儿童造血干细胞移植后巨细胞病毒感染的临床研究

目的了解儿童造血干细胞移植后巨细胞病毒的感染率和防治方法。方法对从2001年8月到2007年3月北京儿童医院血液病中心37例作造血干细胞移植的血液肿瘤及先天遗传性疾病患儿进行回顾性分析。结果31例可研究病例中,5例自体造血干细胞移植及5例同基因造血干细胞移植患儿无人类巨细胞病毒（HCMV）感染,21例异基因造血干细胞移植患儿,发生HCMV感染7例,感染率为33.3%,大剂量阿昔洛韦加丙种球蛋白预防及早期更昔洛韦加大剂量静脉丙种球蛋白治疗,仅1例发生巨细胞病毒相关性间质性肺炎（CMV-IP）,无1例发生巨细胞病毒感染相关死亡。结论巨细胞病毒感染是儿童造血干细胞移植术后的主要并发症,临床上进行定期监测、前瞻性预防、早期诊断和及时合理治疗,对降低移植术后巨细胞病毒感染和提高移植成功率至关重要。     

Immunological recovery post‐hematopoietic stem cell transplantation: Role of prophylactic prevention of infection in post‐transplant period

Abstract: Immunological recovery post-hematopoietic stem cell transplantation is variable. This depends upon the type of transplantation, source of hematopoietic stem cells for transplantation, prophylactic treatment for graft-versus-host disease and ongoing therapy for the treatment of graft-versus-host disease with immunosuppressive agents. Periodic numerical and functional assessment of recovery of the immune system after transplantation can identify the patients with inadequate immune system who are at risk for development of infectious complications. These patients should receive prophylactic therapy to decrease infection-related morbidity and mortality associated with transplantation procedures.     

Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: A retrospective study of the risk factors

Abstract:  CMV infection is one of the major causes of morbidity and mortality after HSCT. The aim of this single center retrospective study was to analyze risk factors for CMV infection in pediatric patients who underwent HSCT. We retrospectively reviewed the medical records of 117 pediatric patients who underwent allogeneic HSCT at Asan Medical Center between December 2000 and January 2007. After HSCT, CMV antigenemia was detected by identifying CMV pp65 early antigen in white blood cells. The incidence of CMV antigenemia was 24% (28/117) at a median of 38 days (range: 19–123 days) after HSCT. In multivariate analysis, CMV antigenemia occurred significantly more often in CMV seropositive recipients, patients who received grafts from alternative donors, T-cell depleted grafts, patients on ATG-containing conditioning regimens, or patients who received steroid for acute GVHD (p < 0.05). CMV antigenemia tend to develop earlier in patients who received ATG-containing conditioning regimens (p = 0.09). A second episode of CMV antigenemia was observed in three out of 28 patients (11%). The incidence of CMV disease was 5.9% (7/117) at a median of 97 days (range: 34–120 days). Manifestation of CMV disease included retinitis in two, pneumonitis in two, hepatitis in one, hepatitis with colitis in one, and gastritis in one. Six of the 12 patients (50%) with HG antigenemia (CMV pp65 antigen positivity ≥40 cells) developed clinical CMV disease, a rate that was significantly higher than seen in patients with LG antigenemia (6.25%; p < 0.01). We recommend that patients with these risk factors should carefully undergo regular evaluations for CMV infection. We also suggest that earlier and more aggressive preemptive treatment and serial follow-up of CMV disease is necessary in patients with HG-antigenemia.     

儿童异基因造血干细胞移植术后巨细胞病毒感染临床分析

目的探讨儿童异基因造血干细胞移植(allo-HSCT)后巨细胞病毒(CMV)感染的危险因素及临床相关特征。方法收集2016年1月至2018年12月共269例allo-HSCT患儿的临床资料。监测移植后全血CMV-DNA拷贝数,分析移植患儿CMV感染发生率、发生时间、危险因素及预后。结果 269例患儿中,男167例、女102例,中位年龄65个月(33～115个月),其中165例发生CMV感染,感染率为61.3%,感染发生时间为移植后23 d(15～34 d),感染持续时间38 d(25～66 d)。Logistic回归分析发现患儿移植年龄65个月、移植后发生Ⅱ～Ⅳ级aGVHD是发生CMV感染的危险因素,而亲缘全相合移植能降低CMV感染发生风险(P0.05)。发生Ⅱ～Ⅳ级急性移植物抗宿主病(aGVHD)及使用脐血移植与发生难治性CMV感染相关(P0.05)。难治性CMV感染组与非难治性CMV感染组总体生存率及无病生存率的差异有统计学意义(P0.05)。结论移植患儿年龄大、Ⅱ～Ⅳ级aGVHD能增加CMV感染的发生风险,亲缘全相合移植能降低CMV感染的发生风险。脐血移植后易发生难治性CMV感染;难治性CMV感染初次检测到CMV感染时间早,峰值高。     

Acute rejection episodes in pediatric renal transplant recipients with cytomegalovirus infection

Abstract:  CMV infection is the most important opportunistic virus infection after renal transplantation leading to increased patient mortality, graft loss, risk for acute rejection episodes and impaired renal function. The potential impact of prophylactic anti-viral therapy on long-term graft outcome is relevant. The aim of this study was to evaluate the incidence of CMV infection, its risk factors and long-term outcome in children after renal transplantation. 103 children (mean age 10.6 ± 5.3, range 1.6–22.0 yr) were monitored weekly for pp65 for the first 6–8 wk after renal transplantation, followed by a monthly monitoring for the first year. CMV infection occurred in 23/103 children (21.1%) with 10 patients (9.7%) developing CMV disease characterized by positive pp65 in the presence of organ involvement. The CMV R−/D+ and R+/D+ serostatus was significantly associated with an increased risk of CMV infection (p < 0.0001 and p = 0.009). 14/28 R−/D+ patients developed CMV infection despite prophylactic treatment with CMV hyperimmune globulin. The incidence of acute rejection episodes after or during CMV infection was significantly increased (p = 0.003) and the D+ serostatus was significantly associated with acute rejection episodes within the first year after transplantation (p = 0.006). In summary the overall incidence of CMV infection in this single center experience is 21.1%. The D+ serostatus represents a serious risk factor for both CMV infection and acute rejection episodes. In future the potential impact of different modalities of prophylactic anti-viral therapy on the prevention of acute rejection should be considered.     

BK nephropathy in pediatric hematopoietic stem cell transplant recipients

Abstract:  BK nephropathy is a known cause of renal insufficiency in kidney transplant recipients. Activation of the polyoma virus may also occur in the native kidneys of non-renal allograft recipients. BK nephropathy has only been reported in a few patients after HCT, most being adult patients, and the single reported pediatric case had evidence of hemorrhagic cystitis. The response to antiviral therapy also seems to differ widely. Here, we describe two cases of BK nephropathy in the native kidneys of HCT recipients exposed to high levels of immunosuppression because of GVHD. Neither of our patients had any evidence of hemorrhagic cystitis. We present definitive renal pathology and detailed chronological evidence of the rising serum creatinine with simultaneous serum and urine BK PCR titers. In one of our cases, antiviral therapy did not seem beneficial as documented by continued renal dysfunction and elevated serum/urine BK PCR titers. Based on our report, intense immunosuppression in pediatric HCT recipients seems to be involved in the activation of BK virus and BK nephropathy should be suspected even in the absence of hematuria in HCT recipients with unexplained renal dysfunction.     

High prevalence of latent tuberculosis in hematopoietic stem cell transplant recipients: A First Report

TB is an increasing health problem, and patients undergoing HSCT are more prone to develop tuberculosis. The aim of our study was to evaluate prevalence of latent tuberculosis in HSCT recipients. In this study, 84 patients (2 months to 18 years) who were candidates for HSCT at the referral hospital of Tehran Children's Medical Center were enrolled. The TST and the QFT‐GIT test were performed in all 84 patients, simultaneously. LTBI was considered when one of the tests was positive. Overall, the prevalence of LTBI in HSCT recipients in our study was 12% (10 cases). TST induration ≥5 mm was seen in only three patients (3.5%). Eight patients (9.5%) had a positive result for IGRA test, and 11 of them (13%) had indeterminate QFT‐GIT result. The agreement between the TST results (induration size ≥5 mm) and the QFT‐GIT results was poor (kappa = 0.14). In conclusion, there was a high rate of discordance between TST and IGRA results with many more positive QFT‐GIT tests. However, more studies are needed in this population to determine whether this discordance reflects true infection.     

Cytomegalovirus (CMV) infections in children undergoing hematopoetic stem cell transplantation

Cytomegalovirus (CMV) is one of the major causes of morbidity and mortality after hematopoetic stem cell transplantations (HSCT). The purpose of the study was to analyze risk factors of CMV disease in children undergoing HSCT. A total of 110 children who undergone hematopoetic stem cells transplantation were analyzed. In 16 patients (14.5%) CMV antigenemia in white blood cells was diagnosed. Most patients with CMV infection had undergone alloHSCT; one patient had undergone autologous transplantation. Second CMV reactivation in 4 of 16 patients was observed. Acute GvHD occurred in 11/15 patients. Early onset of CMV infection in 13/16 patients and late onset in 3/16 patients were diagnosed. CMV serological status of the donor and recipient before transplantation in children with CMV antigenemia was analyzed. The risk factors of CMV infection in analyzed group of children were type of transplant, recipient seropositivity before transplantation, and presence and intensity of GvHD. In most cases reactivation of CMV infection was diagnosed. CMV infection can also occur in the late post-transplantation period. CMV reactivation can occur in patients after autologous HSCT.     

Cytomegalovirus infection after allogeneic stem cell transplant in children

The aim of this study was to examine the frequency and the course of cytomegalovirus (CMV) infection and CMV disease in a group of pediatric and adolescent patients after allogeneic stem cell transplantation. Patients were treated according to a protocol including prophylactic high-dose acyclovir in combination with preemptive administration of ganciclovir, based on weekly examinations of CMV antigenemia. A total of 110 consecutively transplanted patients, with a mean age of 9 yr (range 0-20) were treated according to the protocol. All patients were transplanted between March 1993 and January 2000 at the only Danish allotransplantation center. CMV infection occurred in 21.8% (24 of 110) of the patients. Three patients [12.5% (3/24)] developed CMV disease, all with pneumonitis and one with gastrointestinal disease as well. Mean time of disease onset was day +58. Treatment with ganciclovir was in general well tolerated. Late onset CMV disease was not documented. Multivariate analysis revealed that the use of unrelated donor transplants was significantly associated with an increased risk for CMV infection [hazard ratio (HR) 2.90, p = 0.03] and CMV infection was found to be a risk factor for transplant related mortality before day +100 (HR 10.70, p = 0.0015). Although high-dose acyclovir in combination with antigenemia based preemptive treatment with ganciclovir resulted in a low incidence of CMV disease in pediatric and adolescent patients, CMV infection was a significant risk factor in stem cell transplantation with unrelated donors.     

Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients

This guideline provides clinicians with evidence‐based recommendations on the use of antifungal prophylaxis in children with cancer and undergoing hematopoietic stem cell transplantation (HSCT). Recommendations are divided into: (1) allogeneic HSCT (2) autologous HSCT (3) acute myeloid leukemia or myelodysplastic syndrome and (4) patients with malignancy and neutropenia for >7 days. A systematic review was conducted and evidence summaries compiled. The quality of evidence and strength of each recommendation was determined using GRADE. Implementation of these recommendations will require adaptation to local context. The contribution of this guideline in the prevention of invasive fungal infections requires prospective evaluation. Pediatr Blood Cancer 2014;61:393–400. © 2013 Wiley Periodicals, Inc.     

The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post‐first and post‐second hematopoietic stem cell transplant

The reported incidence of post‐allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T‐cell depletion, and chronic GvHD are significantly associated with post‐transplant AIHA. During an 11‐yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post‐first and post‐second transplants. Demographic, transplant, and post‐transplant‐related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post‐first and post‐second HSCT, respectively. Post‐first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post‐second transplant AIHA. The incidence of AIHA post‐first and post‐second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post‐transplant AIHA.     

Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: a cause of prolonged intestinal failure requiring intensive nutritional support

Norovirus infection is a major cause of nonbacterial gastroenteritis. In immunocompetent individuals the illness caused by norovirus is mostly self limiting. Excretion of norovirus has been reported to be prolonged in the immunocompromised including adult HSCT recipients. We report a case series of 13 children who received HSCT and required prolonged parenteral and enteral nutrition due to severe gut dysfunction accompanying protracted norovirus excretion that was monitored by RT-PCR. The median duration of viral excretion was 150 days (range 60-380) and the eventual clearance of norovirus from feces was closely associated with donor T cell recovery in the peripheral blood. There was no disease manifestation beyond the gut but the severity and length of norovirus associated illness suggests that HSCT should be delayed where possible in patients excreting the virus prior to conditioning therapy.     

Concentrations of adipokines in children before and after hematopoietic stem cell transplantation

Adipokines have multiple effects, including regulation of glucose metabolism, cell proliferation, inflammation, and angiogenesis. The aim of the study was to determine plasma concentrations of adiponectin, apelin, leptin, and resistin as well as soluble leptin receptor in pediatric hematopoietic stem cell transplantation (HSCT). The expression of genes encoding the studied peptides was measured using microarray technique. Plasma concentrations of tested peptides were measured before and after oral glucose tolerance test in children treated with HSCT (n = 38) and in healthy controls (n = 26). The peptides were measured before HSCT (pre-HSCT group; n = 38) and after a median of 6 months after HSCT (post-HSCT group; n = 27 of 38 children treated with HSCT). In addition, measurements of fasting plasma glucose, insulin, lipids, and high-sensitivity C-reactive protein (hsCRP) were performed. In both HSCT groups, atherogenic lipid profile, low-grade systemic inflammation was observed. Leptin, adiponectin, and resistin also appear to be good markers of disease burden and low-grade systemic inflammation. Adipokines may be good markers of disease burden and may influence metabolic complications of HSCT. Future studies on larger groups of patients will explain if changes of the concentrations of leptin, adiponectin, and apelin observed in our study and confirmed by expression levels influence engraftment and reconstitution of cell lines.     

Intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children

Respiratory syncytial virus (RSV) infection can cause lower respiratory tract disease and mortality in pediatric hematopoietic stem cell transplant (HSCT) recipients. We report two children who underwent HSCT and developed RSV infection simultaneously at the Bone Marrow Transplant Unit. The treatment with intravenous palivizumab was provided and sequential viral loads were measured in nasopharyngeal (NP) and whole blood samples. To our knowledge, this is the first report where RSV loads were measured in parallel (NP and blood), before and after palivizumab, in correlation with a favorable clinical outcome in both cases.