Mohamed-Aziz Barkaoui

BACKGROUND: Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed. METHODS: Among 1482 children (< 15 years) registered in the French LCH registry (1994-2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure. RESULTS: The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine-corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging. CONCLUSIONS: Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.

ABSTRACT: Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL, platelets <100 × 109/L, leukopenia (white blood cell count <4 × 109/L), and/or neutrophils <1.5 × 109/L. Among the 2313 patients aged <18 years enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis, 1 year); median follow-up lasted 8.1 years. Bone marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis, or myelofibrosis but never confirm the diagnosis. Fifty-eight patients (17%) developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 × 109/L, respectively) and severe HI (SHI; ≤7 g/dL and/or ≤20 × 109/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities, and outcomes (MHI and SHI 10-year survival rates, 98% and 73%, respectively). Since 1998, mortality first declined with combination cladribine-cytarabine therapy and then with MAPK inhibitors since 2014. Forty-one patients (12%) developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, because it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted therapy approaches would be better adapted for these patients, whereas MHI can be managed with classic therapies.