Patrick Stafler

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.

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.

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

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.

Feasibility of multiple breath washout measurements in infants with bronchiolitis: A pilot study: Multiple Breath Washout in Bronchiolitis

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.

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening

Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan‐population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients.

Clinical Impact of β-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 &bgr;-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 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.

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

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.

Induced sputum versus broncho-alveolar lavage for pathogen surveillance in young cystic fibrosis patients: Low specificity is not necessarily a bad thing

Dear Editor: In the largest study to date assessing sensitivity and specificity of induced sputum (IS) to survey airway pathogens in young cystic fibrosis patients as compared to broncho-alveolar lavage (BAL), D’Sylva et al conclude that sputum is not highly sensitive or specific. In all 61 samples, collected from 49 individual children, 6% hypertonic saline nebulizationwas administered prior to collecting the sample, but airway clearancewas performed in only half the group. Airway clearance raised sensitivity from 27.3% to 50% and reduced specificity from 78.9% to 60.9%.However, due to large overlaps in 95% confidence intervals, this was not considered important. In four out of 32 paired sampleswith any pathogens, P. aeruginosa was identified in IS and missed in BAL, while three children had P. aeruginosa in BAL and not IS. The two sampling methods were performed within a week of each other. We would like to suggest that low specificity of IS as a test modality in this context might counterintuitively represent a virtue: Induced sputum is not only quicker, cheaper, more accessible and less inconvenient than BAL, traditionally regarded as the gold standard for lower airway pathogen identification, but also potentially samples a larger surface area of the airways. Hence, the presence of pathogens on IS that are not present on BAL cannot uncritically be accepted as inaccuracy. The classification of P. aeruginosa growth in IS, which is not grown in BAL fluid, obtainedwithin 7 days of the IS procedure, as “false positive” fails to consider that it may be a true lower airway pathogen that was missed on BAL. D’Sylva et als assumption that these “false positive” sputum cultures are likely to represent upper airway contamination is supported by evidence that oropharyngeal cultures can pick up P. aeruginosa in a small proportion of healthy infants. However, when P. aeruginosa is cultured even from a single upper airway specimen in a previously uninfected child, its treatment has sensibly been advocated in CF, irrespective of quantity of the organism. Considering the results of D’Sylvas study, the long honed notion of BAL representing gold standard for CF airway sampling might be questioned. We propose that optimisation of airway clearance, hypertonic saline and deep oropharyngeal suction, which we have shown to be well tolerated in even very young patients, ought not be discarded as a valuable diagnostic tool in the management of non-expectorating patients with CF. Sensitivity of IS can be maximised using effective physiotherapy, as described in a standard operating procedure document of the European Cystic Fibrosis Society Clinical Trials Network Standardization Committee for collecting induced sputum in non-expectorating young children. Meanwhile, low specificity, reflecting increased identification of potentially important pathogens, is not necessarily a bad thing.

The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews

BACKGROUND The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. METHODS Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. RESULTS Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25-38.2) years, median (range). Sweat chloride was 106 ± 13 meq/L, mean ± SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40-121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1-14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. CONCLUSION In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.