Single-centre prospective evaluation of the first 5†years of cystic fibrosis newborn screening in Germany.

Background: In 2016, nationwide cystic fibrosis newborn screening (CFNS) was newly implemented in Germany, using an immunoreactive trypsin/pancreatitis-associated protein/DNA screening algorithm that differs from most other nationwide screening programmes. Methods: We analysed real-life feasibility of the confirmation process with respect to our pre-specified procedural objectives. These included overall accuracy through false-negative and false-positive results, effectiveness of the Bavarian tracking system, and accuracy of Macroduct and Nanoduct sweat conductivity compared with quantitative chloride determination. All consecutive CFNS-positive newborns assigned to our CF centre and born between 1 September 2016 and 31 August 2021 (n=162) were included. Results: The German CFNS was feasible at our CF centre as all procedural objectives were met. The positive predictive value (PPV) of positive CFNS was low (0.23) and two initially negatively screened children were later diagnosed with CF. The tracking system was highly efficient with a 100% tracking rate. The Macroduct and Nanoduct systems had comparable success rates (93.2% versus 95.9%). Importantly, conductivity via Macroduct was more accurate than via Nanoduct (zero and four false-positive newborns, respectively). Conclusions: CF confirmation diagnostics of neonates in a certified regional CF centre was well managed in daily routine. The PPV of the German CFNS needs to be improved, e.g. by extending the DNA analysis within the screening algorithm and by increasing the number of variants tested. The Bavarian tracking system can serve as a successful model for other tracking systems. We preferred the Macroduct system because of its more accurate sweat conductivity readings.

[Kids Lung Registry and Child-EU Project - Progress in Rare and Interstitial Lung Diseases in Childhood Through Collaboration]. / Kinderlungenregister (chILD-EU) ­ Zusammenarbeit führt zu Fortschritten bei den seltenen und interstitiellen Lungenerkrankungen.

BACKGROUND: Progress in rare and interstitial lung disease in childhood can most usefully be achieved through systematic, registry-based collection. QUESTION AND METHODS: What are the practicalities and benefits of participating in the pediatric lung registry/chILD-EU project? We report our clinical experiences. RESULTS: Pediatricians and pediatric pulmonologists identify children with rare lung diseases. These are reported to the Kid's Lung Register after parental consent. Clinical data, imaging, and blood are sent to the registry. Genetic analysis can be arranged if desired. With completeness of the data, a peer-review process by pediatric radiology, possibly lung pathology, clinical and possibly genetic experts takes place in an interdisciplinary conference. A working diagnosis is established and communicated to the responsible physician via the registry and, if necessary, further discussed in case-related discussions. Assistance in entering the data is provided by the registry. Follow-ups are performed annually, and all registered physicians are invited to regular, web-based case discussions. Significant questions are answered in scientific projects and jointly published (>110 publications to date). CONCLUSIONS: Due to voluntary additional work of all participants beyond clinical routine, more than 1000 children with rare lung diseases have been included in the registry with biobank to date. A deeper understanding of the clinical courses of large cohorts of rare diseases and the initial description of new entities contributes to better care for these children.

Diagnostic workup of childhood interstitial lung disease.

Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of "undefined chILD" is stressed.

ABCA3-related interstitial lung disease beyond infancy.

BACKGROUND: The majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year. METHOD: Over a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly. RESULTS: At the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function. CONCLUSION: The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

Interstitial Lung Disease in Immunocompromised Children.

BACKGROUND: The range of pulmonary complications beyond infections in pediatric immunocompromised patients is broad but not well characterized. Our goal was to assess the spectrum of disorders with a focus on interstitial lung diseases (ILD) in immunodeficient patients. METHODS: We reviewed 217 immunocompromised children attending a specialized pneumology service during a period of 23 years. We assigned molecular diagnoses where possible and categorized the underlying immunological conditions into inborn errors of immunity or secondary immunodeficiencies according to the IUIS and the pulmonary conditions according to the chILD-EU classification system. RESULTS: Among a wide array of conditions, opportunistic and chronic infections were the most frequent. ILD had a 40% prevalence. Of these children, 89% had a CT available, and 66% had a lung biopsy, which supported the diagnosis of ILD in 95% of cases. Histology was often lymphocyte predominant with the histo-pattern of granulomatous and lymphocytic interstitial lung disease (GLILD), follicular bronchiolitis or lymphocytic interstitial pneumonitis. Of interest, DIP, PAP and NSIP were also diagnosed. ILD was detected in several immunological disorders not yet associated with ILD. CONCLUSIONS: Specialized pneumological expertise is necessary to manage the full spectrum of respiratory complications in pediatric immunocompromised patients.