JC polyomavirus‐specific antibody responses in pediatric kidney transplant recipients

BKPyV is widely recognized in KTRs, but little is known about rates of primary and secondary JCPyV exposure in pediatric KTRs. We evaluated JCPyV exposure in pediatric KTRs using antibody responses in the first 12 months post‐transplant. Of 46 children transplanted between 2009 and 2014, 6 lacked any samples for serologic testing, leaving 40 KTRs for study. JCPyV‐specific IgG and IgM antibodies were measured using a normalized VLP ELISA. Significant JCPyV exposure was defined as IgG seroconversion, increasing IgG levels of >0.5 nOD units, or IgM detection. Of 40 recipients (median age 3.2 years), 11 (27.5%) were seropositive, 20 (50%) seronegative for JCPyV‐IgG, while 9 (22.5%) had no specimen at the time of transplantation, but were confirmed as seronegative in post‐transplant samples. Of 29 (72.5%) at risk, JCPyV‐IgG seroconversion occurred in 15/29 (51.7%) including JCPyV‐IgM in 6 patients (20.7%). Two patients (6.9%) developed only JCPyV‐IgM. Among JCPyV‐IgG‐positive KTRs, six (12.5%) had significant IgG increases. Altogether 23 of 40 patients (57.5%) had serological evidence of primary or secondary JCPyV exposure. In these patients, kidney function tended to be lower during the 2 years of follow‐up, but only one patient lost the graft due to JCPyV nephropathy. Thus, JCPyV exposure is common in pediatric KTR and may present serologically as primary or secondary infection. Although only one case of JC‐PyVAN occurred, a trend toward lower renal function was seen. Dedicated studies of larger cohorts are warranted to define impact of JCPyV in pediatric KTR.     

Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts

Olkinuora HA, Taskinen MH, Saarinen‐Pihkala UM, Vettenranta KK. Multiple viral infections post‐hematopoietic stem cell transplantation are linked to the appearance of chronic GVHD among pediatric recipients of allogeneic grafts.
Pediatr Transplantation 2010:14:242–248. © 2009 John Wiley & Sons A/S. Abstract: Delayed immune reconstitution and the ensuing opportunistic infections among children following hematopoietic stem cell transplantation (HSCT) are associated with increased treatment‐related morbidity and mortality (TRM). We retrospectively evaluated the impact of viral infections on the posttransplant recovery of pediatric recipients of stem cell grafts as a reflection of their posttransplant immunoreconstitution in a single institution setting. The case histories of 124 children (during 1/1999‐9/2006) were reviewed for infectious episodes, and correlated with their respective clinical parameters. Patients with a high risk for CMV received prophylaxis, but failures in the prophylaxis were common (40%). 110/124 (89%) of these allogeneic patients had at least one viral reactivation/clinical infection posttransplant. In this group of pediatric patients chronic GVHD (P<0,001) and secondary graft failure were significantly (P=0,001) associated with early (during the first 100 days post HSCT), multiple (≥ 2) viral infections. Our data indicate that viruses are common pathogens among pediatric recipients of allogeneic stem cell grafts. In this group of patients multiple viral infections early on seem to reflect an even more severe degree of immunological derangement in the recipient and identify a group of patients with an increased risk of chronic GVHD and secondary graft failure.     

天津地区KI和WU多瘤病毒在儿童急性呼吸道感染中的分子流行病学研究

目的了解KI和WU多瘤病毒(KIPy V和WUPy V)与天津地区儿童急性呼吸道感染的关系。方法采用PCR扩增方法对2011年1月至2013年12月收集的3 730份来自天津地区的急性呼吸道感染患儿鼻咽分泌物标本进行KIPy V和WUPy V基因检测,同时所有标本均用直接免疫荧光法检测7种常见呼吸道病毒。选取部分KIPy V和WUPy V PCR阳性产物进行测序,利用测序序列与已知序列比对并绘制进化树。再从中选取两株KIPy V VP1基因克隆到T载体上,进行序列测定和分析,并将核苷酸序列提交Gen Bank。结果 3 730份标本中,KIPy V阳性检出453份(12.14%),WUPy V阳性检出63份(1.69%)。KIPy V平均感染率在6~7月明显偏高,WUPy V平均感染率在2~3月达到一个小高峰。两种多瘤病毒感染的阳性患儿年龄主要集中在3岁以内。KIPy V和WUPy V与其他7种呼吸道病毒存在混合感染,混合感染率为2.31%(86/3 730);WUPy V和KIPy V混合感染9份。选取的35份KIPy V阳性PCR产物序列与Gen Bank已公布的KIPy V序列的同源性在94%~100%之间;选取的12份WUPy V阳性PCR产物序列与Gen Bank已公布的WUPy V序列的同源性在95%~100%之间。两株KIPy V VP1基因序列已被Gen Bank收录,登录号为KY465925和KY465926。结论天津地区部分儿童的急性呼吸道感染可能与WUPy V和KIPy V感染相关。KIPy V感染多发于夏季,WUPy V感染多发于春季。KIPy V和WUPy V与国内外流行株间差异较小,基因组相对稳定。     

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??Objective??In order to understand the epidemiological and virologic characteristics of WU Polyomaviruses ??WUPyV?? and KI Polyomaviruses ??KIPyV?? infection in hospitalized children with acute respiratory tract infection ??ARTI?? in Changsha. Methods??A total of773 nasopharyngeal aspirates ??NPA?? specimens were collected from hospitalized children with ARTI between September 2007 and March 2008 inChangsha. Specimens were screened for WUPyV and KIPyV by nested polymerase chain reaction. All positive amplification products were confirmedby sequencing and compared with those in GenBank. Results??Polyomaviruses were detected in 53 patients ??6.8%?? out of the 773 children ??WUPyV was 5.0%??KIPyV was 1.8%??. The patients were from 20 days to 5 years. Similarity of WUPyV and KIPyV with those published in the GenBank at nucleotide levels was 93%??100% and 95%??100%?? respectively. Conclusion??WUPyV and KIPyV may be important pathogens in children with acute lower respiratory tract infection and associated with lower respiratory diseases.     

Low‐dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high‐risk pediatric acute myeloid leukemia

The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high‐risk AML post HSCT who were treated with low‐dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13–41 months despite their high‐risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low‐dose AZA maintenance therapy post HSCT for pediatric patients with high‐risk AML.     

Incidence,risk factors,and outcome of blood stream infections during the first 100 days post‐pediatric allogeneic and autologous hematopoietic stem cell transplantations

Bloodstream infections (BSI) are a frequently observed complication after hematopoietic stem cell transplant (HSCT). Retrospective analysis of clinical and microbiological data during the first 100 days from 302 consecutive pediatric patients who underwent HSCT for a malignant disease at our institute between January 2013 and June 2017. A total of 164 patients underwent autologous and 138 allogeneic HSCT. The overall incidence of BSI was 37% with 92% of infectious episodes occurring during the pre‐engraftment phase. Gram‐positive bacteria (GPB) accounted for 54.6% of the isolated pathogens, gram‐negative bacteria (GNB) for 43.9%, and fungi for 1.4%. Coagulase‐negative staphylococci and Escherichia coli were the most commonly isolated GPB and GNB, respectively. Forty‐five percent of GNB were extended‐spectrum beta‐lactamase producers and 21% were multidrug‐resistant organisms. Fluoroquinolone resistance was 92% and 68%, among GPB and GNB, respectively. Risk factors for BSI in univariate analysis were allogeneic HSCT, delayed time to engraftment more than 12 days, previous BSI before HSCT, and alternative donor. In multivariate analysis, only HSCT type (allogeneic vs autologous P = .03) and previous BSI within 6 months before HSCT (P = .016) were significant. Overall survival at day 100 was 98% and did not differ significantly between patients with and without BSI (P = .76). BSI is common in children undergoing HSCT for malignant diseases. Allogeneic HSCT recipients and previous BSI within 6 months before HSCT are associated with increased risk of post‐transplant BSI. With current supportive measures, BSI does not seem to confer an increased risk for 100‐day mortality.     

Human herpes virus 6 infection in pediatric organ transplant patients

Transplant patients need lifelong immunosuppressive medication, but this reduces their defense mechanisms, making them prone to viral infections and reactivations. We aimed to clarify the prevalence and clinical manifestations of the human herpes virus 6 (HHV‐6) infection in children after pediatric solid organ transplants. Clinical findings and viral loads were compared between primary HHV‐6 infections and reactivations. The study comprised 47 kidney, 25 liver, and 12 heart transplant patients who underwent surgery from 2009 to 2014. HHV‐6 antibodies were analyzed before surgery, and HHV‐6 DNAemia tests were regularly carried out after the transplant using a real‐time quantitative polymerase chain reaction method. We found the primary HHV‐6 infection in 19 of 22 (86%) seronegative patients, and it was more common in patients under 3 years of age (79%) than over 3 (38%, P=.0002). Post‐transplant HHV‐6 DNAemia affected 48 of 84 (57%) patients and was significantly higher in primary infections than reactivations (P=.001), and 17 of 48 (35%) patients had symptoms when it was detected at a median of 2 weeks post‐transplant. The HHV‐6 infection was common after solid organ transplants, especially under 3 years of age, and it typically started 2 weeks after surgery. Testing for HHV‐6 DNAemia is recommended shortly after transplantation, especially in patients with fever, diarrhea, rash, seizures, or abnormal liver enzyme tests.     

Quantiferon‐Cytomegalovirus assay: A potentially useful tool in the evaluation of CMV‐specific CD8+ T‐cell reconstitution in pediatric hematopoietic stem cell transplant patients

Pediatric HSCT recipients are at high risk for CMV reactivation due to their immature immune system and therapy following transplantation. Reconstitution of CMV‐specific T‐cell immunity is associated with control and protection against CMV. The clinical utility of monitoring CMV‐specific CMI to predict CMV viremia in pediatric HSCT patients using the Quantiferon‐CMV (QIAGEN^®) test was investigated prospectively. Thirty‐seven pediatric allogeneic HSCT recipients were enrolled from 3/2010‐6/2012. CMV viremia was detected via weekly real‐time PCR. The Quantiferon‐CMV test was conducted pretransplant, early after transplantation, 30, 90 , 180 , 270, and 360 days post‐transplantation. The incidence of CMV viremia was 51% (19/37) with half of the episodes within ≤30 days post‐transplant. Fifteen patients showed CMV‐specific immunity (average of 82 days). The cumulative incidence of CMV reactivation in patients who developed CMV‐specific immunity was lower than those who did not (15% vs 53%; P = .023). The ROC statistical analysis showed that the AUC was 0.725 in predicting viremia, for Quantiferon‐CMV test. In this cohort, the Quantiferon‐CMV assay was a valuable method for identifying pediatric HSCT patients at high risk for CMV viremia, suggesting potential clinical utility to individualize patient's management post‐transplant.     

Hematopoietic stem cell transplantation and acute kidney injury in children: A comprehensive review

AKI in the setting of HSCT is commonly investigated among adult patients. In the same way, malignancies requiring treatment with HSCT are not limited to the adult patient population, AKI following HSCT is frequently encountered within pediatric patient populations. However, inadequate information regarding epidemiology and pathophysiology specific to pediatric patients prevents development of appropriate and successful therapeutic strategies for those afflicted. Addressing AKI in the context of sinusoidal obstruction syndrome, chemotherapy, thrombotic microangiopathy and hypertension post chemotherapy, glomerulonephritis, and graft versus host disease provides greater insight into renal impairment associated with these HSCT‐related ailments. To obtain a better understanding of AKI among pediatric patients receiving HSCT, we investigated the current literature specifically addressing these areas of concern.     

Dynamics of cell‐mediated immune responses to cytomegalovirus in pediatric transplantation recipients

Patel M, Stefanidou M, Long CB, Fazzari MJ, Tesfa L, Del Rio M, Lamour J, Ricafort R, Madan RP, Herold BC. Dynamics of cell‐mediated immune responses to cytomegalovirus in pediatric transplantation recipients.
Pediatr Transplantation 2012: 16: 18–28. © 2011 John Wiley & Sons A/S. Abstract: CMI responses, combined with quantification of CMV DNA (DNAemia), may identify transplantation recipients at risk for invasive disease. PBMC were collected in pediatric transplantation candidates at one, three, and six months post‐transplant in 10 subjects (six renal, three cardiac, one stem cell) and at single time points in eight HC and 14 children greater than one yr post‐transplant (LTTx). Cells were stimulated with anti‐CD3mAb or CMV pp65 peptide pools and responses assessed by IFNG enzyme‐linked immunosorbent spot assay and cytokine secretion. IFNG responses to anti‐CD3mAb were significantly lower pretransplant relative to HC and were further decreased at one and three months post‐transplant, but recovered to levels comparable to HC by six months. Responses to pp65 among CMV‐seropositive recipients followed a similar pattern but recovered by three months. CMV‐seropositive LTTx and HC showed a Th1 cytokine response to pp65 stimulation. Three LTTx subjects developed CMV DNAemia; two demonstrated decreased responses to anti‐CD3mAB (and pp65 in the CMV seropositive subject) at the onset of DNAemia, which recovered as DNAemia resolved. Monitoring CMI in children is feasible and may provide an adjunct biomarker to predict CMV progression and recovery.     

Autoimmune hemolytic anemia and immune thrombocytopenia following hematopoietic stem cell transplant: A critical review of the literature

Autoimmune cytopenias (AIC) post‐hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post‐HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft‐versus‐host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post‐HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post‐HSCT patients.     

Post‐hematopoietic stem cell transplant hemophagocytic lymphohistiocytosis or an impostor: Case report and review of literature

HLH occurring after HSCT is a relatively rare disease. Many conditions may mimic or trigger HLH in post‐HSCT period (eg, cytokine release syndrome, engraftment syndrome, graft rejection/failure, acute graft‐vs‐host disease, infections systemic inflammatory response syndrome/sepsis, and thrombotic microangiopathy). Moreover, this period is usually marked by febrile illness, cytopenia, and a “cytokine storm” leading to elevation of inflammatory biomarkers like ferritin and sCD25. These parameters overlap with the diagnostic criteria for HLH. Such confounding factors make the management of post‐HSCT HLH quite challenging. We illustrate this critical issue with case report of a patient who was diagnosed with HLH after allogeneic HSCT for tAML. He received MP and CsA for HLH but VP‐16 was not administered due to fear of severe myelosuppression. Fortunately, he responded well to treatment and remains in remission to date. We recommend caution while using HLH‐94/HLH‐2004 guidelines for the diagnosis and management of post‐HSCT HLH. In this article, we pinpoint these issues with a brief review of all the pediatric cases and clinical studies of post‐HSCT HLH along with a critical evaluation of its various diagnostic criteria. Finally, based on the limitations of current diagnostic criteria, we suggest a need for formulating disease‐specific diagnostic criteria for post‐HSCT HLH.     

WU polyomavirus detected in respiratory tract specimens from young children in Japan

Polyomaviruses (PyV) WU and KI are reportedly associated with respiratory tract disease (RTD) worldwide but their incidence is unclear in Japan. In a 2 year prospective study, WU/KIPyV were detected in 48 (13.9%) and in five (1.4%) of 345 children hospitalized with lower RTD, respectively. The seasonal distribution was observed in spring and early summer. Other respiratory viruses were co‐detected in 51% of PyV‐positive patients, but eight (2.3%) of the WUPyV‐positive patients were negative for other known pathogens.     

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.     

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.     

Tolerance and effectiveness of nivolumab after pediatric T‐cell replete,haploidentical, bone marrow transplantation: A case report

To date, there has been a lack of pediatric experience regarding the efficacy and tolerability of immune checkpoint inhibitors after haploidentical hematopoietic stem cell transplant (HSCT). We present the case of a 22‐year‐old female with multiple‐relapsed Hodgkin lymphoma (HL) who presented with a new relapse after haploidentical (post‐haplo) HSCT. Anti‐PD‐1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft‐versus‐host disease (GVHD). This case report suggests that immune checkpoint inhibition may be safely tolerated even in the setting of haploidentical HSCT, without triggering overt GVHD.     

Trichodysplasia spinulosa mimicking lichen nitidus in a renal transplant patient

Trichodysplasia spinulosa (TS) is a rare cutaneous condition associated with the TSPyV and characterized by skin‐colored, folliculocentric papules with keratin spicule formation. TS is seen almost exclusively in immunosuppressed individuals, often presenting in patients with a history of solid organ transplantation or chemotherapy for a lymphoreticular malignancy. We report a case of widespread TS in a 9‐year‐old girl with a history of renal transplantation complicated by BK viremia, which is also caused by a polyomavirus, BKPyV. The clinical presentation of TS in this case morphologically resembled the more common, harmless skin condition known as “lichen nitidus,” and was more extensive than expected for TS, creating a diagnostic challenge. This case illustrates an important presentation of severe TS of which transplant teams, oncologists, primary care providers, and dermatologists should be aware.     

Analysis of factors affecting immune recovery and initial response to tetanus after DTaP vaccination in pediatric allogeneic HSCT patients

Transfer of donor immunity after allo‐HSCT is limited, requiring re‐vaccination after HSCT. The CDC 2009 guidelines introduced earlier vaccination post‐HSCT with a uniform vaccination strategy. This study objective was to describe predictors of immune recovery and initial response to tetanus after DTaP vaccination post‐HSCT. We conducted a retrospective chart review of pediatric allo‐HSCT patients transplanted between July 1, 2007–June 30, 2012 who survived >1 yr without relapse (N = 27). Response to tetanus one month after the initial dose of DTaP was defined as a ≥4 fold increase in tetanus titers ≥1 month after vaccination. Wilcoxon rank‐sum exact test and Kruskall–Wallis tests were used to analyze CD4, CD8, and CD19 counts. Exact conditional logistic regression was utilized to analyze initial tetanus vaccination response. A statistically significant increase in median CD4, CD8, and CD19 counts occurred from six to 12 months post‐HSCT (p ≤ 0.0001, 0.005, 0.004). Only 36% of patients had initial tetanus vaccination response at first attempt post‐HSCT. None of the variables tested were statistically significant in predicting initial tetanus response to vaccination. There was no association between predictors of immune recovery or transplant variables and initial tetanus response. A uniform vaccination strategy is unlikely to provide protective antibodies for many post‐HSCT patients and should be evaluated in larger studies.     

5‐Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High‐Dose Chemotherapy

Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high‐dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5‐azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post‐HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5‐azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy.