Objective:To analyze the efficacy and safety of the L-DEP regimen (asparaginase, liposome doxorubicin, etoposide and methylprednisolone) as a salvage therapy for the refractory primary hemophagocytic lymphohistocytosis triggered by Epstein-Barr virus infection (EBV-pHLH) in children.Methods:In this retrospective case study, clinical and laboratory data before and after L-DEP regimen of 4 children diagnosed with EBV-pHLH in Beijing Children′s hospital between January 2016 and June 2022 were collected, and the efficacy and safety of L-DEP regimen for the treatment of EBV-pHLH were analyzed.Results:Among 4 patients, there were 3 females and 1 male with the age ranged from 0.8 to 7.0 years. Two of them showed compound heterozygous mutations of PRF1, one with a heterozygous mutation of UNC13D, one homozygous mutation of ITK. Before the L-DEP therapy, all of them had anemia and a soaring level of soluble CD25, 3 patients had neutropenia and thrombopenia, 3 patients had a high level of ferritin, 3 patients had hypofibrinogenemia and 1 patient had hypertriglyceridemia. After receiving 1 or 2 cycles of L-DEP treatment, three achieved remission, including complete remission (1 case) and partial remission (2 cases), and the other one had no remission. The levels of blood cell counts, soluble CD25, triglyceride, fibrinogen and albumin were recovered gradually in 3 patients who got remission. All four patients underwent hematopoietic stem cell transplantation (HSCT) after L-DEP regimen, and three survived. All patients had no severe chemotherapy related complications. The main side effects were bone marrow suppression, infection and pancreatitis, which recovered after appropriate treatments, apart from one who died from severe infection after urgent HSCT.Conclusion:L-DEP regimen could be served as an effective and safe salvage treatment for refractory pediatric EBV-pHLH, and also provide an opportunity for patients to receive HSCT.

Decline of immunity is an epidemiological feature of opioid addicts.Recent work reveals a landscape of peripheral immune microenvironment in opioid addicts.Opioid addicts exhibit a significant expansion of fragile-like regulatory T cells(Tregs)and enhanced Treg-derived interferon-y(IFN-γ)expression.IFN-γ signaling reshapes synaptic morphology in nucleus accumbens(NAc)neurons,modulating subsequent withdrawal symptoms.Treg fragility transformation from WT Tregs is primarily due to opioid-induced global hypoxia during acute withdrawal period.Opioids increase the expression of neuron-derived C-C motif chemokine ligand 2(Ccl2)and disrupt blood-brain barrier(BBB)integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7(Fabp7),both of which trigger peripheral Treg infiltration into NAc.Recent studies suggest that subtle homeostatic changes in the peripheralimmune milieu may also contribute to modulating synapses that are responsible for addictive behaviors,which may lead to the development of new therapeutic strategies.

Objective:To analyze the clinical features,treatment and prognosis of drug induced hypersensitivity syndrome related hemophagocytic lymphohistiocytosis (DIHS-HLH).Methods:This was a retrospective case study. Clinical characteristics, laboratory results, treatment and prognosis of 9 patients diagnosed with DIHS-HLH in Beijing Children′s hospital between January 2020 and December 2022 were summarized. Kaplan-Meier survival analysis was used to calculate the overall survival rate.Results:Among all 9 cases, there were 6 males and 3 females, with the age ranged from 0.8 to 3.1 years. All patients had fever, rash, hepatomegaly and multiple lymph node enlargement. Other manifestations included splenomegaly (4 cases), pulmonary imaging abnormalities (6 cases), central nervous system symptoms (3 cases), and watery diarrhea (3 cases). Most patients showed high levels of soluble-CD25 (8 cases), hepatic dysfunction (7 cases) and hyperferritinemia (7 cases). Other laboratory abnormalities included hemophagocytosis in bone marrow (5 cases), hypofibrinogenemia (3 cases) and hypertriglyceridemia (2 cases). Ascending levels of interleukin (IL) 5, IL-8 and interferon-γ (IFN-γ) were detected in more than 6 patients. All patients received high dose intravenous immunoglobulin, corticosteroid and ruxolitinib, among which 4 patients were also treated with high dose methylprednisolone, 2 patients with etoposide and 2 patients with cyclosporin A. After following up for 0.2-38.6 months, 7 patients survived, and the 1-year overall survival rate was (78±14)%. Two patients who had no response to high dose immunoglobulin, methylprednisolone 2 mg/(kg·d) and ruxolitinib died. Watery diarrhea, increased levels of IL-5 and IL-8 and decreased IgM were more frequently in patients who did not survive.Conclusions:For children with fever, rash and a suspicious medication history, when complicated with hepatomegaly, impaired liver function and high levels of IL-5 and IL-8, DIHS-HLH should be considered. Once diagnosed with DIHS-HLH, suspicious drugs should be stopped immediately, and high dose intravenous immunoglobulin, corticosteroid and ruxolitinib could be used to control disease.

【Objective】 To estimate the prevalence, associated factors and patterns of multimorbidity of non-communicable diseases among adults in Shaanxi Province so as to provide evidence for the prevention and control of non-communicable diseases. 【Methods】 We used the data of adults aged 18 years and older collected in the baseline survey of Shaanxi Project in the Regional Ethnic Cohort Study in Northwest China. Multinomial logistic regression was used to explore the associated factors for multimorbidity. Exploratory factor analysis was used to extract patterns of multimorbidity. 【Results】 The prevalence of multimorbidity was 10.7% among the 44 442 participants. Age increase, being males, urban residence, and being overweight or obesity were positively associated with multimorbidity. Compared with women, men had a higher risk of multimorbidity. The OR and 95% CI was 1.25 (1.12-1.39). The risk of multimorbidity increased with age among adults. Compared with participants aged 18.0-34.9 years, the ORs and 95% CIs of those aged 35.0-44.9, 45.0-54.9, 55.0-64.9, and ≥65.0 years were 4.73 (3.47-6.46), 15.61 (11.60-21.00), 41.39 (30.76-55.70) and 90.04 (66.58-121.77), respectively. The primary multimorbidity patterns among adults in Shaanxi were cardiovascular-metabolic multimorbidity (5.4%), viscero-articular multimorbidity (1.0%), and respiratory multimorbidity (0.3%). 【Conclusion】 More than one in ten adults in Shaanxi Province had multimorbidity, and the predominant pattern of multimorbidity was cardiovascular-metabolic multimorbidity. The prevention and control of non-communicable diseases should be reinforced in middle-aged and older people, males, people living in the urban, and overweight or obese people. More attention should be paid to the prevention and control of cardiovascular-metabolic diseases.

Monkeypox is a zoonotic disease.Previous studies have shown that children are vulnerable to monkeypox and are also at high risk for severe disease or complications.In order to improve pediatricians′ understanding of monkeypox and achieve early detection, early diagnosis, early treatment and early disposal, the committee composed of more than 40 experts in the related fields of infectious diseases, pediatrics, infection control and public health formulate this expert consensus, on the basis of the latest clinical management and infection prevention and control for monkeypox released by the World Health Organization (WHO), the guidelines for diagnosis and treatment of monkeypox (version 2022) issued by National Health Commission of the People′s Republic of China and other relevant documents.During the development of this consensus, multidisciplinary experts have repeatedly demonstrated the etiology, epidemiology, transmission, clinical manifestations, laboratory examinations, diagnosis and differential diagnosis, treatment, discharge criteria, prevention, case management process and key points of prevention and control about monkeypox.

Langerhans cell histiocytosis(LCH)and Langerhans cell sarcoma(LCS)are characterized by clone proliferation of Langerhans-type cells, which may occur concurrently or sequentially with T-cell acute lymphoblastic leukemia (T-ALL) and other Lymphoid neoplasms. A 15-year old female patient diagnosed with T-ALL developed LCH involving multiple systems during maintenance chemotherapy of T-AL. After treated with chemotherapy with improved result, the patient showed progression of the illness and refractory to the second-line treatment. We found c.G35A (p.G12D)mutation in the KRAS gene and used the targeted drug Trametinib for treatment. The treatment proved effective, leading to partial remission within a week. Three months after Trametinib treatment, the patient developed new lymphadenopathy. Biopsy revealed the existence of LCS. The disease progressed quickly, and the patient died 7 days after diagnosis of LCS. The case of patients with T-ALL then developing LCH and LCS sequentially is extraordinarily rare. The causes of the case is unclear and may be related to cell transdifferentiation, clonal evolution, and chemotherapy. Targeted drugs can contain this disease for a short time.

Objective:To understand the clinical characteristics and prognosis of Langerhans cell histiocytosis (LCH) with skin-limited lesion.Methods:A retrospective analysis was performed on clinical characteristics and prognosis of 16 skin-limited LCH patients, out of 578 LCH patients who were hospitalized in Beijing Children′s Hospital during December 2013 to June 2018.Results:A total of 16 skin-limited LCH cases, accounted for 2.7% of all 578 cases, were included.Among which, sex ratio (male vs.female) was 1.28∶1.00.Median ages of skin eruption occurrence and of diagnosis of the disease were 3.5 months (3 days to 2 years and 5 months) and 6 months (2 months 14 days to 2 years and 8 months) in this group.Among the 16 cases, seborrheic dermatitis-like lesions(11 cases, 68.7%) was the most common, and the trunk was most frequently involved[75.0% (12 cases)]. Serine/threonine protein kinase gene V600E [ BRAF (p.V600E)] mutation was detected in pathological specimens from 10 skin-limi-ted cases, with 9 cases being positive.Plasma samples from 5 positive cases were further detected for BRAF (p.V600E) mutation, and 4 positive results were gained.Of all 16 patients, 11 cases (68.7%) were treated.Remission were achieved in 3-6 months from treatment start in patients treated whether according to the Histiocyte Society′s LCH-2009 protocol for 25 weeks(6 cases, 37.5%), or with topical mometasonefuroate for 3 months (3 cases, 18.8%). Two patients(12.5%) with solitary cutaneous lesions underwent excision biopsy (one face and one prepuce) and were considered to be in remission immediately after surgery.None of these patients suffered from the recurrence of the disease.The remaining 5 patients (31.3%) with skin-limited LCH were just evaluated regularly, and achieved remission in 3-6 months of commencing observation.Among these untreated patients, 1 with consistently positive BRAF (p.V600E) mutation in plasma had bone involvement in the 24 th month of assessment, and was then treated based on the Histiocyte Society′s LCH-2009 Protocol.No clinical or imageological evidence supporting disease progression was found on this patient.Median follow-up period was 32.8 months (2.9-63.9 months). Except one patient, none of the rest cases had active disease till follow-up ended.Two-year event free survival(EFS) of this research was (92.3± 7.4)%.There was no significant difference between EFS of treated group and that of observation group( χ2=1.250, P=0.264). Conclusions:Skin-limited LCH often occurs in infants and newborns, with strong heterogeneity in clinical manifestations, laboratory indicators, and pathogenesis.Seborrheic dermatitis-like lesions were the most common cutaneous type.The prognosis of the patients is excellent despite progressing into multisystem involvement can be seen in a few patients.

The clinical and laboratory data of a patient with chronic refractory immune thrombocytopenia (ITP) who had a significant increase in the proportion of inhibitory T cells in the hematological oncology center of Beijing Children′s Hospital Affiliated to Capital Medical University in February 2018 and regularly followed up in the outpatient department received a retrospective analysis.This 8-year-old patient′s clinical features were 6 years of skin and mucous membrane bleeding spots and petechiae recurring, with occasionally nasal epistaxis.Physical examination: cardiopulmonary abdomen and nervous system examinations are normal, and no superficial lymphadenopathy is touched.Blood routine indicated that the platelets were 2.00×10 9/L, and white blood cell count and hemoglobin level were normal.Bone marrow suggested that hyperplasia was significantly active, with more than 300 megakaryocytes.The patient was diagnosed with ITP, and he was treated with first-line treatment with gamma globulin and oral Corticosteroids.The first-line treatment with high-dose Dexamethasone therapy was repeated, and the second-line treatment was low-dose Rituximab combined with high-dose Dexamethasone.Evaluations had been conducted with every relapsed course, and Cyclosporine was administered orally on the basis of the highly suppressive T cells.After half a month, the child achieved partial remission and continued for 3 months, and then reached a complete remission of 6 months (till this paper). It is suggested that, with ITP as an immunological disease with high heterogeneity, the immune abnormality index is expected to become a breakthrough in the development of precise treatment.

Objective:To investigate the association between genotype and clinical phenotype in children with primary hemophagocytic lymphohistiocytosis (HLH).Methods:Clinical data of 38 children with primary HLH at Beijing Children′s Hospital from November 2015 to October 2020 were analyzed retrospectively. According to whether destructive mutation site, familial HLH (FHL) or non-familial HLH, degranulation pathway and non-degranulation pathway were detected in them, these patients were divided into different groups. Clinical characteristics, laboratory tests and functional tests were analyzed in different groups. Wilcoxon test or chi-square test were used for comparison between groups.Results:Among 38 cases, there were 23 males and 15 females. The age of onset was 2.5 (0.1-13.7) years. PRF1 (13/38, 34%) and UNC13D (12/38, 32%) gene mutations had the highest detectable rate. Correlation analysis between genotypes and phenotypes suggested that patients in destructive mutation sites group ( n=25) had a younger age of onset than that in non-destructive mutation sites group ( n=13) (1.0 (0.1-9.0) vs. 4.0 (0.4-13.4) years, Z=-2.711, P=0.005). The incidence of central nervous system involvement and convulsion was higher in patients in familial HLH group ( n=26) than that in non-familial HLH group ( n=12)(62% (16/26) vs. 2/12, χ2=6.631, P=0.015; 54% (14/26) vs. 2/12, χ2=4.656, P=0.040). The levels of soluble CD25, bilirubin, interferon γ (IFN-γ) and interleukin 10 (IL-10) were higher in degranulation pathway impairment group than that in the non-degranulation pathway impairment group (38 444 (2 393-44 000) vs.15 304 (1 620-36 937) ng/L, Z=2.634, P=0.008; 23.5 (6.3-126.4) vs. 6.0 (3.6-31.0) μmol/L, Z=2.992, P=0.003; 20.7 (0-248.7) vs. 11.9 (2.6-21.0) ng/L, Z=2.156, P=0.031; 20.7 (4.3-2 500.0) vs. 11.8 (4.0-88.0) ng/L, Z=2.210, P=0.027). However, the levels of neutrophils, ferritin and lactate dehydrogenase (LDH) in degranulation pathway impairment group were lower in the non-degranulation pathway impairment group (0.5 (0.1-8.0)×10 9vs. 1.0 (0.9-2.3)×10 9/L, Z=-3.197, P=0.001; 1 133 (78-10 452) vs. 3 048 (630-37 900) μg/L, Z=-2.407, P=0.016; 410 (188-1 254) vs. 599 (389-3 147) U/L, Z=-2.489, P=0.013). Conclusions:PRF1 and UNC13D gene mutations are most common in primary HLH. Patients with destructive gene mutations have a younger age of onset. Patients with familial HLH are more likely to have central nervous system involvement and convulsions. The levels of sCD25, bilirubin, IFN-γ and IL-10 are higher in the degranulation pathway patients.

Objective: To discuss the clinical characteristics and management approaches to hepatitis associated aplastic anemia (HAAA) presenting as hemophagocytic lymphohistiocytosis (HLH) at onset. Methods: The clinical data and laboratory results of hospitalized 5 HAAA patients presenting as HLH at onset in Beijing Children′s Hospital from January 2017 to May 2019 were analyzed retrospectively. Results: Among 5 cases, there were 4 males and 1 female. The age of onset was 6.0 (2.7-12.7) years. All patients presented with high fever, hepatomegaly, hepatic dysfunction (aspartate aminotransferase 1 716 (1 409-2 570) U/L, alanine aminotransferase 1 699 (937-2 540) U/L) at onset. After admission, the laboratory results showed pancytopenia (white blood cell 1.2 (0.6-6.7) ×10⁹/L, haemoglobin 94 (65-111) g/L, blood platelet 29 (10-41) ×10⁹/L), decreased fibrinogen (1.3 (1.1-2.5) g/L), significantly elevated triglyceride (4.0 (2.8-5.1) mmol/L), ferritin (1 766 (399-5 253) μg/L) and soluble CD25 (27 457 (9 625-44 000) ng/L). Hemophagocytosis was found in the bone marrow smears of all 5 patients. The diagnosis of acute hepatitis and HLH was confirmed. During the treatment of HLH, the blood cells remain below normal level and the further biopsy of bone marrow (iliac bone) indicated low myeloproliferation. After exclusion of congenital bone marrow failure syndromes and other pancytopenic diseases, HAAA was confirmed. After the diagnosis of HAAA, 1 patient received antithymocyte globulin (ATG) and cyclosporin treatment in our hospital, 1 patient received allogeneic stem cell transplantation (HSCT) in other hospital, 2 patients received ATG in other hospitals. Only 1 patient died of severe infection. Conclusions HAAA can present as HLH at onset. It is mainly manifested by high fever, acute severe hepatitis, pancytopenia, elevated ferritin and hemophagocytosis in the bone marrow. The diagnosis of HAAA should be considered whenever cytopenia could not completely corrected while apparent improvement of HLH and hepatitis related complications were improved after immunosuppressive therapy. ATG or HSCT treatment should be performed as soon as the diagnosis of severe or transfusion dependent aplastic anemia is confirmed.