Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis.

RATIONALE: Given the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF). OBJECTIVES: To study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data. METHODS: Intestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature. RESULTS: Across 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit. CONCLUSIONS: Measurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

Are airways structural abnormalities more frequent in children with recurrent lower respiratory tract infections?

UNLABELLED: We report bronchoscopic changes observed in children with recurrent lower airways infections (RLAI) and findings in control children undergoing bronchoscopy for causes other than RLAI. PATIENTS AND METHODS: Retrospective case-control cohorts study. The clinical records of children who had fiberoptic bronchoscopy (FB) for a history of RLAI without any known underlying disorder between 2007 and 2013 and of control children who required FB for other causes were reviewed. Clinical features, bronchospic findings and bronchoalveolar lavage (BAL) results were assessed. RESULTS: Cases were 62 (32 female) children aged 5 years (1-12) and controls 29 children aged 4.5 years (0.5-14). Airway malacia was observed in 32 (52%) vs. 4 (13%) (p = 0.001), profuse respiratory secretions in 34(55%) vs. 6 (20%) (p = 0.007). Endobronchial obstruction: 4 (6.4%) and tracheobronchomegaly were observed only in cases. In cases with profuse respiratory secretions there was a higher prevalence of airways malacia: 64.7% vs. 35.7% (p = 0.04) and of positive BAL cultures: 45.5% vs. 13.3% (p = 0.04). Isolated organisms in cases were non-typable Haemophilus influenzae and Streptococcus pneumoniae most frequently. Pneumocystiis jirovecii, Staphylococcus aureus, and Streptococcus mitis were isolated in controls. CONCLUSIONS: Half of the children with RLAI had tracheo and/or bronchomalacia, their frequency being in keeping with previous reports and far higher than that observed in controls. It was associated with profuse respiratory secretions and with a higher frequency of positive BAL cultures mostly for non typable H. influenzae and S. pneumoniae which were not isolated in controls.

Hereditary pulmonary alveolar proteinosis. Could it be triggered by Mycoplasma pneumoniae pneumonia?

We present a three-year-old girl with respiratory failure due to hereditary pulmonary alveolar proteinosis caused by abnormal alpha chain of the granulocyte-macrophage colony-stimulating factor receptor. Both the patient and an asymptomatic seven-year-old sister were homozygous for the same mutation in CSF2RA. We speculate that the Mycoplasma pneumoniae pneumonia might have triggered the clinical presentation. While a good response to serial partial lung lavage was noticed, the ultimate outcome is uncertain.

Assessment and management of infants with apparent life-threatening events in the paediatric emergency department.

OBJECTIVE: To report our experience with a guideline approach for the assessment of apparent life-threatening events (ALTE) at our paediatric emergency department (PED). METHODS: Prospective observational case series study of a guideline approach for infants under the age of 12 months who suffered an ALTE between 1 April 2005 and 31 June 2006. RESULTS: A total of 66 infants with ALTE were included. Fourteen had perinatal risk factors and 16 previous ALTE. Only 14 presented significant abnormalities at examination at the PED. Eight had recurrent ALTE at the PED. Laboratory investigations were abnormal in 35 infants. A total of 45 infants were admitted. Associated conditions (secondary ALTE) were reported in 24 infants (36%), mostly respiratory infections and gastroesophageal reflux. Laboratory investigations contributed to a related diagnosis in nine cases. Compared with idiopathic group, the secondary ALTE sufferers had more perinatal risk factors, more abnormal examination findings, higher risk of recurrence and more frequent need for intervention in the PED. CONCLUSION: Most infants with a first episode of ALTE have normal physical examination. The absence of data suggesting underlying disease, after detailed history and examination, identifies a pool of infants who may be handled conservatively. This group may be monitored as outpatients after keeping them under watch for a short time at the emergency unit, thus avoiding unnecessary admissions. The low yield of laboratory tests in this group suggests that they could be safely omitted in most ALTE and restricted to cases with risk factors and/or whose progress at the observation unit is not satisfactory.