. OPS and bronchoalveolar lavage (BAL) samples were obtained annually in children with CF from 2005 to 2017. OPS test characteristics were calculated using BAL as “gold standard”. Results were related to lung inflammation (BAL neutrophil elastase and interleukin-8), structural lung disease (chest computed tomography PRAGMA-CF (Perth–Rotterdam Annotated Grid Morphometric Analysis for CF) scores), respiratory exacerbations and future detection of Pseudomonas on BAL. From 181 patients, 690 paired OPS–BAL cultures were obtained. Prevalence of Pseudomonas in BAL was 7.4%. OPS sensitivity was 23.0% and specificity was 91.4%, reducing the post-test probability for a positive BAL following a negative OPS to 6.3%. Pseudomonas on OPS was not associated with lung inflammation or respiratory exacerbations, but was weakly associated with current PRAGMA-CF %Disease score (p=0.043). Pseudomonas on BAL was associated with positive neutrophil elastase (OR 4.17, 95% CI 2.04–8.53; p<0.001), increased interleukin-8 (p<0.001), increased all baseline PRAGMA computed tomography scores (p<0.001), progression of PRAGMA computed tomography scores (p<0.05) and increased risk of respiratory exacerbations (incidence rate ratio 2.11, 95% CI 1.15–3.87; p=0.017). In children with CF OPSs only marginally change the probability of detecting lower airway Pseudomonas and are not associated with lung disease indices nor exacerbations risk. Oropharyngeal swab cultures in children with CF are not helpful for ruling out lower airway Pseudomonas infection and are not associated with structural lung disease, lung inflammation or admissions for respiratory exacerbations http://ow.ly/jAgM30jm2P4