Severe ehrlichia infection in pediatric oncology and stem cell transplant patients

Ehrlichiosis, a tickborne illness transmitted by tick vectors Amblyomma americanum and Ixodes scapularis, can be acquired in endemic areas. Clinical manifestations range from asymptomatic to fulminant in nature. We report three cases of ehrlichiosis in pediatric oncology patients, one of whom was a stem cell transplant recipient. Early symptoms included fever, malaise, and vague gastrointestinal symptoms. Laboratory abnormalities were initially attributed to chemotherapy toxicity. Illness was severe in all three patients and one patient died even after initiation of doxycycline. These cases emphasize the need for a high index of suspicion for tickborne illness in oncology patients, and the importance of a low threshold for starting empiric treatment before confirming the diagnosis. Pediatr Blood Cancer 2010;54:776–778. © 2010 Wiley‐Liss, Inc.     

Pulmonary dysfunction in pediatric hematopoietic stem cell transplant patients: non-infectious and long-term complications

Pulmonary complications are among the most frequently encountered sequelae of pediatric hematopoietic stem cell transplantation (HSCT). Non-infectious complications are becoming increasingly more common in this unique population. This review addresses the diagnosis and management of non-infectious manifestations of lung disease in pediatric HSCT patients and briefly discusses the long-term pulmonary function of childhood HSCT survivors.     

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.     

Transient renal enlargement in pediatric hematopoietic cell transplant recipients

Age‐dependent renal length tables are routinely used when interpreting pediatric ultrasound. Standard renal length tables may not be accurate for HCT patients due to treatment effects on kidney size. The purpose of this study was to determine whether renal size changes from expected lengths based on age after HCT in the absence of other markers of renal disease. Four hundred and fifty renal measurements were made on 101 patients who underwent HCT between 2006 and 2010. Renal length was measured at 1–90 days pre‐HCT and at 0–30, 31–90, 91–180, and 181+ days post‐HCT. Values were compared with normal renal length tables. Average post‐HCT renal lengths were greater than established normative renal length data within every age group. Age‐adjusted average renal lengths measured at 0–30 and 31–90 days post‐transplantation were significantly larger than pre‐HCT renal lengths, with relative increases of 6.9% (4.5, 9.4; p < 0.001) and 3.9% (1.4, 6.4; p = 0.003), respectively. Average renal length did not differ significantly after 90 days post‐transplantation. HCT patients may have larger kidneys in the absence of renal disease. Awareness of the potential phenomenon of transient renal enlargement following HCT can prevent misdiagnosis and eliminate unnecessary diagnostic evaluations, interventions, anxiety, resource allocation, and financial costs.     

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.     

Efficacy of high‐dose steroids for bronchiolitis obliterans syndrome post pediatric hematopoietic stem cell transplantation

BOS is the pulmonary manifestation of cGvHD post‐allogeneic HSCT. Survival and treatment of this often fatal complication have not improved over the last 20 years and there is no clear standard of care. For the past 10 years, BOS was treated in our center with monthly cycles of HDPS. We reviewed the outcomes of patients with post‐HSCT BOS who met the diagnostic criteria for BOS as per the NIH consensus and were treated with at least one cycle of methylprednisolone at a dose of 10‐30 mg/kg/d×3 d. We collected demographic and clinical data, responses to treatment and results of pulmonary function tests at several time points. Between January 2007 and January 2014, 12 patients were treated with HDPS for post‐HSCT BOS. Five patients (42%) had a good response to treatment; four patients (33%) stabilized with moderate lung disease; and three patients (25%) progressed to end‐stage disease. No significant acute side effects attributable to the HDPS treatment were identified. HDPS may be an effective treatment option for all but the most severely ill patients with post‐HSCT BOS.     

Solid organ transplants following hematopoietic stem cell transplant in children

Bunin N, Guzikowski V, Rand ER, Goldfarb S, Baluarte J, Meyers K, Olthoff KM. Solid organ transplants following hematopoietic stem cell transplant in children.
Pediatr Transplantation 2010: 14:1030–1035. © 2010 John Wiley & Sons A/S. Abstract: SOT may be indicated for a select group of pediatric patients who experience permanent organ failure following HSCT. However, there is limited information available about outcomes. We identified eight children at our center who received an SOT following an HSCT. Patients were six months to 18 yr at HSCT. Diseases for which children underwent HSCT included thalassemia, Wiskott–Aldrich syndrome, Shwachman–Diamond/bone marrow failure, sickle cell disease (SCD), erythropoietic porphyria (EP), ALL, chronic granulomatous disease, and neuroblastoma. Time from HSCT to SOT was 13 days to seven yr (median, 27 months. Lung SOT was performed for two patients with BO, kidney transplants for three patients, and liver transplants for three patients (VOD, chronic GVHD). Seven patients are alive with functioning allografts 6–180 months from SOT. Advances in organ procurement, operative technique, immunosuppressant therapy, and infection control may allow SOT for a select group of patients post‐HSCT. However, scarcity of donor organs available in a timely fashion continues to be a limiting factor. Children who have undergone HSCT and develop single organ failure should be considered for an SOT if there is a high likelihood of cure of the primary disease.     

Risk factors in pediatric stem cell transplantation for leukemia

To investigate which factors impact on survival, relapse, relapse free survival, transplant-related mortality (TRM) and graft-versus-host disease (GVHD) in children who undergo allogeneic stem cell transplantation, we included all 181 children transplanted due to leukemia at our unit. At the end of follow up 54% of the patients were alive, 27% had died due to relapse while 19% had died of other causes. Survival was similar in recipients of related (55%) and unrelated grafts (48%). Risk factors identified in univariate analysis were brought into a multivariable analysis. However, an unrelated donor was not identified as a risk factor for any of the five end-points analysed. A donor positive for three to four herpes viruses increased the risk of acute GVHD, TRM and death. A female to male transplant increased the risk of TRM, particularly if combined with a mismatch. Early stage of disease as well as human leukocyte antigen (HLA)-matching independently predicted survival. The risk of relapse increased after 1992. Chronic GVHD independently decreased the risk of relapse (relative risk RR, 0.39) and death (RR 0.42). We conclude that in children with leukemia other specific donor characteristics such as HLA-matching, gender, parity, and exposure to herpes viruses were more important for outcome than relationship.     

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.     

Feasibility of an inpatient exercise intervention for children undergoing hematopoietic stem cell transplant

With improving survival rates following HSCT in children, QOL and management of short‐ and long‐term effects need to be considered. Exercise may help mitigate fatigue and declines in fitness and strength. The aims of this study were to assess the feasibility of an inpatient exercise intervention for children undergoing HSCT and observe the changes in physical and psychological health. Fourteen patients were recruited, mean age 10 yr. A 6MWT, isometric upper and lower body strength, balance, fatigue, and QOL were assessed prior to Tx and six wk post‐Tx. A supervised exercise program was offered five days per week during the inpatient period and feasibility assessed through uptake rate. The study had 100% program completion and 60% uptake rate of exercise sessions. The mean (±s.d.) weekly activity was 117.5 (±79.3) minutes. Younger children performed significantly more minutes of exercise than adolescents. At reassessment, strength and fatigue were stabilized while aerobic fitness and balance decreased. QOL revealed a non‐statistical trend towards improvement. No exercise‐related adverse events were reported. A supervised inpatient exercise program is safe and feasible, with potential physiological and psychosocial benefits.     

Changes in biomarkers of bone resorption over the first six months after pediatric hematopoietic cell transplantation

Polgreen LE, Rudser K, Deyo M, Smith A, Baker KS, Petryk A. Changes in biomarkers of bone resorption over the first six months after pediatric hematopoietic cell transplantation. Abstract: Bone loss has been observed within the first six months after HCT in both children and adults. While there is some evidence that bone formation may be reduced in children after HCT, it is currently unknown whether bone resorption is increased. The objective of this prospective study was to evaluate changes in markers of bone resorption over the first six months after pediatric HCT. Twenty‐six participants (eight females) aged 10.9 ± 3.4 yr entered the study prior to HCT. Bone resorption was measured by urine DPD and PYD, and by plasma NTX and CTX. Seventeen participants who completed day +30 visit and either day +100 or +180 visits were included in the analysis. DPD increased between days +30 and +100 (mean change, 11.3 nmol/nmol creatinine; p = 0.012) and between days +30 and +180 (13.7 nmol/nmol creatinine; p = 0.036). PYD increased between days +30 and +100 (32 nmBCE/L; p = 0.019). CTX increased between baseline and day +100 (5.9 μg/L; p = 0.012). Changes in NTX levels were not statistically significant. This study shows that markers of bone resorption increase in children after HCT, suggesting that increased resorption may be a contributing factor to the pathophysiology of bone loss after pediatric HCT.     

Insulin-related metabolism following hematopoietic stem cell transplantation in childhood

Objectives:  To assess insulin-related metabolism following hematopoietic stem cell transplantation (HSCT) in childhood.
Study design:  Thirty-four patients who underwent HSCT were compared with 21 patients with similar diseases who were not transplanted. Median follow-up was 3.6 yr after HSCT. Anthropometric parameters, fasting plasma glucose and insulin levels, hemoglobin A_1c (HbA_1c) and lipid profile were measured and compared.
Results:  HbA_1c was significantly higher (p = 0.001) in the study group. Two (5.8%) patients in the study group developed type 2 diabetes mellitus. Among thalassemic patients, significantly lower insulin resistance indices (p = 0.05) and fasting plasma insulin levels (p = 0.033) were found in the study group compared with the control group.
Conclusions:  Attentive follow-up of insulin-related metabolism following HSCT in children is needed. The significance of the higher HbA1c values in the study group remains to be evaluated in a larger cohort of patients.     

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.     

Transplant related ocular surface disorders: Advanced techniques for ocular surface rehabilitation after ocular complications secondary to hematopoietic stem cell transplantation

HSCT has been linked to the development of an assortment of ocular surface complications with the potential to lead to permanent visual impairment if left untreated or if not treated early in the course of disease. Strategies for therapy include maintenance of lubrication and tear preservation, prevention of evaporation, decreasing inflammation, and providing epithelial support. The ultimate aim of treatment is to prevent permanent ocular sequelae through prompt ophthalmology consultation and the use of advanced techniques for ocular surface rehabilitation. We describe several rehabilitation options of ocular surface complications occurring secondarily during the post‐HSCT course.     

Favorable response of pediatric stem cell recipients to human protein C concentrate substitution for veno-occlusive disease

Plasminogen activator inhibitor 1 is known to be elevated in patients with hepatic VOD after intensive chemotherapy. To re-establish endogenous fibrinolysis and to inhibit thrombin formation, we used non-APC (zymogen) to normalize PAI-1 levels. As a consequence of thrombin formation inhibition and the consecutive inhibition of the coagulation cascade, this treatment is expected to reduce the elevated D-dimer level. Six pediatric stem cell recipients with moderate or severe VOD after busulfan or total body irradiation conditioning regimen are reported here who were therapy-refractory to defibrotide or rt-PA therapy. All patients had low levels of PC activity (16-39%). The administration of PC (60-240 IU/kg) led to a rapid and sustained rise in PC activity (target level >80%) with near normalization of prothrombin and partial thromboplastin time in all patients. Elevated PAI-1 levels declined. Five of the six patients showed a good clinical response with prompt resolution of clinical, sonographic, and laboratory signs of hepatic blood flow obstruction, while one patient with severe VOD, as well as concomitant liver GVHD and CMV disease, had a slow but detectable response to PC therapy. All patients survived.     

Hematopoietic and immune recovery after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation in a pediatric population

To compare the hematopoietic and immune recoveries after allogeneic transplantation with different cell sources, we analyzed the recovery patterns of blood components after allogeneic peripheral blood stem cell transplantation (PBSCT) in comparison with that after allogeneic bone marrow transplantation (BMT) in a pediatric population. Sixteen patients received PBSCT, and 24 received BMT between January, 1995 and March, 2000. The patients had acute lymphoblastic leukemia (ALL; n = 22), acute myelogenous leukemia (AML; n = 8), myelodysplastic syndrome (MDS; n = 3), or other diseases (n = 7). The median ages of patients in the PBSCT and BMT groups were 9 yr and 6 yr, respectively. Cyclosporin A (CsA) plus methotrexate or methylprednisolone was used as a graft-vs.-host disease (GvHD) prophylaxis regimen in the PBSCT group, whereas CsA alone or methotrexate alone was used in the BMT group. Circulating lymphocyte numbers and subpopulations determined by flow cytometric analysis were used as markers of immune recovery. In the PBSCT group, the median number of harvested CD34+ cells was 7.25 (range: 1.3-27.6) x 106/kg of the recipient's body weight, while the median number of harvested nucleated cells was 4.7 (range: 3.7-10.5) x 108/kg. All of the patients were engrafted. Myeloid engraftment occurred sooner after PBSCT than after BMT (median number of days to achieve absolute neutrophil counts (ANC) > 0.5 x 109/L; 11 and 15, respectively; p < 0.0001) and similar results were found for platelet engraftment (median number of days to achieve a platelet count of > 20 x 109/L; 12 and 21, respectively; p = 0.004). On the other hand, after PBSCT the absolute numbers of total circulating lymphocytes and lymphocyte subpopulations were not significantly different from those after BMT. The incidence of acute GvHD after PBSCT was the same as that after BMT, while chronic GvHD developed more frequently after PBSCT than after BMT (p = 0.005). In a pediatric population, the indications for PBSCT and BMT should be based on these findings in addition to regard for the donor's safety.