Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein‐Barr virus‐associated post‐transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

EBV‐related PTLD developing after HSCT is a potentially life‐threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV‐PTLD with a median age at HSCT of 5.9 years (range: 2.3‐17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV‐PTLD within the first 100‐day post‐HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV‐PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV‐PTLD seems imperative to control the disease, especially if signs of HLH are evolving.     

Secondary acute myeloid leukemia after etoposide therapy for haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is an uncommon disease with a high fatality rate. Etoposide is an important component of current HLH treatment regimes. Two patients with HLH developed etoposide‐related secondary acute myeloid leukemia (sAML) following therapy for HLH. Etoposide, an epipodophyllotoxin, is a topoisomerase II inhibitor that interacts with DNA to potentiate leukaemogenesis. The risk of developing sAML is estimated to be between 1% and 5%, 2–20 years after exposure to etoposide but may also be related to cumulative drug doses, treatment schedules, host factors and co‐administration of other antineoplastic agents. Pediatr Blood Cancer 2009;53:488–490. © 2009 Wiley‐Liss, Inc.     

Development of secondary T‐cell acute lymphoblastic leukemia in a child with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe life‐threatening disorder, characterized by hyperactivation of macrophages. A 12‐year‐old female was referred to our center; the diagnosis of HLH was made for the patient and immunosuppressive regimen was started. After a 2‐year follow‐up, the patient developed secondary T‐cell acute lymphoblastic leukemia (T‐ALL), confirmed by flow cytometric studies. Treatment was started based on T‐ALL protocol, but the patient died because of relapse and sepsis. This case highlights the issue of secondary malignancy following HLH and demonstrates the need for continued follow‐up in such patients. Pediatr Blood Cancer. 2010;55:725–726. © 2010 Wiley‐Liss, Inc.     

An unusual cause of fever

A 5‐month old infant presented with a short history of fever of unknown origin. He initially appeared well although there was a resting tachycardia during periods of normal temperature, and pancytopenia. He remained febrile in spite of antibiotic therapy and by 48 h he had developed marked hepatosplenomegaly and coagulopathy. At 72 h a bone marrow aspirate and trephine biopsy showed haemophagocytosis. By this time the infant was encephalopathic and haemodynamically unstable with multi‐organ dysfunction. Treatment with high‐dose methylprednisolone and cyclosporin was commenced with an initial good response. Unfortunately the patient ultimately died of infective complications of treatment and reactivation of the underlying disease process. Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the mononuclear phagocyte system characterised by proliferation of morphologically benign histiocytes resulting in hypercytokinaemia and uncontrolled activation of immune cells. The diagnosis of familial HLH should be considered in any infant with fever, splenomegaly and cytopenia of at least two cell lines. HLH may be cured by immunosuppressive therapy and eventual stem cell transplantation but rapid disease progression to multi‐organ failure results in a high mortality.     

Successful treatment of non‐Hodgkin's lymphoma using R‐CHOP in a patient with Wiskott–Aldrich syndrome followed by a reduced‐intensity stem cell transplant

WAS is an X‐linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and increased incidence of autoimmunity and malignancy. HSCT is the only curative treatment for WAS. Herein, we report the case of a 17‐yr‐old boy with WAS who received an unrelated HSCT while in complete remission of diffuse large B‐cell lymphoma after chemotherapy. Pretransplant conditioning consisted of fludarabine, busulfan, and total body irradiation (4 Gy). GvHD prophylaxis consisted of tacrolimus and short‐course methotrexate. Following HSCT, rapid and stable engraftment was observed. Platelet count gradually increased, and the generalized eczema improved. The patient developed grade II acute GvHD and limited chronic GvHD on days 30 and 210, respectively, which resolved with immunosuppressive treatment. Symptoms caused by the reactivation of human herpes virus‐6, BK virus, and VZV were observed from days 21, 60, and 96, respectively; they were resolved after conservative treatment and acyclovir administration. No other regimen‐related toxicity was observed. Complete donor bone marrow chimerism was achieved one month after transplantation. RIST is an effective therapeutic option for older children with WAS accompanied by malignant lymphoma.     

Fatal visceral varicella-zoster virus infection without skin involvement in a child with acute lymphoblastic leukemia

A 5-year-old girl with acute lymphoblastic leukemia in remission suffered from fatal visceral varicella-zoster virus (VZV) infection after the oral administration of a high-dose dexamethasone. She abruptly developed fulminant hepatitis and disseminated intravascular coagulation, and died 3 days later. VZV DNA and antigens were detected in the peripheral blood (6 × 10⁸ copies/mL) and a postmortem liver specimen, respectively. The exposure to VZV was not confirmed and no skin lesions were observed. VZV infection should be considered in patients with unexplained liver dysfunction under severe immunosuppressive condition, even in the absence of viral exposure and skin involvement.     

Primary varicella zoster infection compared to varicella vaccine reactivation associated meningitis in immunocompetent children

We diagnosed varicella zoster virus (VZV) meningitis in a healthy adolescent boy who presented without a rash or fever. We aim to compare VZV reactivation meningitis in children after primary VZV infection and VZV vaccination. We reviewed the literature up until June 2020 using Pubmed/MEDLINE and EMBASE databases using ‘varicella zoster’, ‘meningitis’ and ‘children’ as keywords. Only English articles were included. Twenty‐five cases were included in this review. Children who had VZV reactivation meningitis after vaccination were younger (7 ± 3.4 years vs. 11.9 ± 3.6 years, P = 0.0038), had a shorter interval between first exposure to reactivation (5.6 ± 2.9 years vs. 8.8 ± 3.2 years, P = 0.018) and more likely to have a rash (100% vs. 55%, P = 0.04). VZV reactivation meningitis occurs after both primary VZV infection and VZV vaccination. The absence of exanthem, fever or meningism does not rule out VZV meningitis.     

儿童再生障碍性贫血造血干细胞移植后并发播散型带状疱疹3例报告并文献复习

目的 探讨儿童再生障碍性贫血（AA）造血干细胞移植（HSCT）后并发播散型带状疱疹的诊断、高危因素、预防及治疗措施。方法 回顾性分析2014年12月至2015年9月中山大学孙逸仙纪念医院儿科收治的3例AA患儿接受全相合非血缘相关供者HSCT后予免疫抑制剂治疗期间出现播散型带状疱疹的临床资料。结果 3例患儿年龄分别为13、12和10岁,移植后未出现移植物抗宿主病,予抗病毒药物单药预防水痘-带状疱疹病毒（VZV）期间均未出现VZV再激活,在HSCT后4.0、5.5和8.0个月停用抗病毒药物,分别在停用抗病毒药物后13.0、10.5和3.0个月出现皮肤播散型带状疱疹,予静脉更昔洛韦联合口服伐昔洛韦及外用喷昔洛韦抗病毒治疗至皮疹结痂,并予丙种球蛋白治疗,均完全治愈。结论 接受HSCT的AA患者是播散型带状疱疹的高发人群,其发病率高、病情严重且病死率高。移植后予预防性抗病毒处理,出现播散型带状疱疹时减少免疫抑制剂量,联合更昔洛韦、伐昔洛韦及丙种球蛋白治疗,可明显改善疗效。     

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??Objective To discuss the diagnosis, high risk factors, prevention and treatment of disseminated varicella zoster virus??VZV?? infection after allogeneic hematopoietic stem cell transplantation??allo-HSCT?? in children with aplastic anemia??AA??. Methods A retrospective analysis was made about the clinical data of 3 children with disseminated VZV infection after allo-HSCT for AA. Results Three children, aged 10??13 years old??who didn’t present graft-versus host disease??GVHD?? after transplantation, were given single drug as anti-viral prophylaxis of VZV. During the period of prophylaxis, none of them developed VZV reactivation but they showed symptoms of disseminated VZV infection after discontinuation of anti-viral prophylaxis. All of them were treated with intravenous ganciclovir, oral valaciclovir combined with external application of penciclovir and with gamma globulin until the rush crusted, and eventually all of them recovered well. Conclusion Patients with allo-HSCT for aplastic anemia are at high risk of developing disseminated VZV infection and they have high incidence of mortality and poor prognosis. We recommend anti-viral prophylaxis after allo-HSCT for prevention?? and reduced dose of immunosuppressive drugs and combination use of ganciclovir, valaciclovir and gamma globulin when patients present symptoms of VZV infection.     

Varicella vaccination in pediatric kidney and liver transplantation

Prelog M, Zimmerhackl LB. Varicella vaccination in pediatric kidney and liver transplantation.
Pediatr Transplantation 2010: 14: 41–47. © 2009 John Wiley & Sons A/S.
Abstract:  Reports about efficacy and safety of live-virus attenuated vaccines in patients before and after transplantation are mainly based on small patient numbers, making general recommendations for this patient population difficult. Children and adults as well as their close relatives and contact persons should be preferably immune to VZV before solid organ transplantation to avoid VZV-associated complications, thus making VZV vaccination necessary in susceptible individuals. The following literature review focused on efficacy and safety of VZV vaccination in pediatric kidney and liver transplant recipients. Review of literature also revealed that in all pediatric transplant candidates, humoral and cellular immunity against VZV should be consistently monitored to assess waning immunity under immunosuppressive treatment. This approach is desirable to estimate the risk of severe varicella disease after exposure in these patients.     

Hematopoietic stem cell transplantation in children with Griscelli syndrome: A single‐center experience

GS2 is a rare autosomal recessive disease characterized by hypopigmentation, variable immunodeficiency with HLH. HSCT is the only curative treatment for GS2. We analyzed the outcome of 10 children with GS2 who underwent HSCT at our center between October 1997 and September 2013. The median age of the patients at transplant was 13.5 months (range, 6‐58 months). All of the patients developed HLH before HSCT and received HLH 94 or HLH 2004 protocols. Donors were HLA‐identical relatives in 8 patients, HLA‐mismatched relatives in 2 patients. Engraftment was achieved in all except one patient. None of the patients developed acute GVHD. Chronic GVHD occurred in one and veno‐occlusive disease occurred in four patients. Eight of the patients are under remission without any neurologic sequelae—median time of disease‐free survival is 92.4 months. The present study shows successful transplant outcome without long‐term neurologic sequelae in patients with GS2 who underwent HSCT from HLA‐related donors.     

Hemophagocytic lymphohistiocytosis and Kawasaki disease: Combined manifestation and differential diagnosis

Both hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) are diagnosed in patients with prolonged resistant fever by using a scoring system. Concurrent manifestation of both conditions has been reported previously. We describe an infant of 7 weeks whose condition fulfilled the criteria of HLH, but who, after clinical response to treatment, suddenly died from a myocardial infarction at 11 weeks. Post‐mortem examination revealed a previously unknown coronary arteritis typical for KD. Since it is difficult to distinguish between KD and HLH, both diseases should be considered in young children with overlapping symptoms. Repeated echocardiograms may be helpful in these cases. Pediatr Blood Cancer 2009;53:493–495. © 2009 Wiley‐Liss, Inc.     

Trichosporon Asahii,Sepsis, and Secondary Hemophagocytic Lymphohistiocytosis in Children with Hematologic Malignancy

Trichosporon asahii (T. asahii) is an uncommon fungal pathogen rarely seen in patients with hematologic malignancies. Although appropriate therapy is started, infection with T. asahii usually leads to mortality. Here, we describe two patients developed severe T. asahii infection and secondary HLH. Despite rapid identification of T. asahii and negative blood cultures achieved by prompt initiation of treatment with voriconazole, fever and pancytopenia, persisted and both developed hepatosplenomegaly, and their clinical state worsened. Bone marrow aspiraton revealed hemophagocytosis. Elevated ferritin, triglyceride levels were seen. The first patient did not receive HLH directed therapy and died with multiple organ dysfunctions. Prompt diagnosis and treatment of secondary HLH led to rapid improvement in clinical and laboratory abnormalities in the second patient and kept her alive. We suggest that HLH may present as a secondary condition, accompanying a severe infection with T. asahii may, at least in part, contribute to high mortality rates in these cases.     

Latency in vitro of varicella-zoster virus in cells derived from human fetal dorsal root ganglia.

A potential in vitro model of varicella-zoster virus (VZV) latency was developed. Dissociated human dorsal root ganglion cultures were infected with VZV and maintained for 1 wk in the presence of bromovinyl arabinosyl uracil, a potent inhibitor of VZV. Seven to 21 d after removing the inhibitor (> or = 14 d after infection), the cells were trypsinized, passed to monolayers of human embryonic lung fibroblasts, and observed for VZV reactivation as indicated by typical cytopathic effects and the appearance of VZV antigens. VZV reactivated from 56% of the cultures containing both neurons and satellite cells but not from cultures specifically enriched for either neurons, satellite cells, or ganglion-derived fibroblasts. The failure to isolate VZV from cell suspensions that were sonicated before cocultivation with fibroblasts indicated that infectious VZV was not present before reactivation. Moreover, immunohistochemical and immunoprecipitation studies revealed no VZV-specific antigens in any cultures before the reactivation stimulus. VZV antigens were detected after trypsinization and cocultivation. These findings suggest that cultures containing both neurons and satellite cells provide a model system for VZV persistence that possesses many properties of a latent infection.     

The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis

Yoon HS, Im HJ, Moon HN, Lee JH, Kim H‐J, Yoo KH, Sung KW, Koo HH, Kang HJ, Shin HY, Ahn HS, Cho B, Kim HK, Lyu CJ, Lee MJ, Kook H, Hwang TJ, Seo JJ. The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis.
Pediatr Transplantation 2010: 14:735–740. © 2010 John Wiley & Sons A/S. Abstract: Chemoimmunotherapy‐based treatments have improved the survival of patients with HLH, but outcomes of the patients are still unsatisfactory. We report here the outcome of Korean children with HLH who underwent HSCT, which was analyzed from the data of a nation‐wide HLH registry. Retrospective nation‐wide data recruitment for the pediatric HLH patients diagnosed between 1996 and 2008 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. Nineteen patients who received HSCT among the total of 148 enrolled children with HLH were analyzed for the transplant‐related variables and events. The probability of five‐yr survival after HSCT was 73.3% with a median follow‐up of 57. Two months compared to 54.3% for the patients who were treated with chemoimmunotherapy only (p = 0.05). The reasons for HSCT were active disease after eight wk of initial treatment (n = 9), relapsed disease (n = 5), and FHL (n = 5). Fourteen patients are currently alive without disease after HSCT, four patients died of treatment‐related events (infection in two and graft failure in two) at early post‐transplant period, and one patient died of relapse at one yr post transplantation. The survival of patients who were transplanted because of active disease after eight wk of initial treatment was worse compared to those patients who had inactive state at that time (60.6% vs. 100%, respectively, p = 0.06). Of the four patients who received transplants using cord blood, three died of graft failure (n = 2) and relapse (n = 1). The five‐yr probability of survival after HSCT according to the donor type was 85.7% for the MRDs (n = 6), 87.5% for the MUDs (n = 8), and 40% for the MMUDs (n = 5) (p = 0.03). Other variables such as age, CNS involvement at the time of diagnosis, the etiology of HLH (familial or secondary), and the conditioning regimens had no influence on the five‐yr OS of the HLH patients who underwent HSCT. HSCT improved the survival of the patients who had familial, relapsed, or severe and persistent SHLH in the Korean nation‐wide HLH registry. Although numbers were small, these results are similar to other reports in the literature. The disease state after initial treatment, the stem cell source of the transplant, and the donor type were the important prognostic factors that affected the OS of the HLH patients who underwent HSCT.     

Hematopoietic stem cell transplantation with a reduced‐intensity conditioning regimen in pediatric patients with Griscelli syndrome type 2

Partial albinism with variable immunodeficiency are the two major characteristics of Griscelli syndrome type 2 (GS‐2). This syndrome is usually associated with a high mortality rate and commonly results in early childhood death. Patients suffer from different infections and experience crisis of HLH. HSCT remains the sole curative treatment for GS‐2. We prospectively analyzed the outcomes of transplantation with RIC regimen in five patients. The median age at transplantation was 21.6 months (range: 12–30). All of the patients underwent HSCT from HLA‐matched related donors. Currently, four patients are cured, and symptoms of recurrent infections and HLH crisis are not seen in them. The only patient who died had undergone HSCT in the accelerated phase of HLH. One patient who developed acute GvHD had a favorable response to therapy. No chronic GvHD occurred in patients. It seems that the use of RIC regimen as a method of transplant preparation is effective and tolerable in this group of patients with various comorbidities. It is recommended to carry out HSCT in these patients at lower ages, before presentations of different infections and HLH crisis.     

Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality

Hemophagocytic lymphohistiocytosis (HLH) is difficult to diagnose and treat. Highly elevated ferritin is strongly associated with HLH and levels may provide a prognostic marker. A comprehensive review of ferritin data from our patients during treatment was analyzed with respect to mortality. A patient was 17 times more likely to die when percent ferritin decrease was less than 50% as compared to a 96% or greater decrease as indicated with multivariate logistic modeling. Higher maximum ferritin levels in the first 3 weeks also contributed to the odds of death (OR = 5.6; 90% CI = 1.2–24.9). Regular ferritin measurements may be useful predicting outcomes in HLH patients. Pediatr Blood Cancer. 2010;56:154–155. © 2010 Wiley‐Liss, Inc.     

A Diagnostic Dilemma: Similarity of Neuroradiological Findings in Central Nervous System Hemophagocytic Lymphohistiocytosis and Aspergillosis

Central nervous system (CNS) involvement in the context of hemophagocytic lymphohistiocytosis (HLH) is not uncommon. Given the immunosuppressive nature of HLH therapy, infectious complications are also seen. We describe a 9‐year‐old male who developed acute neurological decline secondary to aspergillosis while undergoing HLH therapy. The significant overlap observed in CNS neuroimaging of HLH and aspergillosis and the subtleties that may help differentiate the two are discussed. The importance of obtaining tissue for definitive diagnosis is underscored.     

Clinical Characteristics of Hemophagocytic Lymphohistiocytosis Related to Kawasaki Disease

It is difficult to predict the prognosis or clinical course of secondary hemophagocytic lymphohistiocytosis (HLH) due to the various underlying causes. The authors analyzed the clinical and laboratory findings and outcomes in patients with HLH who had initially been diagnosed with Kawasaki disease (KD), and evaluated the clinical significance of each factor. Among the 21 patients with HLH, 5 had initially been diagnosed with KD and 16 had other etiologies. A comparative analysis was performed for fever duration, presence of cytopenia, serum ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride, fibrinogen, hyponatremia, reactivation, and survival rate in those HLH patients associated with KD (group I) and other causes (group II). In patients in group I, a higher level of reactivation (20%), a lower survival rate (P = .001), higher AST (P = .031) and ferritin (P = .005), and frequent hyponatremia (P = .000) were found compared to patients in group II. Interestingly, patients in group I was older than the average of age of most KD patients. A high index of suspicion on the progression from KD to HLH would be mandatory when the KD patients show elevated AST and ferritin and the presence of hyponatremia, and especially so if the patient is of older age.     

Varicella-zoster reactivation in a patient receiving routine revaccinations after an allogeneic hemopoietic progenitors transplant

Primary varicella-zoster virus (VZV) infection and herpes zoster are important infectious complications after an allogeneic hemopoietic progenitors transplant (HPT). The authors describe a girl with second relapse of acute lymphoblastic leukemia who received an HPT at age 13 years. Two years after the HPT she started a revaccination program of routine childhood vaccines. With each course of vaccines she developed herpes zoster of the C6 dermatome, initially with the rash and later zoster sine herpete. The vaccinations appear to have triggered VZV reactivation by vaccine-induced immunomodulation in this HPT recipient.