Matt S. Zinter

Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality

Angiopoietin-2 (Ang-2) is a key mediator of pulmonary vascular permeability. This study tested the association between plasma Ang-2 and mortality in pediatric acute respiratory distress syndrome (ARDS), with stratification for prior hematopoietic cellular transplantation (HCT), given the severe, yet poorly understood, ARDS phenotype of this subgroup. We enrolled 259 children <18 years of age with ARDS; 25 had prior HCT. Plasma Ang-2, von Willebrand Factor antigen (vWF), and vascular endothelial growth factor (VEGF) were measured on ARDS days 1 and 3 and correlated with patient outcomes. Day 1 and day 3 Ang-2 levels were associated with mortality independent of age, sex, race, and P/F ratio [odds ratio (OR) 3.7, 95% CI 1.1-11.5, P = 0.027; and OR 10.2, 95% confidence interval (CI) 2.2-46.5, P = 0.003, for each log10 increase in Ang-2]. vWF was associated with mortality (P = 0.027), but VEGF was not. The association between day 1 Ang-2 and mortality was independent of levels of both vWF and VEGF (OR 3.6, 95% CI 1.1-12.1, P = 0.039, for each log10 increase in Ang-2). 45% of the cohort had a rising Ang-2 between ARDS day 1 and 3 (adjusted mortality OR 3.3, 95% CI 1.2-9.2, P = 0.026). HCT patients with a rising Ang-2 had 70% mortality compared with 13% mortality for those without (OR 16.3, 95% CI 1.3-197.8, P = 0.028). Elevated plasma levels of Ang-2 were associated with mortality independent of vWF and VEGF. A rising Ang-2 between days 1 and 3 was strongly associated with mortality, particularly in pediatric HCT patients, suggesting vulnerability to ongoing endothelial damage.

New Insights Into Multicenter PICU Mortality Among Pediatric Hematopoietic Stem Cell Transplant Patients.

Objectives:Over 2,500 children undergo hematopoietic stem cell transplantation in the United States each year, and up to 35% require PICU support for life-threatening complications. PICU mortality has dropped from 85% to 44%, but interpretation is confounded by significant cohort heterogeneity. Reports conflict regarding outcomes for patients with different underlying hematopoietic stem cell transplantation indications, and the burden of infectious complications for these patients has not been evaluated. We aim to describe infections, critical care interventions, and mortality for pediatric hematopoietic stem cell transplantation patients requiring PICU admission. Design:A retrospective multicenter cohort analysis. Setting:One hundred twelve centers in the Virtual PICU Systems database, January 1, 2009, to June 30, 2012. Patients:A total of 1,782 admissions for patients who are 21 years old or younger with prior hematopoietic stem cell transplantation. Interventions:None. Measurements and Main Results:Pediatric Index of Mortality-2, Pediatric Risk of Mortality-3, transplant indication, infections, interventions, and mortality were recorded from admission through PICU death or discharge. Pediatric hematopoietic stem cell transplantation patients comprised 0.7% of all PICU admissions (1,782/246,346), which resulted in 16.2% mortality compared with 2.4% mortality for non–hematopoietic stem cell transplantation admissions (odds ratio, 7.8; 95% CI, 6.8–8.8; p < 0.001). Mortality for admissions with underlying hematologic malignancy (22.7%) was similar to that of admissions with primary immunodeficiency (19.4%; p = 0.41) but significantly greater than admissions with underlying nonmalignant non–primary immunodeficiency hematologic disease (15.4%; p = 0.020), metabolic disorder (8.1%; p < 0.001), or solid malignancy (5.7%; p < 0.001). Infection was documented in 45.7% of admissions with 22.2% mortality; viral and fungal mortality were 28.5% and 33.7%, respectively. Invasive positive pressure ventilation and renal replacement therapy were used in only 34.6% and 11.9% of admissions, with mortality of 42.5% and 51.9%, respectively. Conclusions:PICU mortality for pediatric hematopoietic stem cell transplantation patients may be as low as 16.2% but higher for those receiving intubation (42.5%) or replacement therapy (51.9%). Hematologic malignancy and primary immunodeficiency had greater risk for mortality than other transplant indications. Greater understanding of other risk factors affecting mortality and the need for critical care support is needed.

Metagenomic Sequencing Detects Respiratory Pathogens in Hematopoietic Cellular Transplant Patients

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A Simple and Robust Bedside Model for Mortality Risk in Pediatric Patients With Acute Respiratory Distress Syndrome

Objectives: Despite declining mortality, acute respiratory distress syndrome is still involved in up to one third of pediatric intensive care deaths. The recently convened Pediatric Acute Lung Injury Consensus Conference has outlined research priorities for the field, which include the need for accurate bedside risk stratification of patients. We aimed to develop a simple yet robust model of mortality risk among pediatric patients with acute respiratory distress syndrome to facilitate the targeted application of high-risk investigational therapies and stratification for enrollment in clinical trials. Design: Prospective, multicenter cohort. Setting: Five academic PICUs. Patients: Three hundred eight children greater than 1 month and less than or equal to 18 years old, admitted to the ICU, with bilateral infiltrates on chest radiograph and PaO2/FIO2 ratio less than 300 in the clinical absence of left atrial hypertension. Interventions: None. Measurements and Main Results: Twenty clinical variables were recorded in the following six categories: demographics, medical history, oxygenation, ventilation, radiographic imaging, and multiple organ dysfunction. Data were measured 0–24 and 48–72 hours after acute respiratory distress syndrome onset (day 1 and 3) and examined for associations with hospital mortality. Among 308 enrolled patients, mortality was 17%. Children with a history of cancer and/or hematopoietic stem cell transplant had higher mortality (47% vs 11%; p < 0.001). Oxygenation index, the PaO2/FIO2 ratio, extrapulmonary organ dysfunction, Pediatric Risk of Mortality-3, and positive cumulative fluid balance were each associated with mortality. Using two statistical approaches, we found that a parsimonious model of mortality risk using only oxygenation index and cancer/hematopoietic stem cell transplant history performed as well as other more complex models that required additional variables. Conclusions: In the PICU, oxygenation index and cancer/hematopoietic stem cell transplant history can be used on acute respiratory distress syndrome day 1 or day 3 to predict hospital mortality without the need for more complex models. These findings may simplify risk assessment for clinical trials, counseling families, and high-risk interventions such as extracorporeal life support.

JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias

While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 (IL7) stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.

Safe and Effective Prophylaxis with Bimonthly Intravenous Pentamidine in the Pediatric Hematopoietic Stem Cell Transplant Population

Background: Without prophylaxis, Pneumocystis jiroveci pneumonia (PCP) develops in 5%–15% of pediatric hematopoietic stem cell transplant (HCT) patients with mortality above 50%. Trimethoprim–sulfamethoxazole is a standard PCP prophylaxis; pentamidine is frequently used as second-line prophylaxis because of trimethoprim–sulfamethoxazole’s potential for cytopenias. Monthly intravenous (IV) pentamidine has variable efficacy with PCP infection rates of 0%–10% in pediatric patients, and higher breakthrough rates in those younger than 2 years. We hypothesized that bimonthly (twice monthly) pentamidine might have equivalent safety and improved efficacy; therefore, we conducted a retrospective analysis of bimonthly pentamidine PCP prophylaxis. Methods: We retrospectively reviewed records of all pediatric HCT patients who received bimonthly IV pentamidine between December 2006 and June 2013, and collected data regarding demographics, clinical course, prophylaxis rationale, laboratory values and adverse events. Results: Between December 2006 and June 2013, 111 pediatric HCT patients received bimonthly IV pentamidine (574 doses, 8758 patient-days); 31 patients were younger than 2 years at initiation. In the majority (53% of courses), pentamidine was initiated because of cytopenias. Fourteen patients (12.6% of patients, 2.4% of doses) experienced a side-effect prompting discontinuation, including 3 patients with infusion-related hypotension/anaphylaxis and 3 with acute pancreatic dysfunction. No patients [0% (95% confidence interval: 0–3.2)] developed PCP during or after bimonthly IV pentamidine prophylaxis. Conclusions: Bimonthly IV pentamidine for PCP prophylaxis in the HCT pediatric population has comparable safety to monthly IV pentamidine and was highly effective, including in the very young. Bimonthly IV pentamidine should be considered in pediatric patients as second-line PCP prophylaxis.

Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome.

Objectives: In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes. Design: Multicenter prospective observational study. Setting: We enrolled patients from five academic PICUs between 2008 and 2015. Patients: Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome. Interventions: Eight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin. Measurements and Main Results: We measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70–0.83] vs 0.70 [0.62–0.77]; p = 0.042). Conclusions: In pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.

Metagenomic Next-Generation Sequencing Detects Pulmonary Pathogens in Hematopoietic Cellular Transplant Patients with Acute Respiratory Illnesses

BACKGROUND Lower respiratory tract infections (LRTI) are a leading cause of mortality in hematopoietic cell transplant (HCT) recipients. Current microbiologic diagnostics often fail to identify etiologic pathogens, leading to diagnostic uncertainty and precluding the implementation of targeted therapies. To directly address the need for improved LRTI diagnostics, we undertook this study to evaluate the potential utility of metagenomic next generation sequencing (mNGS) approaches for detecting LRTI in the HCT population. METHODS We enrolled 22 post-HCT adults ages 19-69 years with acute respiratory illnesses who underwent bronchoalveolar lavage (BAL) at the University of Michigan between January 2012 and May 2013. Unbiased mNGS was performed on BAL fluid to detect microbes and assess host response. Results were compared to those obtained by standard clinical microbiology testing. RESULTS Unbiased mNGS detected all microbes identified by standard testing (human metapneumovirus, respiratory syncytial virus, Stenotrophomonas maltophilia, human herpesvirus 6 and cytomegalovirus). Previously unrecognized LRTI pathogens were identified in six patients for whom standard testing was negative (human coronavirus 229E, human rhinovirus A, Corynebacterium propinquum and Streptococcus mitis) and findings were confirmed by independent PCR testing. mNGS identified microbes of unlikely or uncertain pathogenicity in 10 patients with clinical evidence of non-infectious respiratory conditions. Patients with respiratory pathogens were found to have significantly increased expression of immunity related gene biomarkers relative to those without (p=0.022) as well as lower alpha diversity of their respiratory microbial communities (p=0.017). CONCLUSIONS Compared to conventional diagnostics, host/pathogen mNGS enhanced detection of microbial pathogens in BAL fluid from HCT patients. Furthermore, this approach simultaneously evaluated the association between identified microbes and the expression of innate immunity gene biomarkers. Host/pathogen mNGS holds promise for precision diagnosis of post-HCT respiratory infection.Current microbiologic diagnostics often fail to identify the etiology of lower respiratory tract infections (LRTI) in hematopoietic cellular transplant recipients (HCT), which precludes the implementation of targeted therapies. To address the need for improved LRTI diagnostics, we evaluated the utility of metagenomic next generation sequencing (mNGS) of bronchoalveolar lavage (BAL) to detect microbial pathogens in HCT patients with acute respiratory illnesses. We enrolled 22 post-HCT adults ages 19-69 years with acute respiratory illnesses who underwent BAL at the University of Michigan between January 2012 and May 2013. mNGS was performed on BAL fluid to detect microbes and simultaneously assess the host transcriptional response. Results were compared against conventional microbiologic assays. mNGS demonstrated 100% sensitivity for detecting respiratory microbes (human metapneumovirus, respiratory syncytial virus, Stenotrophomonas maltophilia, human herpesvirus 6 and cytomegalovirus) when compared to standard testing. Previously unrecognized LRTI pathogens were identified in six patients for whom standard testing was negative (human coronavirus 229E, human rhinovirus A, Corynebacterium propinquum and Streptococcus mitis); findings were confirmed by independent PCR and 16S rRNA sequencing. Relative to patients without infection, patients with infection had increased expression of immunity related genes (p=0.022) and significantly lower diversity of their respiratory microbiome (p=0.017). Compared to conventional diagnostics, mNGS enhanced detection of pathogens in BAL fluid from HCT patients. Furthermore, our results suggest that combining unbiased microbial pathogen detection with assessment of host gene biomarkers of immune response may hold promise for enhancing the diagnosis of post-HCT respiratory infections.

Multicenter mortality and morbidity associated with pulmonary hypertension in the pediatric intensive care unit

Despite advances in the diagnosis and management of pediatric pulmonary hypertension (PH), children with PH represent a growing inpatient population with significant morbidity and mortality. To date, no studies have described the clinical characteristics of children with PH in the pediatric intensive care unit (PICU). A retrospective multicenter cohort study of 153 centers in the Virtual PICU Systems database who submitted data between 1 January 2009 and 31 December 2015 was performed. A total of 14,880/670,098 admissions (2.2%) with a diagnosis of PH were identified. Of these, 2190 (14.7%) had primary PH and 12,690 (85.3%) had secondary PH. Mortality for PH admissions was 6.8% compared to 2.3% in those admitted without PH (odds ratio = 3.1; 95% confidence interval = 2.9–3.4). Compared to patients admitted to the PICU without PH, those with PH were younger, had longer length of stay, higher illness severity scores, were more likely to receive invasive mechanical ventilation, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, and more likely to have co-diagnoses of sepsis, heart failure, and respiratory failure. In a multivariate model, factors significantly associated with mortality for children with PH included age < 6 months or > 16 years, invasive mechanical ventilation, and co-diagnoses of heart failure, sepsis, hemoptysis, disseminated intravascular coagulation, stroke, and multi-organ dysfunction syndrome. Despite therapeutic advances, the disease burden and mortality of children with PH remains significant. Further investigation of the risk factors associated with clinical deterioration and mortality in this population could improve the ability to prognosticate and inform clinical decision-making.

A review of pathogens causing lower respiratory tract infection in the pediatric hematopoietic stem cell transplant recipient

Pediatric hematopoietic stem cell transplant recipients are at risk for acquiring a variety of lower respiratory tract infections (LRTI), which result in frequent pediatric intensive care unit admission with high mortality. Recent advances in conditioning regimens, opportunistic infection prophylaxis, diagnostic tools, and treatment modalities have broadly impacted our understanding of LRTI among these vulnerable patients. In this review, the most common bacteria, viruses, and fungi causing LRTI in pediatric hematopoietic stem cell transplant patients are discussed.