European Respiratory Society guidelines for the Diagnosis and Management of Pulmonary Alveolar Proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage, evaluation of antibodies against granulocyte macrophage colony stimulating factor (GM-CSF), genetic testing, and, eventually, lung biopsy. The management options are focused at removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis, and lung transplantation. The presented diagnostic and management guideline aim to provide guidance to physicians managing patients with PAP. METHODS: A European Respiratory Society Task Force committee composed of clinicians, methodologists, and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of the evidence and strength of recommendations. The committee formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions, and two narrative questions to develop specific evidence-based recommendations. RESULTS: The Task Force committee developed recommendations for five PICOs. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis, and lung transplantation. Also, the committee made recommendations regarding the use of GM-CSF antibody testing, diagnostic bronchoalveolar lavage (BAL) and biopsy based on narrative questions.In addition to the recommendations, the committee provided information on the hierarchy of diagnostic interventions and therapy. CONCLUSIONS: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.

Radiation-free and injection-free imaging of the paediatric chest using a magnetic resonance imaging protocol including zero time echo sequence (3D-ZTE).

Computed tomography (CT) is commonly used for paediatric thoracic diseases but involves radiation exposure and often requires intravenous contrast. We evaluated the performance of a magnetic resonance imaging (MRI) protocol including a 3D zero echo time (3D-ZTE) sequence for radiation-free and contrast-free imaging of the paediatric chest. In this prospective, single-centre study, children aged 6-16 years underwent chest CT and MRI within 48 h. CT and MRI exams were independently assessed by two paediatric radiologists. The primary outcome was the image quality of the 3D-ZTE sequence using a scoring system based on the acceptability of the images obtained and visibility of bronchial structures, vessels and fissures. Secondary outcomes included radiologists' ability to detect lung lesions on 3D-ZTE MRI images compared with CT images. Seventy-two children were included. Overall, the image quality achieved with the 3D-ZTE MRI sequence was inferior to that of CT for visualising pulmonary structures, with satisfactory lung image quality observed for 81.9% (59/72) and 100% (72/72) of patients, respectively. However, MRI sensitivity was excellent (above 90%) for the detection of certain lesions such as lung consolidation, proximal mucoid impactions, pulmonary cysts, ground glass opacities and honeycombing. Intermodality agreement (MRI versus CT) was consistently higher for the senior reader compared to the junior reader. CONCLUSION: Despite its overall lower image quality compared to CT, and the additional years of experience required for accurate interpretation, the 3D-ZTE MRI sequence demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications. WHAT IS KNOWN: • Chest radiography and CT are the main imaging modalities for paediatric thoracic diseases but involve radiation exposure and CT often requires IV contrast. • MRI is promising for radiation-free lung imaging in children but faces challenges of low signal-to-noise ratio and motion artefacts. WHAT IS NEW: • An MRI protocol including a 3D zero echo time (ZTE) sequence allows satisfactory visualisation of lung parenchyma in 82% of children. • Despite overall inferior image quality compared to CT, MRI demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications.

Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Inflammatory rebound and postinfectious inflammatory response in children with pleural infection: A single-center retrospective study.

INTRODUCTION: As pleural inflammation plays a central role in pleural infection (PI), corticosteroids are increasingly being considered as a potential therapy. However, the timing of treatment and the identification of patients who might benefit most remain unresolved. The aim of this study was therefore to investigate the inflammatory trajectories of children with PI. METHODS: This retrospective single-center study included children aged 3 months to 17 years and 11 months hospitalized for PI due to Streptococcus pyogenes, Streptococcus pneumonia, and Staphylococcus aureus over 10 years. An inflammatory rebound was defined biologically as a reincrease in C-reactive protein (CRP) of at least 50 mg/L after an initial decrease in CRP of at least 50 mg/L. RESULTS: We included 53 cases of PI, including 16 due to S. pyogenes, 27 due to S. pneumonia, and 10 due to S. aureus. An inflammatory rebound occurred in 20 patients (38%) after a median of 4.5 (3-6) days. This inflammatory rebound occurred in 9 (56%) children with S. pyogenes, 8 (30%) children with S. pneumonia, and 3 (30%) children with S. aureus. Children with an inflammatory rebound also had a higher rate of persistent fever after Day 7 and a longer length of stay (p = .01 for both). CONCLUSION: We postulate that the inflammatory rebound identified in nearly 40% of our patients corresponds to an early postinfectious inflammatory response, and thus that corticosteroids may be most beneficial for children with PI if administered early (between Days 2 and 5).