• Proteinuria and elevated markers of complement activation at TMA diagnosis are associated with poor outcome.• Clinical interventions should be considered in HSCT patients with these high-risk features at the time TMA is diagnosed.Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multiorgan injury, and severe cases are associated with poor outcomes after hematopoietic stem cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty-nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher nonrelapse mortality (43.6% vs 7.8%, P < .0001) at 1 year post-HSCT compared with those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30 mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1 year), whereas all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (P < .01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest-risk patients who might benefit from prompt clinical interventions. (Blood. 2014;124(4):645-653)

Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience of 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab. We demonstrate significant improvement in 1y post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with same high-risk TA-TMA features that had 1y post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive eculizumab therapy course using PK/PD guided dosing, requiring a median of 11 doses of eculizumab (IQR 7-20). Therapy was discontinued due to resolution of TA-TMA at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of therapy were less likely to respond to treatment (OR =0.15, p-value 0.0014), and required more doses of eculizumab [r = 0.43, p-value = 0.0004]. Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9, p=0.0015), and had lower 1y survival (44% vs 78%, p=0.01). Over 70% of survivors had proteinuria on long term follow up. The best GFR recovery in survivors was a median 20% lower (IQR 7.3-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for high risk TA-TMA, but some patients with severe disease lack a complete response, prompting us to propose early intervention strategies and search for additional targetable endothelial injury pathways.

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an understudied complication of HSCT that significantly affects transplant-related morbidity and mortality. Over the past several decades, the cause of TA-TMA has remained unknown, limiting treatment options to non-specific therapies adapted from other diseases. Recent prospective studies dedicated to the study of TA-TMA have provided new insights into the pathogenesis of, and genetic susceptibility to TA-TMA, raising awareness of this important transplant complication and allowing for the identification of potentially novel therapeutic targets. Specifically, many patients with TA-TMA develop multi-organ tissue injury through endothelial damage mediated by the activation of the complement pathway, leading to rational therapeutic strategies including complement blockade. This new knowledge has the potential to favorably influence clinical practice and change the standard of care for how patients with TA-TMA are managed. In this review, we summarize novel approaches to the recognition and management of TA-TMA, using case examples to illustrate key clinical points that hopefully lead to improved short and long-term outcomes for these complex HSCT patients, who remain at significant risk for treatment-related morbidity and mortality.

Mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBIs) lead to significant morbidity, mortality, and healthcare resource utilization in hematopoietic stem cell transplant (HSCT) patients. Determination of the healthcare burden of MBI-LCBIs and identification of patients at risk of MBI-LCBIs will allow researchers to identify strategies to reduce MBI-LCBI rates. The objective of our study was to describe the incidence, risk factors, timing, and outcomes of MBI-LCBIs in hematopoietic stem cell transplant patients. We performed a retrospective analysis of 374 patients who underwent HSCT at a large free-standing academic children’s hospital to determine the incidence, risk factors, and outcomes of patients that developed a bloodstream infection (BSI) including MBI-LCBI, central line–associated BSI (CLABSI), or secondary BSI in the first year after HSCT. Outcome measures included nonrelapse mortality (NRM), central venous catheter removal within 7 days of positive culture, shock, admission to the pediatric intensive care unit (PICU) within 48 hours of positive culture, and death within 10 days of positive culture. One hundred seventy BSIs were diagnosed in 100 patients (27%): 80 (47%) MBI-LCBIs, 68 (40%) CLABSIs, and 22 (13%) secondary infections. MBI-LCBIs were diagnosed at a significantly higher rate in allogeneic HSCT patients (18% versus 7%, P = .007). Reduced-intensity conditioning (OR, 1.96; P = .015) and transplant-associated thrombotic microangiopathy (OR, 2.94; P = .0004) were associated with MBI-LCBI. Nearly 50% of all patients with a BSI developed septic shock, 10% died within 10 days of positive culture, and nearly 25% were transferred to the PICU. One-year NRM was significantly increased in patients with 1 (34%) and more than 1 (56%) BSIs in the first year post-HSCT compared with those who did not develop BSIs (14%) (P ≤ .0001). There was increased 1-year NRM in patients with at least 1 MBI-LCBI (OR, 1.94; P = .018) and at least 1 secondary BSI (OR, 2.87; P = .0023) but not CLABSIs (OR, 1.17; P = .68). Our data demonstrate that MBI-LCBIs lead to substantial use of healthcare resources and are associated with significant morbidity and mortality. Reduction in frequency of MBI-LCBI should be a major public health and scientific priority.

High-risk transplantation-associated thrombotic microangiopathy (TMA) can present with multisystem involvement and is associated with a poor outcome after hematopoietic stem cell transplantation (HSCT), with < 20% 1-year survival. TMA may involve the intestinal vasculature and can present with bleeding and ischemic colitis. There are no established pathologic criteria for the diagnosis of intestinal TMA (iTMA). The goal of our study was to identify histologic features of iTMA and describe associated clinical features. We evaluated endoscopic samples from 50 consecutive HSCT patients for 8 histopathologic signs of iTMA and compared findings in 3 clinical groups based on the presence or absence of systemic high-risk TMA (hrTMA) and the presence or absence of clinically staged intestinal graft-versus-host disease (iGVHD): TMA/iGVHD, no TMA/iGVHD, and no TMA/no iGVHD. Thirty percent of the study subjects had a clinical diagnosis of systemic hrTMA. On histology, loss of glands, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, endothelial cell separation, and total denudation of mucosa were significantly more common in the hrTMA group (P < .05). Intravascular thrombi were seen exclusively in patients with hrTMA. Mucosal hemorrhages and endothelial cell swelling were more common in hrTMA patients but this difference did not reach statistical significance. Patients with hrTMA were more likely to experience significant abdominal pain and gastrointestinal bleeding requiring multiple blood transfusions (P < .05). Our study shows that HSCT patients with systemic hrTMA can have significant bowel vascular injury that can be identified using defined histologic criteria. Recognition of these histologic signs in post-transplantation patients with significant gastrointestinal symptoms may guide clinical decisions.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant that can result in multi-organ failure (MOF). Patients undergoing high-dose chemotherapy with autologous stem cell transplant (aHCT) for neuroblastoma require good organ function to receive post-transplant radiation and immunotherapy. We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens. Sixty patients underwent aHCT using high-dose chemotherapy: 41 patients received carboplatin/etoposide/melphalan (CEM), 13 patients busulfan/melphalan (Bu/Mel) and six patients received tandem transplant (cyclophosphamide/thiotepa and CEM). TA-TMA with MOF was diagnosed in 13 patients (21.7%) at a median of 18 days after aHCT. TA-TMA occurred in 12 patients receiving CEM and in 1 after cyclophosphamide/thiotepa. There were no incidences of TA-TMA after Bu/Mel regimen. Six of 13 patients with TA-TMA and MOF received terminal complement blocker eculizumab for therapy. They all recovered organ function and received planned post-transplant therapy. Out of seven patients who did not get eculizumab, two died from TA-TMA complications and four progressed to ESRD. We conclude that the CEM regimen is associated with a high incidence of clinically significant TA-TMA after aHCT and eculizumab can be safe and effective treatment option to remediate TA-TMA associated MOF.

Vitamin D has endocrine function as a key regulator of calcium absorption and bone homeostasis and also has intracrine function as an immunomodulator. Vitamin D deficiency before hematopoietic stem cell transplantation (HSCT) has been variably associated with higher risks of graft-versus-host disease (GVHD) and mortality. Children are at particular risk of growth impairment and bony abnormalities in the face of prolonged deficiency. There are few longitudinal studies of vitamin D deficient children receiving HSCT, and the prevalence and consequences of vitamin D deficiency 100 days after transplant has been poorly studied. Serum samples from 134 consecutive HSCT patients prospectively enrolled into an HSCT sample repository were tested for 25-hydroxy (25 OH) vitamin D levels before starting HSCT (baseline) and at 100 days after transplantation. Ninety-four of 134 patients (70%) had a vitamin D level < 30 ng/mL before HSCT, despite supplemental therapy in 16% of subjects. Post-transplant samples were available in 129 patients who survived to day 100 post-transplant. Vitamin D deficiency persisted in 66 of 87 patients (76%) who were already deficient before HSCT. Moreover, 24 patients with normal vitamin D levels before HSCT were vitamin D deficient by day 100. Overall, 68% of patients were vitamin D deficient (<30 ng/mL) at day 100, and one third of these cases had severe vitamin D deficiency (<20 ng/mL). Low vitamin D levels before HSCT were not associated with subsequent acute or chronic GVHD, contrary to some prior reports. However, severe vitamin D deficiency (<20 ng/mL) at 100 days post-HSCT was associated with decreased overall survival after transplantation (P = .044, 1-year rate of overall survival: 70% versus 84.1%). We conclude that all pediatric transplant recipients should be screened for vitamin D deficiency before HSCT and at day 100 post-transplant and that aggressive supplementation is needed to maintain sufficient levels.

Background BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. Methods In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1–4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. Results We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1–4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia &lt;10 000 copies/mL, but not cidofovir exposure. Conclusions Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.