Publications by authors named "Sonata Jodele"

93 Publications

A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant.

Blood Adv 2021 Jan;5(1):1-11

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.
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http://dx.doi.org/10.1182/bloodadvances.2020003455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805323PMC
January 2021

Pneumatosis intestinalis after hematopoietic stem cell transplantation: When not doing anything is good enough.

J Pediatr Surg 2021 Jan 6. Epub 2021 Jan 6.

Surgical Critical Care / Pediatric Surgery, Phoenix Children's Hospital / Mayo Clinic, Phoenix, AZ, USA.

Background/purpose: Pneumatosis intestinalis (PI) has been reported in hematopoietic stem cell transplant recipients (HSCT) since 1980s and at present there is no uniform consensus of the significance and management of this condition.

Methods: We retrospectively reviewed medical records of 990 consecutive pediatric HSCT recipients and examined data for clinical PI presentation, management and outcomes RESULTS: PI was identified in 53 patients (5.4%), mainly allogeneic HSCT recipients receiving systemic steroids. Abdominal X-ray was the main diagnostic modality. Forty-seven patients (89%) were evaluated because of clinical concerns and others were identified as incidental findings. Pneumoperitoneum was reported in 15 patients (28%). None of these patients had signs of acute abdomen. The majority of patients (43/53, 81%) had no targeted clinical intervention for PI and resolved PI in a median of 15 days (IQR 3-61). Surgery consult was only requested for 7/53 (13%) patients, three of whom had evidence of pneumoperitoneum. None of these patients required any surgical interventions.

Conclusions: Pneumatosis intestinalis commonly occurs in HSCT recipient receiving steroids, but unlike with NEC, PI rarely poses clinical risk after transplant. The majority of HSCT recipients with PI require only close monitoring without interventions. Surgical evaluation should be based on clinical symptoms and not PI presence alone.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.12.020DOI Listing
January 2021

BK Polyomavirus Genotypes in Two Patients after Hematopoietic Cell Transplant.

Microbiol Resour Announc 2021 Jan 14;10(2). Epub 2021 Jan 14.

Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

BK polyomavirus (BKPyV) infection can lead to nephropathy and hemorrhagic cystitis (HC). We evaluated BKPyV genotypes in two individuals after hematopoietic cell transplant (HCT). The first case developed HC and was infected with genotype Ib-2, while the second did not develop HC and was infected with genotype Ia.
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http://dx.doi.org/10.1128/MRA.01122-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849698PMC
January 2021

Prospective pilot trial of calcipotriene as a novel topical treatment for acute skin graft versus host disease.

Bone Marrow Transplant 2021 Jan 8. Epub 2021 Jan 8.

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.

Skin graft versus host disease (GVHD) can affect quality of life in hematopoietic stem cell transplant recipients. Therapeutic options for steroid-refractory GVHD are limited. We report the first prospective pilot study evaluating the topical vitamin D3 analog Calcipotriene (DOVONEX 0.005% cream) for acute skin GVHD in children, with associated analyses of target organ chemokine CXCL10 changes in response to therapy. We observed that Calcipotriene applications were safe and well tolerated. There were no symptom progression nor new symptoms requiring GVHD therapy escalation during study period. The most consistent response observed by study subjects was resolution of pruritus in eight patients and significant improvement in pruritus in two study subjects. Nine of ten patients had improvement or resolution of skin rash. In addition, we documented reduction of CXCL10 levels in the skin of seven subjects with GVHD after Calcipotriene course using non-invasive D-Squame® disc application to the skin for chemokine analysis. Our pilot study shows promising observation that topical Calcipotriene could be a novel therapeutic option for acute skin GVHD, especially in patients presenting with pruritus and should be studied in larger prospective studies.
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http://dx.doi.org/10.1038/s41409-020-01189-3DOI Listing
January 2021

Diagnostic Considerations in H1N1 Influenza-induced Thrombotic Microangiopathy.

J Pediatr Hematol Oncol 2020 Dec 23;Publish Ahead of Print. Epub 2020 Dec 23.

Department of Pediatrics, University of Cincinnati College of Medicine Cancer and Blood Diseases Institute Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Influenza virus can trigger atypical hemolytic uremic syndrome and present with complement-driven thrombotic microangiopathy (TMA). When administered promptly, complement-blocking therapies can spare organ injury and be lifesaving. However, diagnosing TMA in the setting of a severe viral infection can be challenging, as a significant overlap of symptoms and disease complications exists. This is particularly true in influenza virus infections and more recently, Coronavirus disease 2019 (COVID-19) infections. We present a 16-year-old male with H1N1 influenza-induced atypical hemolytic uremic syndrome who quickly improved with complement-blocking therapy, highlighting an urgent need to include TMA in the differential diagnosis of severe viral infections.
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http://dx.doi.org/10.1097/MPH.0000000000002036DOI Listing
December 2020

Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients.

Blood Adv 2020 Nov;4(22):5745-5754

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital, Cincinnati, OH.

BK polyomavirus (BKPyV) infection is a major complication of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT). Treatment options are limited, poorly effective, and have significant toxicities. Cellular therapy using T cells directed against BKPyV is an emerging therapy, and we report efficacy in controlling BKPyV-associated disease in highly immunocompromised patients. Virus-specific T cells (VSTs) against BKPyV were manufactured using either blood from the patient's stem cell donor (donor-derived VSTs) or from unrelated donors (third-party VSTs). VSTs were used to treat BKPyV in 38 HSCT recipients and 3 SOT recipients between June 2017 and December 2019. Overall response rate was 86% in patients treated for BK viremia, 100% in patients treated for hemorrhagic cystitis, and 87% in patients treated for both BK viremia and hemorrhagic cystitis. No infusional toxicity, de novo graft-versus-host disease, or rejection of the organ occurred attributable to the VST infusion. BKPyV-specific immune responses were demonstrated by interferon-γ production by peripheral blood mononuclear cells postinfusion in response to BKPyV antigens. VSTs are a safe and potentially effective strategy to treat BKPyV and associated symptoms in recipients of HSCT and SOT. Cellular therapy should be considered for all patients with BKPyV and underlying immune suppression at risk of complications. This trial was registered at www.clinicaltrials.gov as #NCT02532452.
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http://dx.doi.org/10.1182/bloodadvances.2020003073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686882PMC
November 2020

Tackling COVID-19 infection through complement-targeted immunotherapy.

Br J Pharmacol 2020 Jul 9. Epub 2020 Jul 9.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

The complement system is an ancient part of innate immunity sensing highly pathogenic coronaviruses by mannan-binding lectin (MBL) resulting in lectin pathway activation and subsequent generation of the anaphylatoxins (ATs) C3a and C5a as important effector molecules. Complement deposition on endothelial cells and high blood C5a serum levels have been reported in COVID-19 patients with severe illness, suggesting vigorous complement activation leading to systemic thrombotic microangiopathy (TMA). Complement regulator gene variants prevalent in African-Americans have been associated with a higher risk for severe TMA and multi-organ injury. Strikingly, severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)-infected African-Americans suffer from high mortality. These findings allow us to apply our knowledge from other complement-mediated diseases to COVID-19 infection to better understand severe disease pathogenesis. Here, we discuss the multiple aspects of complement activation, regulation, crosstalk with other parts of the immune system, and the options to target complement in COVID-19 patients to halt disease progression and death.
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http://dx.doi.org/10.1111/bph.15187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361469PMC
July 2020

Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy.

J Clin Immunol 2020 07 23;40(5):699-707. Epub 2020 May 23.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients.
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http://dx.doi.org/10.1007/s10875-020-00789-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245179PMC
July 2020

Endothelial injury, F-actin and vitamin-D binding protein after hematopoietic stem cell transplant and association with clinical outcomes.

Haematologica 2020 04 2. Epub 2020 Apr 2.

Department of Pediatric, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA;

Endothelial injury after hematopoietic stem cell transplant is an important initiating factor for early transplant toxicities of thrombotic microangiopathy and acute graft versus host disease. We hypothesized that release of the angiopathic molecule filamentous actin from hematopoietic cells lysed during conditioning prior to stem cell transplant would be associated with clinical outcomes. We detected filamentous actin in the blood of 52% of stem cell transplant recipients in the first 14 days after transplant, and children with detectable filamentous actin had significantly elevated risk of thrombotic microangiopathy (p= 0.03) and non-relapse mortality (p= 0.04). Filamentous actin is cleared from the circulation by vitamin D binding protein so we expected that higher levels of vitamin D binding protein would improve outcomes. In a cohort of 190 children receiving allogeneic transplant, risk of thrombotic microangiopathy was reduced in those with serum concentrations of vitamin D binding protein above the median at day 30 (10% vs 31%, p=0.01), and graft versus host disease and non-relapse mortality were reduced in those with levels above the median at day 100 (3% vs 18%, p=0.04 and 0% vs 15%, p=0.002). Western blot analyses demonstrated actin-vitamin D binding protein complexes in the blood, which cleared by day 21-28. Our data support modulation of cytokine secretion and macrophage phenotype by vitamin D binding protein later after transplant. Taken together, our data identify an association between filamentous-actin, a mediator of endothelial damage, and vitamin D binding protein, an actin scavenger, as modifiers of risk of clinical consequences of endothelial injury.
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http://dx.doi.org/10.3324/haematol.2019.233478DOI Listing
April 2020

Interferon-complement loop in transplant-associated thrombotic microangiopathy.

Blood Adv 2020 03;4(6):1166-1177

Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an "interferon-complement loop" that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
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http://dx.doi.org/10.1182/bloodadvances.2020001515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094010PMC
March 2020

Acute Kidney Injury in Children after Hematopoietic Cell Transplantation Is Associated with Elevated Urine CXCL10 and CXCL9.

Biol Blood Marrow Transplant 2020 07 9;26(7):1266-1272. Epub 2020 Mar 9.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic HCT provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant. Children (>2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at 2 large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value, which was recorded ±1 day from when the research urine sample was obtained, as compared with the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI). A total of 176 patients were included from 2 pediatric centers. Thirty-six patients from 1 center were analyzed as a discovery cohort and the remaining 140 patients from the second center were analyzed as a validation cohort. AKI rates were 18% to 35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (P < .01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-γ and interferon-α. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding. CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population.
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http://dx.doi.org/10.1016/j.bbmt.2020.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306432PMC
July 2020

Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Blood 2020 03;135(13):1049-1057

Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (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 hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.
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http://dx.doi.org/10.1182/blood.2019004218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099329PMC
March 2020

The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation.

Clin Infect Dis 2020 Dec;71(12):3044-3054

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

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 <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.
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http://dx.doi.org/10.1093/cid/ciz1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819507PMC
December 2020

Association between Vitamin D and Risk for Early and Late Post-Transplant Complications.

Biol Blood Marrow Transplant 2020 02 22;26(2):343-350. Epub 2019 Oct 22.

Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital of Los Angeles, Los Angeles, California; Keck School of Medicine, University of Southern California, Los Angeles, California.

Vitamin D (VD) deficiency is a well-described phenomenon in pediatric patients undergoing hematopoietic stem cell transplant (HSCT). VD modulates inflammation, and deficiency pre-HSCT and at day +100 has been associated with graft-versus-host disease (GVHD) and poorer survival. However, a paucity of data has specifically described the association between VD status and immune-mediated complications including GVHD and veno-occlusive disease (VOD). Additionally, data to guide recommendations for VD monitoring and supplementation during HSCT are scarce. Our primary objective was to evaluate the association between VD and post-HSCT complications. The key secondary aim was to evaluate the routine use and efficacy of VD monitoring and supplementation practices. To our knowledge, this is the largest study of its kind in the pediatric population. This retrospective study evaluated VD level (VDL) before and 1 year after HSCT, VD supplementation practices, and their association with acute GVHD, VOD, and survival in pediatric patients who received autologous and allogeneic HSCT for both malignant and nonmalignant diseases from January 2013 to April 2018. Of 314 HSCTs, 43% of patients (n = 136) had VDL measured before HSCT; 61% of this cohort had pre-HSCT VD insufficiency (<30 ng/mL). Neither pre-HSCT nor follow-up VDL was associated with the incidence of GVHD or VOD. Supplementation did not result in significantly different post-HSCT VDL.VDL was correlated with overall survival; every 10-ng/mL increase in VDL was associated with a 28% decreased risk of death (P = .01). Current accepted VD supplementation regimens for pediatric HSCT do not achieve sufficient VDL in most patients after HSCT. VD status was associated with all-cause mortality but not with individual comorbidities; prospective studies are required to establish the connection between VD status, inflammatory-mediated HSCT complications, and potential benefit of VD supplementation before and after HSCT. These studies are needed to inform evidence-based guidelines for monitoring and supplementing VD during HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.011DOI Listing
February 2020

Improving the Timeliness of Chemotherapy Administration in the Bone Marrow Transplant Unit.

Biol Blood Marrow Transplant 2020 01 25;26(1):150-156. Epub 2019 Sep 25.

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; James M. Anderson Center for Health Systems Excellence, Cincinnati, Ohio.

Patients undergoing hematopoietic stem cell transplantation (HSCT) are often admitted to the hospital the day they are due to begin their conditioning regimen. Timely initiation of chemotherapy during regular work hours is important for patient safety, because during the night shift fewer physicians and pharmacists are available for urgent or unexpected matters. A review of the data at our institution from October 2017 to August 2018 showed that approximately one-third of our chemotherapy was started during the night shift (after 19:00), and the average time from admission to start of chemotherapy was over 8 hours. There are currently no well-defined benchmarks for timeliness of chemotherapy initiation. The aim of this quality improvement initiative was to increase the percentage of patients who start chemotherapy in the bone marrow transplant unit before 19:00 from 65% to >80% by March 31, 2019. We identified barriers to timely initiation of chemotherapy through process mapping and analysis of failures. The primary barriers were late admissions (after 12:00 pm) and time from admission to preparation of chemotherapy. We addressed mechanisms to mitigate these barriers through Plan-Do-Study-Act testing. Interventions included providing families specific admission times and their rationales and process for notifying pharmacy of admissions immediately on arrival. We used standardized control charts to measure the impact of the interventions on change. We also monitored medication errors before and during the intervention. From September 2018 to March 2019 the percentage of patients who started preparative chemotherapy before 19:00 increased from 65% to 85%, the percentage of patients who were admitted after 12:00 remained similar before (31%) and after the interventions (33%), and the average time from admission to start of chemotherapy decreased from 8.6 hours (513 minutes) to 6.4 hours (382 minutes). Medication errors were similar before (n = 50) and after the interventions (n = 43). Using standardized processes, we demonstrated a substantial decrease in the percentage of HSCT patients starting their preparative regimen after 19:00 without a concurrent increase in errors. We believe these interventions and measurements can be used in all transplant centers and have the potential to influence patient safety and outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513385PMC
January 2020

EASIX and mortality after allogeneic stem cell transplantation.

Bone Marrow Transplant 2020 03 26;55(3):553-561. Epub 2019 Sep 26.

Charité Universitätsmedizin Berlin, Hematology, Oncology and Tumorimmunology, Berlin, Germany.

Allogeneic stem cell transplantation (alloSCT) is an effective immunotherapy in patients with hematological malignancies. Endothelial dysfunction was linked to major complications after alloSCT. We asked the question if the "Endothelial Activation and Stress Index" (EASIX; [(creatinine × LDH) ÷ thrombocytes]) can predict mortality after alloSCT. We performed a retrospective cohort analysis in five alloSCT centers in the USA and Germany. EASIX was assessed prior to conditioning (EASIX-pre) and correlated with mortality in 755 patients of a training cohort in multivariable models. The predictive model established in the training cohort was validated in 1267 adult allo-recipients. Increasing EASIX-pre predicted lower overall survival (OS) after alloSCT, and successful model validation was achieved for the validation cohort. We found that EASIX-pre predicts OS irrespective of established scores. Moreover, EASIX-pre was also a significant prognostic factor for transplant-associated microangiopathy. Finally, EASIX-pre correlated with biomarkers of endothelial homeostasis such as CXCL8, interleukin-18, and insulin-like-growth-factor-1 serum levels. This study establishes EASIX-pre based on a standard laboratory biomarker panel as a predictor of individual risk of mortality after alloSCT independently from established clinical criteria.
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http://dx.doi.org/10.1038/s41409-019-0703-1DOI Listing
March 2020

Haptoglobin degradation product as a novel serum biomarker for hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Pediatr Nephrol 2019 05 19;34(5):865-871. Epub 2018 Dec 19.

Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.

Background: Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a well-known complication of HSCT and carries high risk of morbidity and mortality. A lack of consistent non-invasive diagnostic criteria can delay diagnosis and lead to irreversible organ damage.

Methods: Serum samples of 100 patients that underwent HSCT at Cincinnati Children's Hospital were serially collected. Unbiased proteomic profiling by SELDI-TOF-MS was performed on serum from TA-TMA patients at baseline (pre-HSCT), 2 weeks before TMA diagnosis (pre-TMA), and at clinical TMA diagnosis. Two proteins with mass to charge ratios of 12-13 kDa were consistently elevated at the 2 week pre-TMA time point by SELDI-TOF, compared to control samples. Potential peptides were isolated and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the Linear Trap Quadropole (LTQ). A MASCOT search identified haptoglobin fragments in the 12-17-kDa range. Western blot was performed to validate haptoglobin fragments as a potential biomarker.

Results: Western blot of TA-TMA patients showed haptoglobin fragments at 12, 14, and 17 kDa that varied between baseline, pre-TMA, and TMA time points for each patient. By densitometric analysis, the 17-kDa fragment in the pre-TMA samples differed significantly from TMA diagnosis (p < 0.0001). There was no significant difference in the concentrations of the 12-kDa and 14-kDa fragments.

Conclusion: The 17-kDa haptoglobin degradation product may represent a novel early serum biomarker for TA-TMA that could potentially allow for earlier diagnosis and intervention.
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http://dx.doi.org/10.1007/s00467-018-4178-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728916PMC
May 2019

Multiple bloodstream infections in pediatric stem cell transplant recipients: A case series.

Pediatr Blood Cancer 2018 12 9;65(12):e27388. Epub 2018 Aug 9.

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Bacterial bloodstream infections (BSIs) are associated with poor outcomes following stem cell transplantation (SCT). We describe the demographics, treatment, complications, and outcome of 23 pediatric SCT recipients who developed three or more BSIs in the first year after SCT at our center from 2011 through 2016. The majority underwent allogeneic SCT (n = 22/23;96%), mainly from an unrelated donor (n = 19/22,86%); developed grade 2-4 graft versus host disease (GVHD; n = 14/23, 61%), all steroid refractory; and were diagnosed with thrombotic microangiopathy (n = 21/23, 91%). One-year overall survival was 56% (n = 13/23). We observed a high rate of transplant-associated thrombotic microangiopathy and steroid-refractory acute GVHD in patients with three or more BSIs.
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http://dx.doi.org/10.1002/pbc.27388DOI Listing
December 2018

Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma.

Leuk Res 2018 11 19;74:130-136. Epub 2018 Jul 19.

Department of Oncology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.

Background: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Methods: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS.

Results: 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort.

Conclusions: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.
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http://dx.doi.org/10.1016/j.leukres.2018.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219911PMC
November 2018

Complement in Pathophysiology and Treatment of Transplant-Associated Thrombotic Microangiopathies.

Authors:
Sonata Jodele

Semin Hematol 2018 07 11;55(3):159-166. Epub 2018 Apr 11.

Department of Hematology, Oncology and Blood & Marrow Transplantation, USC Keck School of Medicine, Children's Hospital Los Angeles, Los Angeles, CA. Electronic address:

Transplant-associated thrombotic microangiopathy (TA-TMA) is a form of microangiopathy specifically occurring in the context of hematopoietic stem cell transplantation. Similarly, to other microangiopathies, TA-TMA is characterized by hemolytic anemia, thrombocytopenia, and organ failure due to endothelial injury. Although its clinical association with medications (eg, calcineurin inhibitors), immune reactions (eg, graft vs host disease) or infectious complications is well established, the pathophysiology remains largely unknown. Recent data have highlighted the role of complement in the pathophysiology of TA-TMA, which are frequently associated with a functional impairment (either inherited or acquired) of the endogenous regulation of the complement classic and alternative pathway. This manuscript will review the data supporting the involvement of complement in the pathophysiology of TA-TMA, as well as the clinical data supporting the use of anticomplement agents in this rare condition.
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http://dx.doi.org/10.1053/j.seminhematol.2018.04.003DOI Listing
July 2018

Single Ultra-High-Dose Cholecalciferol to Prevent Vitamin D Deficiency in Pediatric Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2018 09 18;24(9):1856-1860. Epub 2018 May 18.

Division of Endocrinology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio. Electronic address:

Vitamin D deficiency is prevalent among childhood hematopoietic stem cell transplantation (HSCT) recipients and associated with inferior survival at 100 days after transplantation. Achieving and maintaining therapeutic vitamin D levels in HSCT recipients is extremely challenging in the first 3 to 6 months after transplantation due to poor compliance in the setting of mucositis and the concomitant use of critical transplantation drugs that interfere with vitamin D absorption. We sought to evaluate the safety and efficacy of a single, ultra-high-dose of vitamin D given before childhood HSCT to maintain levels in a therapeutic range during the peritransplantation period. Ten HSCT recipients with pretransplantation 25-OH vitamin D (25OHD) level <50 ng/mL and with no history of hypercalcemia, nephrolithiasis, or pathological fractures were enrolled on this pilot study. A single enteral vitamin D dose (maximum 600,000 IU) was administered to each patient based on weight and pretransplantation vitamin D level before the day of HSCT. Vitamin D levels between 30 and 150 ng/mL were considered therapeutic. All patients received close clinical observation and monitoring of 25OHD levels, calcium, phosphate, parathyroid hormone, urine calcium/creatinine ratio, and n-telopeptide for safety and efficacy assessment. The mean age of the study subjects was 5.8 ± 4.9 years, and the mean pretransplantation 25OHD level was 28.9 ± 13.1 ng/mL. All patients tolerated single, ultra-high-oral dose of vitamin D under direct medical supervision. No other oral vitamin D supplements were administered during the observation window of 8 weeks. Three of 10 patients received 400 IU/day of vitamin D in parenteral nutrition only for 5 days during the study window. A mean peak serum vitamin D level of 80.4 ± 28.6 ng/mL was reached at a median of 9 days after the vitamin D dose. All patients achieved a therapeutic vitamin D level of >30 ng/mL. Mean vitamin D levels were sustained at or above 30 ng/mL during the 8-week observation window. There were no electrolyte abnormalities attributed to the ultra-high-dose of vitamin D. Most patients had mildly elevated urine calcium/creatinine ratios during treatment, but none showed clinical or radiologic signs of nephrocalcinosis or nephrolithiasis. Our findings indicate that single ultra-high-oral dose vitamin D treatment given just before HSCT is safe and well tolerated in the immediate peritransplant period in children. Patients in our study were able to achieve and sustain therapeutic vitamin D levels throughout the critical period during which vitamin D insufficiency is associated with decreased overall survival. Larger prospective studies are needed to address the impact of single ultra-high-dose vitamin D treatment on HSCT outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.019DOI Listing
September 2018

Interleukin-22 levels are increased in gastrointestinal graft--host disease in children.

Haematologica 2018 10 17;103(10):e480-e482. Epub 2018 May 17.

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, OH, USA.

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http://dx.doi.org/10.3324/haematol.2017.174771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165817PMC
October 2018

High-dose Carboplatin/Etoposide/Melphalan increases risk of thrombotic microangiopathy and organ injury after autologous stem cell transplantation in patients with neuroblastoma.

Bone Marrow Transplant 2018 10 19;53(10):1311-1318. Epub 2018 Apr 19.

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

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.
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http://dx.doi.org/10.1038/s41409-018-0159-8DOI Listing
October 2018

Topical vitamin D analog for chronic graft versus host disease of the skin.

Bone Marrow Transplant 2018 05 15;53(5):628-633. Epub 2018 Jan 15.

Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

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http://dx.doi.org/10.1038/s41409-017-0031-2DOI Listing
May 2018

Successful management of concurrent acquired hemophilia A and a lupus anticoagulant in a pediatric hematopoietic stem cell transplant patient.

Bone Marrow Transplant 2018 04 12;53(4):487-489. Epub 2018 Jan 12.

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 11027, Cincinnati, OH, 45229, USA.

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http://dx.doi.org/10.1038/s41409-017-0041-0DOI Listing
April 2018

In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy.

Blood Adv 2017 Sep 23;1(20):1632-1634. Epub 2017 Aug 23.

Division of Bone Marrow Transplantation and Immune Deficiency and.

Transplantation-associated thrombotic microangiopathy is associated with complement activation in vitro.This data further supports the use of eculizumab for the treatment of patients with TA-TMA.
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http://dx.doi.org/10.1182/bloodadvances.2017008250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728339PMC
September 2017

Improving Time to Antibiotic Administration for Bone Marrow Transplant Patients With First Fever.

Pediatrics 2018 01;141(1)

Divisions of Bone Marrow Transplantation and Immune Deficiency and.

Background And Objective: Timely antibiotic administration in immunocompromised patients is associated with improved outcomes. The aim of our study was to decrease the mean time to administration of antibiotics in hospitalized bone marrow transplant patients with fever from 75 to <60 minutes.

Methods: By using the Model of Improvement, we performed plan-do-study-act cycles to design, test, and implement high-reliability interventions to decrease time to antibiotics. Nursing, physician, and pharmacy interventions were successfully applied to improve timely antibiotic administration.

Results: The study period was from April 2014 through March of 2017. Through heightened awareness, dedicated roles and responsibilities, a standardized order set specifically used for first fever patients, notification to the pharmacy about newly febrile first fever patients through a dedicated order, the creation of a dedicated sticker ("STAT first dose antibiotic, give directly to nurse") to be printed when antibiotics were entered via the order set in the pharmacy, and prioritization of antibiotic delivery on arrival on the floor, we saw an increase in the percentage of patients receiving antibiotics within 60 minutes of documented fever from a mean of 40% to over 90%. Our mean time for antibiotic administration decreased from 75 to 45 minutes.

Conclusions: Implementation of a standardized process for notifying providers of new fever in patients, prioritization of antibiotic preparation in the central pharmacy, and timely antibiotic order entry resulted in improved times to antibiotic administration in the febrile bone marrow transplant population.
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http://dx.doi.org/10.1542/peds.2017-1549DOI Listing
January 2018

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Biol Blood Marrow Transplant 2018 01 20;24(1):91-95. Epub 2017 Sep 20.

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.007DOI Listing
January 2018