Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood.

BACKGROUND: Hermansky-Pudlak syndrome (HPS), a hereditary multisystem disorder with oculocutaneous albinism, may be caused by mutations in one of at least 10 separate genes. The HPS-2 subtype is distinguished by the presence of neutropenia and knowledge of its pulmonary phenotype in children is scarce. METHODS: Six children with genetically proven HPS-2 presented to the chILD-EU register between 2009 and 2017; the data were collected systematically and imaging studies were scored blinded. RESULTS: Pulmonary symptoms including dyspnea, coughing, need for oxygen, and clubbing started 3.3 years before the diagnosis was made at the mean age of 8.83 years (range 2-15). All children had recurrent pulmonary infections, 3 had a spontaneous pneumothorax, and 4 developed scoliosis. The frequency of pulmonary complaints increased over time. The leading radiographic pattern was ground-glass opacities with a rapid increase in reticular pattern and traction bronchiectasis between initial and follow-up Computer tomography (CT) in all subjects. Honeycombing and cysts were newly detectable in 3 patients. Half of the patients received a lung biopsy for diagnosis; histological patterns were cellular non-specific interstitial pneumonia, usual interstitial pneumonia-like, and desquamative interstitial pneumonia. CONCLUSIONS: HPS-2 is characterized by a rapidly fibrosing lung disease during early childhood. Effective treatments are required.

Lung disease caused by ABCA3 mutations.

BACKGROUND: Knowledge about the clinical spectrum of lung disease caused by variations in the ATP binding cassette subfamily A member 3 (ABCA3) gene is limited. Here we describe genotype-phenotype correlations in a European cohort. METHODS: We retrospectively analysed baseline and outcome characteristics of 40 patients with two disease-causing ABCA3 mutations collected between 2001 and 2015. RESULTS: Of 22 homozygous (15 male) and 18 compound heterozygous patients (3 male), 37 presented with neonatal respiratory distress syndrome as term babies. At follow-up, two major phenotypes are documented: patients with (1) early lethal mutations subdivided into (1a) dying within the first 6 months or (1b) before the age of 5 years, and (2) patients with prolonged survival into childhood, adolescence or adulthood. Patients with null/null mutations predicting complete ABCA3 deficiency died within the 1st weeks to months of life, while those with null/other or other/other mutations had a more variable presentation and outcome. Treatment with exogenous surfactant, systemic steroids, hydroxychloroquine and whole lung lavages had apparent but many times transient effects in individual subjects. CONCLUSIONS: Overall long-term (>5 years) survival of subjects with two disease-causing ABCA3 mutations was <20%. Response to therapies needs to be ascertained in randomised controlled trials.

Eradication of methicillin resistant Staphylococcus aureus detected for the first time in cystic fibrosis: A single center observational study.

OBJECTIVE: To retrospectively identify CF patients with methicillin resistant Staphylococcus aureus (MRSA) and to assess the long-term success of an eradication scheme introduced in 2002 for all newly colonized patients. PATIENTS: All microbiological results from all 505 CF patients followed between 2002 and 2012 were analyzed focusing on the detection of MRSA. METHODS: Retrospective patient record analysis of MRSA positive CF patients regarding eradication and clinical outcome. RESULTS: We identified 57 patients with MRSA, mean age 15.3 years (range: 0.6-36.9, incidence 0.9%/year). Of these, nine patients were lost to follow-up; seven chronically colonized patients were excluded from the intervention. Eradication was suggested to all patients, 37/41 gave their consent to the following two-step approach: (i) dual iv antibiotic treatment over 3 weeks, accompanied by hygienic directives and topical therapy for 5 days followed by a 6-week period with dual oral antibiotic therapy and inhalation with vancomycin. (ii) Each new MRSA detection was treated with 6 weeks inhalation of vancomycin and topical therapy for 5 days. Long-term eradication was rated by the microbiological status in the third year after first detection. MRSA was eradicated in 31 of 37 patients (84%) whose clinical course was stable (mean FEV1 one year before MRSA 80.4%, 3 years after MRSA 81.0%). CONCLUSIONS: MRSA colonization mandates complex and expensive hygienic measures which are not well accepted by patients. Therefore, MRSA eradication is desirable. Intensive therapy regimens may be successful in patients with CF and might help to maintain a stable clinical course. Pediatr Pulmonol. 2016;51:1010-1019. © 2016 Wiley Periodicals, Inc.

Surfactant proteins in pediatric interstitial lung disease.

BACKGROUND: Children's interstitial lung diseases (chILD) comprise a broad spectrum of diseases. Besides the genetically defined surfactant dysfunction disorders, most entities pathologically involve the alveolar surfactant region, possibly affecting the surfactant proteins SP-B and SP-C. Therefore, our objective was to determine the value of quantitation of SP-B and SP-C levels in bronchoalveolar lavage fluid (BALF) for the diagnosis of chILD. METHODS: Levels of SP-B and SP-C in BALF from 302 children with chILD and in controls were quantified using western blotting. In a subset, single-nucleotide polymorphisms (SNPs) in the SFTPC promoter were genotyped by direct sequencing. RESULTS: While a lack of dimeric SP-B was found only in the sole subject with hereditary SP-B deficiency, low or absent SP-C was observed not only in surfactant dysfunction disorders but also in patients with other diffuse parenchymal lung diseases pathogenetically related to the alveolar surfactant region. Genetic analysis of the SFTPC promoter showed association of a single SNP with SP-C level. CONCLUSION: SP-B levels may be used for screening for SP-B deficiency, while low SP-C levels may point out diseases caused by mutations in TTF1, SFTPC, ABCA3, and likely in other genes involved in surfactant metabolism that remain to be identified. We conclude that measurement of levels of SP-B and SP-C was useful for the differential diagnosis of chILD, and for the precise molecular diagnosis, sequencing of the genes is necessary.

Persistent Tachypnea of Infancy. Usual and Aberrant.

RATIONALE: Persistent tachypnea of infancy (PTI) is a specific clinical entity of undefined etiology comprising the two diseases neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis. The outcome of typical NEHI is favorable. The outcome may be different for patients without a typical NEHI presentation, and thus a lung biopsy to differentiate the diseases is indicated. OBJECTIVES: To determine whether infants with the characteristic clinical presentation and computed tomographic (CT) imaging of NEHI (referred to as "usual PTI") have long-term outcome and biopsy findings similar to those of infants with an aberrant presentation and/or with additional localized minor CT findings (referred to as "aberrant PTI"). METHODS: In a retrospective cohort study, 89 infants with PTI were diagnosed on the basis of clinical symptoms and, if available, CT scans and lung biopsies. Long-term outcome in childhood was measured on the basis of current status. MEASUREMENTS AND MAIN RESULTS: Infants with usual PTI had the same respiratory and overall outcomes during follow-up of up to 12 years (mean, 3.8 yr) as infants who had some additional localized minor findings (aberrant PTI) visualized on CT images. Both usual and aberrant PTI had a relatively favorable prognosis, with 50% of the subjects fully recovered by age 2.6 years. None of the infants died during the study period. This was independent of the presence or absence of histological examination. CONCLUSIONS: PTI can be diagnosed on the basis of typical history taking, clinical findings, and a high-quality CT scan. Further diagnostic measures, including lung biopsies, may be limited to rare, complicated cases, reducing the need for an invasive and potentially harmful procedure.

Blood Pressure Monitoring During the Induction and Maintenance Period of Propranolol Therapy for Complicated Infantile Hemangiomas: A Prospective Study of 109 Infants.

BACKGROUND: Propranolol has become the first-line treatment for complicated infantile hemangiomas (CIHs) worldwide. Recommendations for monitoring infants undergoing propranolol therapy vary. Data on long-term blood pressure (BP) monitoring have not been reported before. OBJECTIVE: The objective of the current study was to monitor BP in full-term infants during the induction and maintenance phase of propranolol therapy. METHODS: BP was monitored prospectively in 109 infants (mean age 2.8 mos, range 1-5 mos) with CIHs during the induction (3-4 days in the hospital during up-dosing from 0.5 to 2.0 mg/kg/day) and maintenance (6 mos) phases of oral propranolol therapy. RESULTS: Four children were excluded from the study because of sinus bradycardia (n = 2 [1.8%]) or lethargy (n = 2 [1.8%]). Mean systolic BP (SBP) decreased by 5 mmHg with the increase in propranolol dosage. Low (<5th percentile) SBP or diastolic BP (DBP) was observed in 2 of 105 children (1.9%) each. During the maintenance phase, 2 of 105 children (1.9%) had occasional SBP readings of less than 70 mmHg. No hypotension was observed after the third month of therapy. Low DBP (<36 mmHg) was recorded in 16 (15.2%) children after the first month, in 8.6% after the second, and in 2.9% during the third and fourth months of therapy. No patients exhibited clinical hypotension, bradycardia, or other known side effects of propranolol. Clinical response to therapy was excellent. LIMITATIONS: Reference BP values were derived from published tables, not from an untreated control group. CONCLUSIONS: In healthy full-term infants, propranolol (2 mg/kg/day divided in three doses) is well tolerated. No clinically significant hypotension was observed. We conclude that for otherwise healthy infants, BP monitoring during long-term propranolol therapy for CIHs is not necessary.

European protocols for the diagnosis and initial treatment of interstitial lung disease in children.

Interstitial lung disease in children (chILD) is rare, and most centres will only see a few cases/year. There are numerous possible underlying diagnoses, with specific and non-specific treatment possibilities. The chILD-EU collaboration has brought together centres from across Europe to advance understanding of these considerations, and as part of this process, has created standard operating procedures and protocols for the investigation of chILD. Where established consensus documents exist already, for example, for the performance of bronchoalveolar lavage and processing of lung biopsies, these have been adopted. This manuscript reports our proposals for a staged investigation of chILD, starting from when the condition is suspected to defining the diagnosis, using pathways dependent on the clinical condition and the degree of illness of the child. These include the performance of genetic testing, echocardiography, high-resolution CT, bronchoscopy when appropriate and the definitive investigation of lung biopsy, in order to establish a precise diagnosis. Since no randomised controlled trials of treatment have ever been performed, we also report a Delphi consensus process to try to harmonise treatment protocols such as the use of intravenous and oral corticosteroids, and add-on therapies such as hydroxychloroquine and azithromycin. The aim is not to dictate to clinicians when a therapeutic trial should be performed, but to offer the possibility to collaborators of having a unified approach when a decision to treat has been made.

Low to medium WU-virus titers in young children with lower respiratory tract infections.

The WU-virus (WUV), a novel polyomavirus, has recently been recovered from respiratory tract samples. Within a study collective of children with severe lower respiratory tract disease, 3% of the patients tested WUV positive. Viral loads ranged from 5 x 10(2) copies/ml to 1 x 10(4) copies/ml. The WUV genome-positive patients did not display specific clinical or radiological characteristics to be distinguished from other respiratory tract infections.