Ranjit S Chima

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

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Publications (38)138.95 Total impact


  • No preview · Article · Nov 2015 · Critical care medicine
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    ABSTRACT: Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplant (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity (CH50), and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined inter-individual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n=18) to patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n=11). In the PK analysis, we found significant inter-patient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, were significant determinants of eculizumab clearance and disease response. Sixty one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared to untreated patients (56% versus 9%, p=0.003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinurina. Our eculizumab dosing algorithm, including pre-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
    No preview · Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by vision changes, altered mental status, and seizures typically caused by an acute rise in blood pressure. PRES has been reported after hematopoietic stem cell transplant (HSCT) in association with hypertension from calcineurin inhibitors and corticosteroids. The imaging evaluation of PRES after HSCT in children and young adults has not been well described. We performed a retrospective review of all HSCT recipients presenting to the intensive care unit (ICU) with new neurologic symptoms. A neuroradiologist reviewed all radiologic images and compared CT versus MRI findings indicative of diagnosis of PRES. Alternative imaging diagnoses explaining the patients' symptoms were also recorded. Fifty-four transplant recipients were admitted to the ICU with new neurologic symptoms. Thirty nine percent (21/54) of subjects had imaging findings consistent with PRES, 24% (13/54) had imaging findings consistent with an alternative diagnosis, 9% (5/54) had nonspecific finding and 28% (15/54) had no acute imaging findings. PRES was diagnosed at a median of 49 days (IQR 29-94) after HSCT. The presenting symptom for the majority of patients with PRES was seizures (86%), while 14% presented with acute encephalopathy. Ninety five percent of subjects diagnosed with PRES (20/21) underwent a head CT as their initial imaging evaluation. CT scan was diagnostic of PRES in 40% (8/20). Subsequently 16 patients underwent brain MRI with 12 additional patients being diagnosed with PRES on MRI. The median time elapsed between negative CT and a positive MRI examination was 20 hours (range: 3.6 hours to 9 days). CT scan serves as an excellent screening test for acute pathology such as intracranial hemorrhage, however it lacks sensitivity for the diagnosis of PRES. Patients with clinical symptoms suggestive of PRES who have a negative CT, should be treated appropriately for PRES and should undergo MRI of the brain as soon as clinically stable to confirm the diagnosis. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation

  • No preview · Article · Feb 2015 · Biology of Blood and Marrow Transplantation
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    ABSTRACT: Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.
    No preview · Article · Feb 2015 · Biology of Blood and Marrow Transplantation

  • No preview · Article · Feb 2015 · Biology of Blood and Marrow Transplantation
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    ABSTRACT: Pediatric hospital-acquired venous thromboembolism (VTE) is an increasingly prevalent and morbid disease. A multidisciplinary team at a tertiary children's hospital sought to answer the following clinical question: "Among hospitalized adolescents, does risk assessment and stratified VTE prophylaxis compared with no prophylaxis reduce VTE occurrence without an increase in significant adverse effects?" Serial literature searches using key terms were performed in the following databases: Medline, Cochrane Database, CINAHL (Cumulative Index to Nursing and Allied Health), Scopus, EBMR (Evidence Based Medicine Reviews). Pediatric studies were sought preferentially; when pediatric evidence was sparse, adult studies were included. Abstracts and titles were screened, and relevant full articles were reviewed. Studies were rated for quality using a standard rating system. Moderate evidence exists to support VTE risk assessment in adolescents. This evidence comes from pediatric studies that are primarily retrospective in design. The results of the studies are consistent and cite prominent factors such as immobilization and central venous access. There is insufficient evidence to support specific prophylactic strategies in pediatric patients because available pediatric evidence for thromboprophylaxis efficacy and safety is minimal. There is, however, high-quality, consistent evidence demonstrating efficacy and safety of thromboprophylaxis in adults. On the basis of the best available evidence, we propose a strategy for risk assessment and stratified VTE prophylaxis for hospitalized adolescents. This strategy involves assessing risk factors and considering prophylactic measures based on level of risk. We believe this strategy may reduce risk of VTE and appropriately balances the adverse effect profile of mechanical and pharmacologic prophylactic methods. Copyright © 2015 by the American Academy of Pediatrics.
    No preview · Article · Jan 2015 · Hospital Pediatrics
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    ABSTRACT: Cardiac complications after hematopoietic stem cell transplant (HSCT) can lead to significant morbidity and mortality. Cardiac evaluation during the first 100 days after HSCT is usually performed only if clinically indicated and there are no studies examining if routine screening would be of benefit in this patient population at high risk for tissue injury. We conducted a single center prospective clinical study to screen for cardiac complications in pediatric and young adult patients. One hundred consecutive HSCT patients underwent scheduled echocardiographic screening on day +7 after transplantation, independent of their clinical condition. At least one abnormality was identified in 30% of cases. Seventeen children had a pericardial effusion, 13 elevated right ventricular pressure and 3 reduced left ventricular function. Survival was reduced in children with any echocardiographic abnormality at day 7 (67% vs. 80% in those with and without abnormality, p= 0.073). Moreover, raised right ventricular pressure at day +7 was significantly associated with transplant-associated thrombotic microangiopathy (TA-TMA) (p=0.004), and may indicate early vascular injury in the lungs. These data suggest that echocardiography 7 days after HSCT can detect early cardiac complications of HSCT and may identify early vascular injury associated with TA-TMA.
    No preview · Article · Oct 2014 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    ABSTRACT: Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multi-organ injury and severe cases are associated with poor outcomes after hematopoietic 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 non-relapse mortality (43.6% versus 7.8%, p<0.0001) at 1 year post-HSCT compared to those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30mg/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), while all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (p<0.01). 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.
    Full-text · Article · May 2014 · Blood
  • Katja M Gist · Ranjit S Chima

    No preview · Article · May 2014 · Critical care medicine
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    ABSTRACT: Human metapneumovirus (hMPV) is a relatively recent addition to the multiplicity of viruses causing respiratory illness in infants and children. Although well described in its ability to cause respiratory illness, there is limited data detailing the association of hMPV with neurologic complications. In this report, we describe 2 toddlers with hMPV infection who presented in status epilepticus and went on to develop respiratory failure. Both patients fully recovered over 2 weeks and were discharged from the hospital with no sequelae. The association between hMPV infection and neurologic complications is increasingly being reported in the literature. Clinicians should be aware of these uncommon manifestations of a common respiratory pathogen and consider testing for hMPV when managing pediatric patients who present with unexplained status epilepticus or encephalitis.
    No preview · Article · Feb 2014 · PEDIATRICS
  • Shilpa K. Shah · Sonata Jodele · Stella M. Davies · Ranjit S. Chima
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    ABSTRACT: Hematopoietic stem cell transplantation (SCT) is a therapeutic option for patients with bone marrow failure, certain malignancies and inborn errors of metabolism. Complications requiring intensive care are frequent, and intensivists need to be familiar with the transplantation process and the disorders that are unique to these patients. The transplant process involves the use of high dose chemotherapy or radiation, followed by intravenous infusion of stem cells matched with the recipient at the human leukocyte antigen (HLA) loci. Full recovery of a normal immune system can take a year or more, so following transplantation, patients are exquisitely susceptible to infections. Moreover, complications such as graft versus host disease, idiopathic pneumonia syndrome, sinusoidal obstruction syndrome and transplant associated thrombotic microangiopathy are common in the first hundred days after stem cell infusion. Respiratory failure is a common presentation necessitating intensive care admission and may be due to infectious or non-infectious causes. Mechanical ventilation may be needed along with broad spectrum anti-microbial coverage; corticosteroids are commonly used if graft versus host disease is present. Acute graft versus host disease is most frequent in children receiving grafts from unrelated donors and results in significant morbidity. Increased immunosuppression is the cornerstone of therapy for graft versus host disease, and protection of the children from infection is essential to survival. Sinusoidal obstruction syndrome and transplant associated thrombotic microangiopathy may lead to multiple organ failure with limited therapeutic options, but both disorders can resolve with good supportive care during the period of organ failure. Outcomes for patients who develop multiple organ failure following SCT remain poor despite aggressive supportive care, however, children with failure of a single organ can do well. Integrated multi-disciplinary care between intensivists and transplant physicians, and other specialists such as nephrologists and pulmonologists leads to improved outcomes.
    No preview · Article · Feb 2014
  • Ranjit S. Chima · Dawn Pinchasik · Cristina Tarango
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    ABSTRACT: The burden of thromboembolic disease in hospitalized children appears to be increasing. This is likely a reflection of increased survival of children with complex medical problems with increased utilization of invasive procedures and central venous catheters. Infants and teenagers appear to be at the highest risk for thromboembolic disease due to age-associated changes in the hemostatic system. Venous thromboembolism in the PICU usually presents as deep vein thrombosis and requires a high index of suspicion for diagnosis; pulmonary embolism may occur as a consequence. Numerous inherited and acquired risk factors are associated with venous thrombosis in children, notably the use of central venous catheters and the presence of underlying diseases such as trauma, malignancy, congenital heart disease and congenital thrombophilic disorders. Radiologic studies are needed to make the diagnosis of venous thromboembolism, and evaluation for underlying thrombophilia should be considered. Anticoagulation is the mainstay of treatment for venous thrombosis and pulmonary embolism in children, while systemic or site-directed thrombolysis is reserved for life or limb threatening thrombosis. Management strategies and duration of anticoagulation therapy are extrapolated from adult data. While the role of thromboprophylaxis remains unclear in critically ill children, its use in high risk patients should be considered. Long term outcomes are not known, however recurrent thromboembolism and post thrombotic syndrome are known complications of venous thrombosis in children.
    No preview · Chapter · Feb 2014
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    ABSTRACT: The insulin sensitizing thiazolidinedione drugs, rosiglitazone and pioglitazone are specific peroxisome proliferator-activated receptor-gamma agonists and reduce pro-inflammatory responses in patients with type 2 diabetes and coronary artery disease, and may be beneficial in sepsis. Sepsis was induced in 8-10-wk-old C57BL/6 mice by cecal ligation and puncture (CLP) with a 22 -g double puncture technique. Mice received an i.p. injection of vehicle (DMSO:PBS) or pioglitazone (20 mg/kg) at 1 h and 6 h after CLP, and were sacrificed at various time points. In sepsis, vehicle-treated mice had hypoglycemia, increased lung injury and increased lung neutrophil infiltration. Pro-inflammatory plasma cytokines were increased, but the plasma adipokine, adiponectin, was decreased in vehicle-treated septic mice. This corresponded with inhibitor κB (IκBα) protein degradation and an increase in NF-κB activity in lung. Pioglitazone treatment improved plasma Glc and adiponectin levels, and decreased pro-inflammatory cytokines. Lung IκBα protein expression increased and corresponded with a decrease in NF-κB activity in the lung from pioglitazone-treated mice. Pioglitazone reduces the inflammatory response in polymicrobial sepsis in part through inhibition of NF-κB and may be a novel therapy in sepsis.
    No preview · Article · Sep 2013 · Innate Immunity
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    ABSTRACT: Pulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Given its non-specific clinical presentation it is likely that this clinical entity is under diagnosed after HSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients is minimal. Physicians caring for HSCT recipients should be aware of this severe post-transplant complication since timely diagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinical presentation, diagnosis and management of PH in HSCT recipients.
    Preview · Article · Jul 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation

  • No preview · Article · Jun 2013 · Pediatric Blood & Cancer
  • Ranjit S Chima · Kamal Abulebda · Sonata Jodele
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    ABSTRACT: Hematopoietic stem cell transplant (SCT) remains a curative option for a variety of malignant and non-malignant disorders in children. Following transplant a proportion of SCT recipients become critically ill and need intensive care. Critical illness may occur in the setting of transplant complications such as graft versus host disease (GVHD), idiopathic pneumonia syndrome (IPS), veno-occlusive disease (VOD) and transplant associated thrombotic microangiopathy (TA-TMA). Hence, familiarity with recent advances in the transplant process and complications is crucial for the intensivist. This article will highlight common complications encountered in the critically ill SCT recipient.
    No preview · Article · Jun 2013 · Pediatric Clinics of North America
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    ABSTRACT: Deep venous thrombosis (DVT) is being increasingly recognized as a significant issue in children. Despite the low incidence of DVT, the risks of pulmonary embolism and death in children are significant. Post-thrombotic syndrome, a syndrome of chronic venous insufficiency, can have long-term adverse consequences in children and adolescents. Adult studies have shown that catheter-directed therapy can reduce the incidence of post-thrombotic syndrome. Safety of catheter-directed therapy in adolescents has also been demonstrated. These reasons compelled us to institute a pediatric endovascular thrombolysis program at our institute for management of pediatric DVT. We describe the process of developing a multi-disciplinary thrombolysis program involving interventional radiology (pediatric and adult), pediatric hematology, critical care, anesthesia and vascular surgery, and describe the role of each specialty in the development of the program. We also describe our experience with patient selection, endovascular therapy procedure, pre-, intra- and post-procedure monitoring, and follow-up management for endovascular therapy for DVT.
    No preview · Article · Mar 2013 · Pediatric Radiology
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    Full-text · Article · Feb 2013 · Biology of Blood and Marrow Transplantation
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is rarely included in the differential diagnosis of cardiorespiratory failure after pediatric hematopoietic stem cell transplant (HSCT) as the clinical presentation is nonspecific and may mimic other etiologies. The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion. We describe 5 children diagnosed with PAH after allogeneic HSCT. All 5 patients had prolonged clinical signs of transplantation-associated thrombotic microangiopathy (TA-TMA) when they presented with hypoxemic respiratory failure and evidence of PAH. Four of the 5 patients had echocardiographic evidence of PAH and 1 patient was diagnosed with PAH only on autopsy. PAH was diagnosed a median of 76 days (range, 56-101 days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy. Three of the 4 deceased patients had an autopsy performed demonstrating severe pulmonary vascular disease consistent with TA-TMA and severe PAH. We conclude that TA-TMA can be associated with significant pulmonary vascular injury presenting as hypoxemic respiratory failure with PAH after HSCT. Pediatric patients with unexplained hypoxemia after HSCT should be evaluated for both transplantation complications, TA-TMA, and PAH, accordingly.
    Preview · Article · Sep 2012 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation