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.     

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.     

Surgical consultation and intervention during pediatric hematopoietic stem cell transplantation

Children undergoing HSCT are at risk for complications due to immune system impairment, toxicity from prior therapies and conditioning regimens, and long‐term use of indwelling catheters. These problems may require assessment by the surgical team. We sought to characterize the role of surgical consultation during primary hospital stay for HSCT. We retrospectively reviewed the records of consecutive patients undergoing HSCT between September 2010 and September 2012. One hundred and seventy‐three patients underwent 189 HSCTs. General surgery consultations occurred during 33% (n = 62) of primary hospitalizations for HSCT, with a total of 85 consults. Sixty‐three (73%) consults resulted in an intervention in the operating room or at the bedside. The majority of consults were for CVL issues (59%, n = 50), followed by abdominal complaints (16%, n = 14). Patients requiring surgical consultation had significantly higher in‐hospital mortality (16% vs. 2%, p < 0.01) and 100‐day TRM (10% vs. 2%, p < 0.01), compared with those not requiring consultation. Patients undergoing HSCT often require surgical consultation, most commonly for line‐related issues. Surgical consultation heralded an increased risk of in‐hospital and 100‐day TRM. Issues among this high‐risk cohort of children who have undergone HSCT must be familiar to the general surgeon and oncologist alike.     

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.     

Neurological complications after allogeneic hematopoietic stem cell transplantation in children,a single center experience

In this study, we retrospectively examined the data of children who underwent allo‐HSCT from HLA‐matched family donors. We analyzed the incidence, etiological factors, clinical characteristics, possible reasons, risk factors, and follow‐up of neurologic complications. BU‐based conditioning regimens were used in most of the cases (n = 62). The median duration of follow‐up for the 89 patients was 20 months (range 1–41 months). Eleven percent of transplanted children developed one or more neurological symptoms after HSCT with a median observation time of two months (range ?6 days to 18 months). The median age of the four girls and six boys with neurological complication was 13 yr (range 5.3–17.6 yr). Cylosporine A neurotoxicity was diagnosed in five children, four of them were PRES. The rest of complications were BU and lorazepam toxicity, an intracranial hemorrhage, a sinovenous thrombosis, and a transient ischemic attack during extracorpereal photopheresis. No difference was found between groups of neurological complication according to age, gender, diagnosis, hospitalization time, neutrophil and platelet engraftment time, stem cell source, and conditioning regimen, acute and chronic GVHD or VOD. Neurological complication was the cause of death in one patient (1.1%).     

Nutritional status and weakness following pediatric hematopoietic cell transplantation

Survivorship after pediatric HCT has increased over the past decade. Focus on long‐term care and well‐being remains critical due to risk of poor dietary habits and exaggerated sedentary behavior, which can lead to muscle weakness, increased risk for obesity, and cardiometabolic disorders. Nutrition and physical activity are key factors in survivorship; however, data are limited. Comprehensive nutritional assessments, including nutrition‐focused physical examination, grip strength, and food/activity surveys, were completed in 36 pediatric HCT survivors (aged 2‐25 years). Patients were divided into undernutrition, normal‐nutrition, and overnutrition categories. Fifty percent of participants were classified as normal nutrition, 22% undernutrition, and 28% overnutrition. Few patients met the U.S. Dietary Guidelines recommended intake for vegetables, fiber, saturated fat, and So FAS. Patients in the undernutrition group demonstrated significantly lower grip strength than those in the normal‐ and overnutrition groups. When grip strength was normalized to body mass, patients in the overnutrition group had the highest prevalence of weakness. Using NHANES reference data, maximum grip strength and NGS cutoffs were identified that could significantly distinguish the nutrition groups. Comprehensive nutritional assessments and grip strength measurements are feasible, non‐invasive, easy to perform, and inform both under‐ and overnutrition in pediatric HCT survivors.     

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.     

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.     

Evaluation of chimerism by quantitative PCR analysis of DNA polymorphism after allogeneic hematopoietic stem cell transplantation in a pediatric population with malignancies

Relapse remains the major pitfall to success for Allo-HSCT in children with malignancies. Ninety-one patients undergoing Allo-HSCT were retrospectively reviewed. Chimerism status was evaluated at days +30, +60, and +100 in PB. VNTR-PCR and STR-PCR were used for this purpose. Thirty-one patients recurred (34%) and none survived. Thirty-two remain alive in CR (35%). Patients who achieved a CC at those days had a significant higher RFS and OS than patients who did not. Twelve patients showing PMC had an increased risk of recurrence (p=0.02. OR 7.7). In the univariate analysis, the probability of death was higher in patients who were not in first CR before transplant (p=0.008.OR 2.09) and in those receiving cells not from PB (p=0.002.OR 2.03). In the multivariate analysis, the absence of CC at day +100 was associated with a higher probability of relapse (p=0.004. OR 10.8) and death (p=0.016. OR 9.3). Serial chimerism PCR-based analyses of polymorphic DNA markers can predict relapse. Patients with PMC are at the highest risk of recurrence. Patients receiving an Allo-HSCT in first CR from PB who achieve a CC at day +100 have a better outcome.     

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.     

Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment for sickle cell disease (SCD), being successful in around 85-90% of patients. Mortality and long-term morbidity (including infertility, gonadal failure, and chronic graft-vs.-host disease) associated with conventional approaches curtail the number of patients who undergo allo-HSCT. Recently, it has been demonstrated that cord blood is as effective as and possibly safer than bone marrow in pediatric patients with SCD. Likewise, transplant strategies based on the use of reduced-intensity regimens and the induction of mixed chimerism have been explored to decrease allo-HSCT short- and long-term complications.     

Pulmonary function impairment in children following hematopoietic stem cell transplantation

BACKGROUND: Deterioration of pulmonary function after hematopoietic stem cell transplantation (SCT) is a well-known late effect of this treatment, but the course of pulmonary function over time is less clear. The aim of our study was to establish both the prevalence and course of pulmonary function abnormalities in children following SCT. METHODS: Thirty-nine of 106 patients, who visited a post-SCT late effects clinic and who underwent a pulmonary function test (PFT) both before and at least twice after SCT were included in this study. Forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), total lung capacity (TLC), and total lung diffusion capacity (TLCO) were determined and recorded as percentage predicted for age, sex, and length matched controls. Values of less than 80% of predicted were considered abnormal. Change in PFT parameters over time was determined by comparing the mean PFT parameter in our group at three different time points: pre-SCT, < or =1 year post-SCT (SCTpost1) and >1 year post-SCT (SCTpost2). RESULTS: After SCT restrictive and/or diffusion abnormalities are most prevalent (45% and 76% at SCTpost1, respectively). A significant decrease of TLC (-9.7%) and TLCO (-20.3%) was observed during the first year after SCT, with improvement over time, but no normalization. Obstructive lung disease was less common (6% at SCTpost1). Clinical signs of lung function impairment were rare. CONCLUSIONS: Restrictive and diffusion lung function disorders are common after SCT. They improve over time but do not normalize. As only a few patients with pulmonary function abnormalities had clinical signs of lung function impairment, the clinical relevance of performing long-term follow-up of PFT is questionable.     

Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation

Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant‐associated thrombotic microangiopathy following pediatric hematopietic stem cell transplantation.
Pediatr Transplantation 2012: 16: E39–E42. © 2010 John Wiley & Sons A/S. Abstract: TA‐TMA is a serious complication of hematopoietic stem cell transplantation, presenting as microangiopathic hemolytic anemia with severe renal injury and mortality as high as 60%. Diagnosis and treatment of TA‐TMA is very challenging after HSCT because anemia, thrombocytopenia, hypertension, and renal impairment are multifactorial, leading to delayed recognition and management of this complication. We report a successful outcome following early intervention for hyperacute TA‐TMA after allogeneic HSCT.     

脐血造血干细胞移植研究进展

随着血液学和移植免疫学的快速发展,尤其是人类白细胞抗原(HLA)配型技术的不断发展,造血干细胞移植(hematopoietic stem cell transplantation,HSCT)技术逐渐成熟并广泛应用,成为治愈某些血液病的重要方法,并有望在今后的生物学治疗和基因治疗中发挥重要的作用.     

Squamous cell carcinoma development in Fanconi anemia patients who underwent hematopoietic stem cell transplantation

We examined SCC development of 24 FA patients, who received HSCT from HLA‐matched relatives. In our BMT center, we applied low‐dose CY + LFI + ATG (n:13) as conditioning regimen for FA patients between 1992 and 1999, and CY + BU + ATG (n:11) between 1999 and 2002. The aim of this study was to investigate SCC development after HSCT and examine features of the follow‐up patients. The 10‐year overall survival (OS) of the group with LFI + regimen was 43%, whereas the group without LFI regimen was 60%. There was a statistically significant relationship between infections (viral/bacterial) and overall survival (Fisher's Exact test P < .001). Five out of 13 long‐term (>1 year) surviving patients developed SCC in the HNSCC (n:4) and esophagus (n:2) region (a patient with oral SCC developed a second primary esophageal SCC). The SCC rate in our FA patients was 38%, four of the SCC patients were transplanted with irradiation used conditioning regimens, three of them had acuteGvHD (Grade II‐III), only one developed chronic GvHD. The interval between HSCT and SCC diagnosis was median 13 (range 6‐18) years, the age for the development of cancer was median 21 (range 15‐32) years. Survival after SCC was low, median 6 months (range 6‐12), due to delayed SCC diagnosis, tumor progression under therapy and treatment‐related toxicities of the usually reduced RT and/or CT.     

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.