Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children.

2020

5174-5183

2020 Oct 27

2473-9537

<p>Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.</p>

10.1182/bloodadvances.2020002592

Blood Adv

33095872

Distinguishing Multisystem Inflammatory Syndrome in Children From Kawasaki Disease and Benign Inflammatory Illnesses in the SARS-CoV-2 Pandemic.

2020

2020 Sep 22

1535-1815

<p><strong>OBJECTIVE: </strong>The aim of the study was to compare presenting clinical and laboratory features among children meeting the surveillance definition for multisystem inflammatory syndrome in children (MIS-C) across a range of illness severities.</p>

<p><strong>METHODS: </strong>This is a retrospective single-center study of patients younger than 21 years presenting between March 1 and May 15, 2020. Included patients met the Centers for Disease Control and Prevention criteria for MIS-C (inflammation, fever, involvement of 2 organ systems, lack of alternative diagnoses). We defined 3 subgroups by clinical outcomes: (1) critical illness requiring intensive care interventions; (2) patients meeting Kawasaki disease (KD) criteria but not requiring critical care; and (3) mild illness not meeting either criteria. A comparator cohort included patients with KD at our institution during the same time frame in 2019.</p>

<p><strong>RESULTS: </strong>Thirty-three patients were included (5, critical; 8, 2020 KD; 20, mild). The median age for the critical group was 10.9 years (2.7 for 2020 KD; 6.0 for mild, P = 0.033). The critical group had lower median absolute lymphocyte count (850 vs 3005 vs 2940/uL, P = 0.005), platelets (150 vs 361 vs 252 k/uL, P = 0.005), and sodium (129 vs 136 vs 136 mmol/L, P = 0.002), and higher creatinine (0.7 vs 0.2 vs 0.3 mg/dL, P = 0.002). In the critical group, 60% required vasoactive medications, and 40% required mechanical ventilation. Clinical and laboratories features were similar between the 2020 and 2019 KD groups.</p>

<p><strong>CONCLUSIONS: </strong>We describe 3 groups with inflammatory syndromes during the SARS-CoV-2 pandemic. The initial profile of lymphopenia, thrombocytopenia, hyponatremia, and abnormal creatinine may help distinguish critically ill MIS-C patients from classic/atypical KD or more benign acute inflammation.</p>

10.1097/PEC.0000000000002248

Pediatr Emerg Care

32970023

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

2020

e28693

2020 Sep 04

1545-5017

<p>There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.</p>

10.1002/pbc.28693

Pediatr Blood Cancer

32885904

Human Adenovirus 7-Associated Hemophagocytic Lymphohistiocytosis-Like Illness: Clinical and Virological Characteristics in a Cluster of Five Pediatric Cases.

2020

2020 Aug 31

1537-6591

<p><strong>BACKGROUND: </strong>Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation. Children often suffer from primary genetic forms of HLH, which can be triggered by infection. Others suffer from secondary HLH as a complication of infection, malignancy, or rheumatologic disease. Identifying the exact cause of HLH is crucial, as definitive treatment for primary disease is hematopoietic stem cell transplant. Adenoviruses have been associated with HLH but molecular epidemiology data are lacking.</p>

<p><strong>METHODS: </strong>We describe the clinical and virologic characteristics of 5 children admitted with adenovirus infection during 2018-2019 who developed HLH or HLH-like illness. Detailed virologic studies, including virus isolation and comprehensive molecular typing were performed.</p>

<p><strong>RESULTS: </strong>All patients recovered; clinical management varied but included immunomodulating and antiviral therapies. A genetic predisposition for HLH was not identified in any patient. Adenovirus isolates were recovered from 4/5 cases; all were identified as genomic variant 7d. Adenovirus type 7 DNA was detected in the fifth case. Phylogenetic analysis of genome sequences identified two clusters - one related to strains implicated in 2016-2017 outbreaks in Pennsylvania and New Jersey, the other related to a 2009 Chinese strain.</p>

<p><strong>CONCLUSIONS: </strong>It can be challenging to determine whether HLH is the result of an infectious pathogen alone or genetic predisposition triggered by an infection. We describe 5 children from the same center presenting with an HLH-like illness after onset of adenovirus type 7 infection. None of the patients were found to have a genetic predisposition to HLH. These findings suggest that adenovirus 7 infection alone can result in HLH.</p>

10.1093/cid/ciaa1277

Clin. Infect. Dis.

32866230

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

2020

2020 Jul 30

1558-8238

<p><strong>BACKGROUND: </strong>Initial reports from the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to Coronavirus Disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed Multisystem Inflammatory Syndrome in Children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.</p>

<p><strong>METHODS: </strong>We prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data. Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8 and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. Cts and burr cells on blood smears also differentiated between patients with severe COVID-19 and those with MIS-C.</p>

<p><strong>CONCLUSION: </strong>Pediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and severe COVID-19.</p>

10.1172/JCI140970

J. Clin. Invest.

32730233

Partially CD3-depleted unrelated and haploidentical donor PSCT has favorable GVHD and survival rates in pediatric hematologic malignancy.

2019

2019 Nov 22

1523-6536

<p>Most children who may benefit from stem cell transplantation lack matched related donors. Alternative donor transplantations with unrelated (URD) or partially matched related donors (PMRD) carry increased risks of graft-versus-host-disease (GVHD) and mortality compared to matched related donor transplants. We hypothesized a strategy of partial CD3/CD19-depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015 (NCT00579124: https://clinicaltrials.gov/ct2/show/NCT00579124; NCT01071226: https://clinicaltrials.gov/ct2/show/NCT01071226). Two (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced non-relapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 (35.3%) and extensive in 8 (11.7%). Three-year OS was 61.8% (95% CI 50.2 -71.4%) and EFS 52.0% (95% CI 40.3 - 62.4%). Age ≥15 years was associated with decreased OS (p=0.05) and EFS (p=0.05). Relapse was more common in children in second complete remission (p=0.03). Partially CD3-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCTs have had a high ratio of extensive compared to limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study despite similar overall rates of chronic GVHD. Partial T cell-depletion may expand donor options for children with malignant transplant indications lacking matched related donors by mitigating but not eliminating chronic GVHD.</p>

10.1016/j.bbmt.2019.11.022

Biol. Blood Marrow Transplant.

31765697

Tisagenlecleucel for the treatment of B cell acute lymphoblastic leukemia.

2018

2018 Aug 15

1744-8328

<p><strong>INTRODUCTION: </strong>Cure rates for pediatric and young adult patients with refractory or recurrently relapsed acute lymphoblastic leukemia are dismal. Survival from time of relapse is typically measured in weeks to months, and standard chemotherapy and currently approved targeted therapy achieve remission in less than a third of affected patients. To date, the only definitive curative therapy has been allogeneic hematopoietic stem cell transplant (HSCT). Advances in immunotherapy, with the introduction of chimeric antigen receptor T cell therapies and the development of tisagenlecleucel, have changed the landscape. Areas covered: This review will describe the pharmacology of tisagenlecleucel and summarize the clinical evidence for its use in the treatment of multiple-relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Also discussed are other immunotherapies for B-ALL as well as the most commonly-encountered toxicities and corresponding management strategies. Expert commentary: Early phase trials indicate that tisagenlecleucel significantly improves survival for patients with B-ALL that is refractory or in second or later relapse. In responding patients, remissions have been reported on the order of years, and thus, tisagenlecleucel may herald a dramatic shift in the treatment paradigm of this largely fatal disease.</p>

10.1080/14737140.2018.1512411

Expert Rev Anticancer Ther

30111196

Hypofibrinogenemia Is Associated With Poor Outcome and Secondary Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in Pediatric Severe Sepsis.

2018

397-405

2018 May

1529-7535

<p><strong>OBJECTIVES: </strong>Some children with sepsis exhibit a sustained hyperinflammatory response that can trigger secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Although hypofibrinogenemia is a shared feature of sepsis and hemophagocytic lymphohistiocytosis, there are no data about fibrinogen as a biomarker to identify children with sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap. We hypothesized that hypofibrinogenemia is associated with poor outcomes and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome and has utility as a screening biomarker for this sepsis phenotype.</p>

<p><strong>DESIGN: </strong>A retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014.</p>

<p><strong>SETTING: </strong>Emergency department and PICU at a single academic children's hospital.</p>

<p><strong>PATIENTS: </strong>Consecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen &lt; 150 mg/dL) within 7 days of sepsis were compared with a random sample of patients without hypofibrinogenemia using an a priori sample size target of 190. Thirty-eight patients with hypofibrinogenemia were compared with 154 without hypofibrinogenemia.</p>

<p><strong>INTERVENTIONS: </strong>None.</p>

<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>The primary outcome was "complicated course" (composite of 28-d mortality or ≥ two organ failures at 7 d). Secondary outcomes were 28-day mortality and fulfillment of diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. We used Wilcoxon rank-sum, Fisher exact test, and multivariable logistic regression to compare patients with versus without hypofibrinogenemia. Patients with hypofibrinogenemia were more likely to have a complicated course (73.7% vs 29.2%; p &lt; 0.001), 28-day mortality (26.3% vs 7.1%, p = 0.002), and meet diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (21.1% vs 1.3%; p &lt; 0.001). After controlling for confounders, hypofibrinogenemia remained associated with complicated course (adjusted odds ratio, 8.8; 95% CI, 3.5-22.4), mortality (adjusted odds ratio, 6.0; 95% CI, 2.0-18.1), and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (adjusted odds ratio, 27.6; 95% CI, 4.4-173).</p>

<p><strong>CONCLUSIONS: </strong>Hypofibrinogenemia was independently associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome in pediatric sepsis. Measurement of fibrinogen may provide a pragmatic biomarker to identify children with possible sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap for whom further diagnostic testing and consideration of adjunctive immunomodulatory therapies should be considered.</p>

10.1097/PCC.0000000000001507

Pediatr Crit Care Med

29470247

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL).

2018

995-9

2018 Mar

1528-0020

<p>As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.</p>

10.1182/blood-2017-07-794214

Blood

29305553

Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia.

2016

664-79

2016 06

2159-8290

<p><strong>UNLABELLED: </strong>Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill.</p>

<p><strong>SIGNIFICANCE: </strong>CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664-79. ©2016 AACR.See related commentary by Rouce and Heslop, p. 579This article is highlighted in the In This Issue feature, p. 561.</p>

10.1158/2159-8290.CD-16-0040

Cancer Discov

27076371