Intravesical cidofovir to treat BK virus‐associated hemorrhagic cystitis in children after hematopoietic stem cell transplantation

HC related to BK virus replication might be a severe complication following allogeneic HSCT. There are no clearly defined treatment guidelines in pediatric population. The data on the effectiveness of ICI to manage severe bleeding in children are very limited. We report our experience of intravesical cidofovir in four children, 6–15 yr of age, to manage grade III–IV BK virus‐associated HC. Three of four children had high CSA serum level prior to developing cystitis. Intravesical instillations of cidofovir resulted only in temporal relief of bleeding. After immune suppression was withdrawn or tapered, intravesical instillations of formalin solution had to be undertaken to abort severe bleeding. We concluded that intravesical cidofovir alone did not appear to be sufficiently effective in case of severe HC, necessitating complimentary procedures to stop macrohematuria.     

造血干细胞移植后出血性膀胱炎的诊疗

出血性膀胱炎(HC)是异基因造血干细胞移植的常见并发症之一,是移植防治的重点,文章就HC病因、发病机制和防治现状作一介绍.HC的发生常与移植前大剂量放化疗毒性,药物代谢酶基因多态性,病毒感染,移植物抗宿主病,患者的年龄、性别,供者类型和移植方式等相关.根据相关病史、典型临床表现和必要的辅助检查可以诊断.有效的预防措施是...     

Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant

BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT.     

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目的分析小儿造血干细胞移植(HSCT)后出血性膀胱炎(HC)的临床特点,探讨其发病危险因素。方法对1998年10月至2004年6月中山大学附属二院儿科完成的52例小儿HSCT后11例HC的临床资料进行回顾分析。结果11例HC中轻度(Ⅰ～Ⅱ度)6例,重度(Ⅲ～Ⅳ度)5例;早发性4例,迟发性7例;发病时间为术后+2d至+25d(中位数为+15d),病程3～60d(中位数为17d)。临床表现均有血尿,其中典型尿频、尿急、尿痛及肉眼血尿7例。HC患儿组中性粒细胞植入时间和血小板植入时间与非HC患儿组比较差异无显著性(P>0.05)。受者移植年龄≥6岁、aGVHD阳性、CMV感染组的HC发生率分别高于年龄<6岁(32.1%和8.3%,P<0.05)、GVHD阴性(34.6%和7.7%,P<0.05)、CMV未感染组(62.5%和13.6%,P<0.05)。结论小儿HSCT后HC有其自身的临床特征;受者移植年龄≥6岁、aGVHD阳性、CMV感染为其发生的危险因素。     

BK virus nephropathy in a pediatric patient after hematopoietic stem cell transplantation

We report the case of a seven‐yr‐old Caucasian girl who presented with progressive deterioration of renal function 13 months after HSCT for myelodysplastic syndrome. BK virus nephropathy was suspected and confirmed. After reduction of immunosuppression and treatment with IVIG, leflunomide, ciprofloxacin, and cidofovir, clearance of BK virus from blood was achieved, and further progression or renal failure was prevented. We believe that BK virus nephropathy should be considered in cases of renal function deterioration in all immunocompromised patients.     

儿童造血干细胞移植并发出血性膀胱炎的危险因素分析与防治研究

目的观察儿童造血干细胞移植（HSCT）中出血性膀胱炎（HC）的发病情况,探讨其发病危险因素和防治策略。方法回顾分析1998年10月—2004年6月本移植中心完成的53例儿童HSCT的临床资料,其中脐血移植（UCBT）37例,外周血造血干细胞移植（PBSCT）16例。HC的预防分为2组：（1）常规组（15例）,采用水化、碱化尿液、强力利尿和巯乙磺酸钠（Mesna）;（2）前列腺素E1（PGE1）组（38例）,在常规组的基础上加用PGE1。结果53例中发生HC11例（21％）,其中Ⅰ度2例（2／11,18％）,Ⅱ度4例（4／11,36％）,Ⅲ度5例（5／11,46％）;11例HC中,早发性4例（36％）,迟发性7例（64％）。HC发病时间为＋2d-＋25d（中位时间＋15d,移植后为“＋”）。15例常规预防组中发生HC2例（13％）,38例PGE1组中发生9例（24％,P〉0．05）。单因素分析显示,受者移植年龄≥6岁、预防移植物宿主病（GVHD）阳性、巨细胞病毒（CMV）感染组的HC发生率分别高于年龄〈6岁（32％vs8％,χ^2=4．68,P〈0．05）、GVHD阴性（35％vs7％,χ^2=5．96,P〈0．05）、CMV未感染组（62％vs 13％,χ^2=7．22,P〈0．05）。logistic回归分析表明,HC发病仅与年龄（OR=3．53,P〈0．05）和CMV感染（OR=4．31,P〈0．05）有显著的相关性。采用充分水化、碱化尿液、选择性输注血小板、抗病毒和尿道膀胱冲洗等综合性治疗,全部病例均获得治愈。结论受者移植年龄≥6岁和CMV感染是儿童HSCT并发HC的重要危险因素,PGE1不能降低HC的发生。儿童HSCT后HC预后多良好。     

High incidence of BK virus‐associated hemorrhagic cystitis in children after second or third allogeneic hematopoietic stem cell transplantation

BKV‐HC is a serious complication of allogeneic HSCT. To characterize the incidence, risk factors, and clinical outcomes of post‐HSCT BKV‐HC, we retrospectively analyzed 112 patients who underwent one or more allogeneic HSCTs at our hospital between 2001 and 2017. Twenty underwent second or third HSCT thereafter. Ten patients developed BKV‐HC at a median of 30 days after HSCT. The 100‐day cumulative incidences of grade 0‐4 and grade 2‐4 BKV‐HC were 7.8% and 6.2%, respectively. HSCTs performed in 2011‐2017 associated with significantly higher 100‐day cumulative incidence of grade 2‐4 BKV‐HC (14.0%) than HSCTs performed in 2001‐2010 (1.3%, P = 0.004). On multivariate analysis, second or third HSCT was the only independent significant risk factor for development of grade 2‐4 BKV‐HC (P = 0.015). Serial PCR monitoring of urine and blood BKV load did not predict BKV‐HC. The recent increase in the incidence of BKV‐HC may reflect recent innovations in transplant technologies that facilitate second or third HSCT, which are known to cause prolonged immune deficiency. If safe and effective treatment or prophylaxis becomes available, it could be used to target the high‐risk patients for BKV‐HC.     

Emerging viral infections after hematopoietic cell transplantation

Abstract:  This overview summarizes recent data on emerging viruses after hematopoietic cell transplantation (HCT), including adenovirus, BK virus, human metapneumovirus (hMPV), and human herpesvirus (HHV) 6. The increased recognition of these infections is due to improved molecular detection methods, increased surveillance and more profound immunosuppression in the host. Adenovirus can cause serious disease especially in T-cell depleted transplant recipients. Adenovirus viremia is an important risk factor for disease in this setting. BK virus has been associated with hemorrhagic cystitis in HCT recipients. BK viremia is significantly associated with hemorrhagic cystitis. hMPV shows a seasonal distribution and can cause fatal pneumonia in HCT recipients. hMPV may be the etiology of some cases previously categorized as idiopathic pneumonia syndrome. HHV-6 commonly leads to viremia in HCT recipients. HHV-6 has been strongly associated with encephalitis and delayed platelet engraftment. Prospective studies are needed to further examine epidemiology, disease associations, and management strategies for these viruses.     

Human herpesvirus 7 in pediatric hematopoietic stem cell transplantation

BACKGROUND: Little is known about the significance of human herpesvirus 7 (HHV-7) in pediatric hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To evaluate children post autologous and allogeneic HSCT, with a positive PCR or immunohistochemistry for HHV-7 either from blood, cerebrospinal fluid (CSF) or any other pathology specimen. Clinical data for these patients were collected examining symptoms and signs, engraftment, acute infectious complications, graft versus host disease (GVHD) where applicable, and survival. RESULTS: Between June 1999 and June 2003, 265 HSCT were performed in The Hospital for Sick Children, Toronto, allogeneic (n = 163) and autologous (n = 102). Nine children were positive for HHV-7 at a median of 21 days (range 16-27 days) post-HSCT. All had allogeneic transplantation. The most common underlying diagnosis was acute leukemia and 7 had matched unrelated donor (MUD) transplantation. Eight of the nine patients had grade II-IV acute GVHD and all of them had multiple infectious episodes with fungal, bacterial and other viral pathogens. Although not fully attributed to HHV-7, the clinical syndrome varied from fever, vomiting and diarrhea to septic shock. Four patients died due to GVHD and sepsis. CONCLUSION: HHV-7 was uncommon post-HSCT. It was associated with severe GVHD and sepsis secondary to severe immunosuppression.     

Long-term parental distress after pediatric hematopoietic stem cell transplantation for nonmalignant diseases

Background

Survival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high-intensity treatment, knowledge about long-term parental impact is lacking.

Procedure

This cross-sectional study assessed parental distress and everyday problems in parents of patients 2 years and older after pediatric HSCT for a nonmalignant disease using Distress Thermometer for Parents (DT-P), and compared outcomes to matched Dutch parents of healthy children and Dutch parents of children with a chronic condition (CC).

Results

Median follow-up was 5.3 years (interquartile range [IQR]: 2.9–8.6). Underlying diseases were inborn errors of immunity (N = 30), hemoglobinopathies (N = 13), and bone marrow failure (N = 27). Mothers of pediatric HSCT recipients (N = 70) reported comparable overall distress levels to mothers of healthy children, but experienced more distress related to parenting problems, specifically managing their child's emotions, discussing disease consequences, and fostering independence. Fathers of HSCT recipients (N = 45) reported higher overall distress levels and had more emotional distress compared to fathers of healthy children.

Conclusions

Overall, parental distress and everyday problems of parents of HSCT recipients are comparable to those of parents of children with CC. However, there is ongoing parental burden, both emotional and in parenting, long-term after HSCT compared to parents of healthy children, and the type of burden differs between mothers and fathers. These results indicate that individualized parental supportive care should not remain restricted to the acute hospitalization phase, but also be actively offered during long-term follow-up after pediatric HSCT.     

Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report

IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT.     

儿童造血干细胞移植后中枢神经系统并发症的临床分析

目的：探讨儿童造血干细胞移植（HSCT）后中枢神经系统（CNS）并发症的发病情况、病因、临床特点、高危因素及预后,提高 CNS 并发症的诊断和治疗水平,改善患儿的生存质量。方法回顾性分析113例行HSCT治疗的患儿发生癫痫、高血压脑病、可逆性后部白质脑病综合征和移植相关的血栓性微血管病等HSCT后CNS并发症的诱因、发病特点及预后。结果113例行HSCT治疗患儿中共7例（6.2％）发生了CNS并发症,其中1例死亡。7例患儿中,6例为HLA不全相合,1例患儿为HLA全相合。7例患儿在预处理时均应用ATG。结论 VHLA配型不全相合可能是HSCT后发生CNS并发症的高危因素。早期发现、早期诊断并积极治疗CNS 并发症,可降低其病死率及后遗症的发生,有效改善患儿的生存质量。     

Surveillance cultures in pediatric allogeneic hematopoietic stem cell transplantation

The value of surveillance cultures in predicting systemic infections and in guiding antimicrobial treatment is controversial. We investigated 57 pediatric allo‐SCTs between 2007 and 2009. ALL (34), AML (5), and severe aplastic anemia (4) were the largest patient groups. Conditioning was TBI‐based in 87% and 54% developed GVHD (21% grade III‐IV). Of the 2594 weekly colonization samples, 24% were positive (fecal bacteria 86%, fecal fungi 16%, Clostridium difficile 16%; throat bacteria 17% and throat fungi 4%). Enterobacteria and enterococci were the most common fecal findings, staphylococci and streptococci in the throat. Of the bacterial stool samples pretransplant, 74% (mostly enterococci) were resistant to our first‐line antibiotics (ceftazidime and cloxacillin). Candida species accounted for the majority of the fungal findings: 62% of the fecal and 78% in the throat. A total of 170 clinical infection episodes were recorded, and in 12 of these, the bacterial blood culture was positive. In 4/12 cases, the pathogen was detected in surveillance culture previously, leading to sensitivity and specificity of 33.3 and 47.4%, respectively. Positive predictive value of bacterial surveillance cultures was 0.9%. The antimicrobial treatment was changed in only five cases based on the surveillance culture results. Weekly surveillance cultures seldom provided clinical benefit and were not cost‐effective.     

The impact of alternative donor types on viral infections in pediatric hematopoietic stem cell transplantation

Viral infections remain one of the most important complications following allogeneic HSCT. Few reports compare virus infection between different donor types in pediatric patients. We retrospectively analyzed viral infections and the outcome of one hundred and seventy‐one pediatric patients (median 7.38 years) who underwent allogeneic HSCT from matched related donor (MRD, n = 71), 10 of 10 HLA allele‐matched unrelated donors (MUD1; n = 29), 9 of 10 HLA allele‐matched unrelated donors (MUD2; n = 40), and haploidentical donors (n = 31). PCR screening for BK virus, adenovirus, Epstein‐Barr virus, parvovirus B19, human herpesvirus 6, and CMV were performed routinely weekly. Infections between 0‐30, 31‐100, and 101 days‐2 years were identified separately. BK virus and CMV reactivations were significantly low in MRD transplant patients (P = .046 and P < .0001, respectively), but incidences of all virus infections between MUD1, MUD2, and haplo‐HSCT were found statistically not different. The OS was found to be affected by having one or multiple virus infection (P = .04 and P = .0008). Despite antiviral prophylaxis and treatments, post‐transplant viral infections are associated with reduced overall survival. Haplo‐HSCT is comparable with MUD transplantation in the setting of viral infections. A larger study group and prospective studies are needed to confirm this observation.     

Management of refractory hemorrhagic cystitis following hematopoietic stem cell transplantation in children

HC is a complication associated with HSCT, but occurs rarely in solid organ recipients. The reported incidence varies from <10% to more than 70%. HC is characterized by hemorrhagic inflammation in urinary tract mucosa with symptoms varying from asymptomatic microscopic hematuria to frank hematuria with clot formation and urinary tract obstruction. Early onset HC may be explained by toxicity of chemo- and/or radiotherapy, while multiple factors including viral infections and their interplay seem to be involved in late onset HC. So far, only incidence of cyclophosphamide-associated HC has been reduced with preventive treatment. Likely, once HC is established, the treatment principles are similar regardless of the etiology and depend on the intensity of HC. Prevention of urinary tract obstruction, transfusion support, analgesic, and spasmolytic therapy are generally accepted in HC management. Treatment beyond this conservative approach entails higher risk for side effects, and thus treatment escalation proportional to HC intensity is warranted. No standard and evidence-based treatment escalation algorithm has been widely adopted yet. As severe HC following HSCT is a potentially life-threatening complication, a multidisciplinary and individual approach is required in children suffering from this devastating complication.     

儿童异基因造血干细胞移植后淋巴细胞增殖性疾病的临床研究

目的探讨儿童异基因造血干细胞移植（allo-HSCT）后淋巴细胞增殖性疾病（PTLD）的诊治及预后。方法回顾性分析4例allo-HSCT后EBV相关性PTLD（EBV．PTLD）患儿的临床资料。其中,急性淋巴细胞白血病（高危）（ALL—HR）2例,重型再生障碍性贫血（SAA）2例。异基因外周血造血干细胞移植（allo-PBSCT）3例,异基因脐血造血干细胞移植（allo-UCBSCT）1例。结果4例患儿分别于allo．HSCT后第53、101、22、42d发生PTLD。临床表现为发热、鼻塞、扁桃体肿大、淋巴结肿大和肝脾肿大,移植前均EBNA-1-IgG（＋）、VCA．IgG（＋）;移植后EBV．DNA1．69×10^4～8．62×10^8 copies／mL。经淋巴结病理活检确诊为EBV-PTLD,其中1例为T细胞来源,3例为B细胞来源。例1予减停免疫抑制剂、使用利妥昔单抗、联合COP方案化疗及供者淋巴细胞输注（DU）治疗,PTLD反复且发生严重皮肤GVHD、肺部感染,移植后第193d死亡。余3例予减停免疫抑制剂及利妥昔单抗治疗,临床表现消失且EBV．DNA转阴,分别随访17、12、7个月均无病存活。结论动态监测EBV—DNA对PTLD早期发现具有重要意义。减停免疫抑制剂联合利妥昔单抗治疗EBV-PTLD疗效明显。化疗可导致严重感染,DLI治疗存在严重GVHD危险,不宜作为一线治疗。     

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目的探讨母亲供髓异基因造血干细胞移植(Allo-HSCT)治疗恶性复发非霍奇金淋巴瘤的疗效和供体造血干细胞来源问题。方法2004年1月,第一军医大学南方医院儿科与海军总医院儿科给1例8岁男性淋巴母细胞淋巴瘤(LBL)患儿移植了母亲来源的HLA不全相合、ABO血型不合的骨髓造血干细胞。预处理选用阿糖胞苷、足叶乙苷、环磷酰胺和全身照射。预防移植物抗宿主病(GVHD)采用兔抗人T-淋巴细胞免疫球蛋白、环孢菌素A、甲氨蝶呤和CD25单克隆抗体。移植有核细胞数8.92×108/kg,单个核细胞数为1.89×108/kg,CD34细胞数为1.37×106/kg,CD3细胞数为32.9×107/kg。结果粒细胞绝对数>0.5×109/L的天数是移植后15d(+15d),血小板>30×109/L的天数是+20d,+27d采用荧光原位杂交性染色体检测显示99%为供者型。+37d受者血型由O型转变为供者血型B型。患儿于+19d出现Ⅰ度急性GVHD,给予激素冲击后,口服小剂量维持治疗,渐消退,随访1年余,未发生慢性GVHD。结论母亲来源的骨髓造血干细胞移植对LBL有根治性治疗作用,而且在一定程度上解决造血干细胞来源问题。     

Haploidentical parental hematopoietic stem cell transplantation in pediatric refractory Langerhans cell histiocytosis

Children with MS‐LCH that fail to respond to conventional chemotherapy have poor outcomes. HSCT represents a potential salvage approach. It has been applied in over 50 cases in recent years. HSCT can achieve greater disease control than chemotherapy, but it carries a high risk of transplant‐related mortality; thus, the haploidentical parental HSCT is used infrequently in pediatric refractory LCH. We report the first successful haploidentical parental HSCT, with no T‐cell depletion, in two girls, aged 26 months and five months, with refractory MS‐LCH. The mothers were donors with 5/6 and 4/6 HLA matches, respectively. The conditioning regimen included busulfan + cyclophosphamide + etoposide + antithymocyte‐globulin ± fludarabine; the GVHD prophylaxis was based on cyclosporine + methotrexate ± mycophenolate‐mofetil ± zenapax. In both cases, the stem cells were sourced from peripheral blood and BM, which included CD34+ cells (13.17 × 10⁶/kg and 40.23 × 10⁶/kg, respectively). These patients survived and showed no signs of disease activity in 54‐ and 44‐month post‐HSCT follow‐ups. Our results indicated that, for patients that fail chemotherapy delivered early in the disease, but do not show organ dysfunction progression, it may be possible to achieve successful haploidentical parental HSCT with a strong myeloablative regimen.     

Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation

Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated‐donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft‐versus‐tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT.