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Objective This study intended to explore behavioral and emotional problems and quality of life, as well as their related factors in Chinese children with Langerhans cell histiocytosis (LCH). Methods This was a cross-sectional study. Subjects were included from April 2023 to September 2023. Child behavior checklist (CBCL), pediatric quality of life inventory™ version 4.0 (PedsQL TM 4.0), and version 3.0 (PedsQL TM 3.0) Cancer Module were used to assess behavioral and emotional problems and quality of life. Results A total of 120 children with LCH were included. Twenty-six (21.7%) children had behavioral and emotional problems. Age at diagnosis ≥ 4 years [odds ratio (OR) = 0.344, P  = 0.022] and major caregiver with an educational level of junior college and above (OR = 0.314, P  = 0.035) were independently associated with a lower possibility of achieving CBCL total problem score ≥ 35. Electronic product usage time ≥ 2 h per day ( B =-6.024, P  = 0.011) and caesarean section ( B =-6.006, P  = 0.012) were independently related to a lower total PedsQL TM 4.0 score, while age at diagnosis ≥ 4 years ( B  = 9.183, P  = 0.004) showed an inverse trend. Second-line treatment was independently related to a lower total PedsQL TM 3.0 Cancer Module score ( B =-5.578, P  = 0.021). Conclusion In this study, 21.7% of Chinese children with LCH exhibit behavioral and emotional problems. Age at diagnosis < 4 years, major caregiver with an educational level of high school and below, electronic product usage time ≥ 2 h, caesarean section, and second-line treatment are related to behavioral and emotional problems and impaired quality of life in Chinese children with LCH. Clinical trial number Not applicable.

Background The patients with multisystem and risk organ involvement Langerhans cell histiocytosis (MS-RO + LCH) have poor prognosis. The patients with MS-LCH who failed front-line therapy have a high mortality rate and the standard salvage treatment has not been established. The combination of cytarabine (Ara-c), vincristine (VCR) and prednisone might be effective for refractory/relapse MS-RO + LCH, with low toxicity. Methods We retrospectively analyzed pediatric refractory/relapse MS-RO + LCH patients treated with the low-dose Ara-c (100mg/m 2 /d×5days) or high-dose Ara-c (500mg/m 2 /d×5days) combined with vindesine (VDS) and prednisone in a single center. The efficacy, outcomes and adverse events were analyzed. Results From January 2013 to December 2016, 13 patients receiving the low-dose Ara-c chemotherapy (LAC) and 7 patients receiving the high-dose Ara-c chemotherapy (HAC) were included in the study. 11 (84.6%) of the 13 patients treated with the LAC regimen and 6 (85.7%) of the 7 patients treated with the HAC regimen had response after four courses of the therapy. All patients in the study were alive during follow-up and the 3-year event-free survival rate (EFS) was 53.7% and 85.7% in the LAC and HAC groups. The most frequent adverse event was Grade 1/2 myelosuppression, which was observed in 38.5% (5/13) and 42.9% (3/7) of the patients receiving the LAC and HAC regimen. Conclusions A combination of Ara-c, VDS and prednisone was effective and safe for some patients with refractory/relapse MS-RO + LCH. The high-dose Ara-c regimen was associated with a numerically higher EFS rate.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis ( P <0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement ( P <0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis ( P <0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy ( n =89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment ( n =29) or to targeted therapy ( n =13) ( P =0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy ( n =13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy ( n =16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients’ liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.

Purpose We intended to investigate the clinical features of paediatric patients with chronic active Epstein–Barr virus infection (CAEBV) and to examine the effectiveness of the L-DEP regimen before haematopoietic stem cell transplantation (HSCT). Methods A retrospective analysis was performed on 35 patients with CAEBV at Beijing Children’s Hospital from January 2016 to January 2020. The efficacy and adverse events of the L-DEP regimen were evaluated. Results The median age of the 35 patients was 7.0 years old (range 2.5–17.5 years). Twenty-eight patients achieved a clinical response (80.0%, 22 in clinical CR, 6 in clinical PR) after L-DEP. In terms of virological response, 7 patients (20%) were assessed as having virological CR, and 23 patients (65.7%) had virological PR. Finally, 29 patients underwent allo-HSCT. The median survival time was 18 months (2–50 months). The 3-year overall survival rates in patients treated with chemotherapy only (n = 6) and chemotherapy followed by HSCT (n = 25) were 33.3% and 75.4%, respectively. After L-DEP 1st treatment and L-DEP 2nd treatment, the EBV-DNA loads in blood and plasma were significantly reduced compared with those before chemotherapy (median: 4.29 × 10 5 copies/ml vs. 1.84 × 10 6 copies/ml, Mann–Whitney U: P  = 0.0004; 5.00 × 10 2 copies/ml vs. 3.17 × 10 3 copies/ml, Mann–Whitney U; P  = 0.003; 2.27 × 10 5 copies/ml vs. 1.84 × 10 6 copies/ml, P  = 0.0001; 5.00 × 10 2 copies/ml vs. 3.17 × 10 3 copies/ml, P  = 0.003). Compared with the liver and spleen size before chemotherapy, the size of the liver and spleen shrank significantly after L-DEP 2nd (median 3.8 cm vs. 1.9 cm, P  = 0.003; 3.8 cm vs. 0 cm, P  < 0.008). In addition, after L-DEP treatment, there was no difference in the clinical or virological response rate regardless of HLH status (clinical response: 77.3% vs. 84.6%, P  = 0.689; virological response: 90.9% vs. 76.9%, P  = 0.337). Conclusion The L-DEP regimen is an effective therapy in CAEBV for bridging to allo-HSCT .

Objective To investigate the clinical characteristics, treatment, prognosis and risk factors for chronic active Epstein–Barr Virus infection (CAEBV) associated with coronary artery dilatation (CAD) in children. Methods Children with CAEBV associated with CAD hospitalized at Beijing Children’s Hospital, Capital Medical University from March 2016 to December 2019 were analyzed. Children with CAEBV without CAD were selected as the control group and matched by sex, age, treatment and admission time. The clinical manifestations, laboratory and ultrasound examinations, treatment and prognosis of the children were collected in both groups. Results There were 10 children with CAEBV combined with CAD, including 6 males and 4 females, accounting for 8.9% (10/112) of CAEBV patients in the same period, with an onset age of 6.05 (2.8–14.3) years. The median follow-up time was 20 (6–48) months. All the patients had high copies of EBV-DNA in whole blood [1.18 × 10 7 (1.90 × 10 5 –3.96 × 10 7 ) copies/mL] and plasma [1.81 × 10 4 (1.54 × 10 3 –1.76 × 10 6 ) copies/mL], and all biopsy samples (bone marrow, lymph nodes or liver) were all positive for Epstein–Barr virus-encoded small RNA. Among the 10 children, 8 had bilateral CAD, and 2 patients had unilateral CAD. After diagnosis, 7 children were treated with L-DEP chemotherapy in our hospital. After chemotherapy, four patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). The others were waiting for HSCT. At the time of the last patients follow up record, the CAD had returned to normal in 3 patients, and the time from the diagnosis of CAD to recovery was 21 (18–68) days. LDH, serum ferritin, TNF-α and IL-10 levels were statistically significantly different between the two groups ( P  = 0.009, 0.008, 0.026 and 0.030). There were no significant differences in survival rate between the two groups ( P  = 0.416). Conclusion The incidence of CAEBV with CAD was low. CAEBV with CAD did not influence the prognosis. Patients who had high LDH, serum ferritin, TNF-α, and IL-10 levels early in their illness were more likely to develop CAD.

PurposeLangerhans cell histiocytosis (LCH) can affect any organ. Central nervous system (CNS) involvement is rare, and its management is poorly understood. This study aimed to analyze the clinical response and prognosis of pediatric LCH with central diabetes insipidus (CDI) treated with second-line therapy with cytarabine (Ara-c), cladribine (2-cdA), dexamethasone, and vindesine.MethodsThis retrospective case series study included pediatric LCH with CDI treated at Beijing Children’s Hospital affiliated with Capital Medical University (11/2012–01/2018). After the first-line 2009-LCH regimen, patients with active disease/worse response, relapse, or no significant improvement in risk organs, pituitary, or lung were given the second-line therapy. Baseline characteristics, clinical response and adverse reactions were observed.ResultsTwenty-six children with CDI and disappearance of hyperintensity in the posterior pituitary were included. They received “Regimen A” Ara-c + dexamethasone + vindesine (n = 7) or “Regimen B” Ara-c + dexamethasone + vindesine + 2-cdA (n = 19) as second-line therapy. There were 14 patients with CDI but without pituitary stalk thickening (PST) and 12 with CDI and PST. In patients with CDI alone, 4/4 patients receiving Regimen A and 3/10 receiving Regimen B improved. All patients with CDI and PST showed improvement for PST. The reappearance of hyperintensity at the posterior pituitary was observed in 10 patients with CDI. All 26 children were alive after a median follow-up of 40.5 months. There were no chemotherapy-related deaths.ConclusionA combined therapy with Ara-c, 2-cdA, dexamethasone, and vindesine could partially alleviate pituitary disease conditions in pediatric LCH with CNS involvement, with good tolerance.

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially fatal illness characterized by impaired natural killer and cytotoxic T cell function. Chronic granulomatous disease (CGD) is an inherited immune deficiency caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients display an increased susceptibility to infection with bacteria and fungi. Repeated infections lead to an increased risk for developing HLH. The case of CGD with repeated Salmonella septicemia complicated with HLH is very rare, and the CGD mutation identified has not been reported. Case presentation A 3-year-old boy was admitted to our hospital for fever, hepatosplenomegaly and pancytopenia. According to the clinical manifestations and laboratory results, hemophagocytic lymphohistiocytosis (HLH) was diagnosed. Blood and bone marrow culture confirmed septicemia due to Salmonella Typhimurium. On the basis of antiinfection treatment, methylprednisolone was used to control HLH. After treatment, the clinical symptoms and laboratory results improved. Gene analysis showed a novel hemizygous CYBB gene mutation: c.302A > G (p.H101P). Combined with a past history of recurrent infection, the child was diagnosed with HLH secondary to CGD triggered by septicemia. Conclusions In case of a known (or highly suspected) CGD with a documented infection, clinical or biological features of HLH should encourage the physician to make possible to confirm or not the HLH. Therefore, to initiate the adequate treatment in association with anti-infective therapy.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasia in children. BRAF mutations are associated with permanent diabetes insipidus (DI). The onset of clinical DI is always latent with imaging evidence of pituitary involvement. In this study, we reported three children with BRAF-mutated LCH with pituitary involvement who improved after targeted therapy (dabrafenib and trametinib). The results may indicate that pituitary involvement may be reversible in some patients with LCH if it is observed and treated before clinical DI. Targeted therapy may be an effective choice for LCH patients with early pituitary involvement who were irresponsive to first-line or second-line chemotherapy. However, a relapse after targeted therapy is completed in patients with persistently positive cfBRAF V600E mutations is still a challenge that needs to be resolved. The timing of introducing targeted therapy, its appropriate duration and effective combinations with chemotherapy or other targeted drugs should be explored further.Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasia in children. BRAF mutations are associated with permanent diabetes insipidus (DI). The onset of clinical DI is always latent with imaging evidence of pituitary involvement. In this study, we reported three children with BRAF-mutated LCH with pituitary involvement who improved after targeted therapy (dabrafenib and trametinib). The results may indicate that pituitary involvement may be reversible in some patients with LCH if it is observed and treated before clinical DI. Targeted therapy may be an effective choice for LCH patients with early pituitary involvement who were irresponsive to first-line or second-line chemotherapy. However, a relapse after targeted therapy is completed in patients with persistently positive cfBRAF V600E mutations is still a challenge that needs to be resolved. The timing of introducing targeted therapy, its appropriate duration and effective combinations with chemotherapy or other targeted drugs should be explored further.

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21 years (0.17–12.92 years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10–30 days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.

This study aimed to compare the serum levels of 34 cytokines of children with hemophagocytic lymphohistiocytosis (HLH) and explored the specific cytokine pattern of HLH subtypes and the relationship between cytokine levels and prognosis. This retrospective study assessed the clinical data and cytokine levels of newly diagnosed children with HLH in Beijing Children’s Hospital, Capital Medical University, from January 2017 to December 2021. A total of 101 children were enrolled in the study. The levels of IFN-γ and IL-18 increased in more than 90% of patients, and MIP-1α, SDF-1α, IP-10, IL-6, IL-8, IL-10, IL-1 RA, and TNF-α increased at different levels in more than 50% of patients. The levels of IL-10 in EBV-HLH increased significantly, followed by IFN-γ and IL-18, while IL-10 and IFN-γ in CAEBV-HLH had a slight increase. Except for IL-10, the levels of IL-6, Eotaxin, IL-13, IL-18, IFN-γ, and MIP-1β in Rh-HLH increased significantly. F-HLH had significantly high IL-10 levels and a slight increase in IL-13. We showed that various cytokines could assist in differentiating HLH subtypes with ROC curve analysis. When IL-10/IL-6 was 1.37, the sensitivity and specificity of diagnosing EBV-HLH were higher than 80% (AUC = 0.837, p < 0.001). The effect of cytokine ratio on classifying HLH subtypes (17/22, 77.3%) was more significant than the single cytokine (5/22, 22.7%). The 3-year overall survival (OS) rate of children with F-HLH was the lowest during the follow-up. The 3-year OS of patients with EBV-HLH and CAEBV-HLH was significantly higher than that with F-HLH (88.1% ± 5.0% vs. 94.1% ± 5.7% vs. 57.1% ± 14.6%, p = 0.017). Cox proportional hazards model revealed that elevated GM-CSF and MCP-1, as well as CNS involvement, were independent risk factors for poor outcomes for patients with HLH. Various cytokines play important roles in HLH. Different subtypes of HLH have their specific cytokines pattern, and the ratio of cytokines may be more significant in differentiating HLH subtypes than the single one. Elevated GM-CSF and MCP-1 could be useful biomarkers for a poor prognosis for patients with HLH.