scholarly journals Hyperglycemia Requiring Insulin Among Pediatric Patients Diagnosed With Hemophagocytic Lymphohistiocytosis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A451-A452
Author(s):  
Cintya Schweisberger ◽  
Nila Palaniappan ◽  
Nicole Wood ◽  
Lauren Amos ◽  
Kelsee Halpin
Keyword(s):  
Parenteral Nutrition ◽  
Insulin Therapy ◽  
T Cell Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Retrospective Chart Review ◽  
Regular Insulin ◽  
Severe Illness ◽  
Subcutaneous Insulin ◽  
Laboratory Findings

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder marked by massive cytokine release due to macrophage and T-cell activation. Hallmarks of the diagnosis include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogemia, and elevations in ferritin and soluble IL-2 receptor. Given HLH is associated with critical illness, elevation in inflammatory markers, and treated with glucocorticoids, the development of hyperglycemia during its course is not unexpected. However, detailed descriptions of the severity of hyperglycemia and strategies in insulin management among HLH patients are lacking. We describe 10 years’ experience at a single tertiary pediatric health center with HLH patients who developed insulin dependent hyperglycemia. Objectives: To describe the demographics, clinical and laboratory findings, treatment regimens, and outcomes for children with HLH treated with insulin due to hyperglycemia. Study Design: Retrospective chart review from 2010 through 2019 of youth 0 to 21 years of age who required insulin therapy during or shortly after a hospitalization where they were diagnosed with HLH using established criteria. Descriptive statistics were used to characterize the population of interest. Results: Of 30 patients diagnosed with HLH, 33% (n=10) required insulin therapy. Half (n=5) were female and half (n=5) male. The mean age was 8.4 years (7.8 months - 17 years). The majority (80%) were non-Hispanic white. Mean BMI at admission was 53rd percentile (5th - 87th percentile). Max serum glucose ranged from 267 to 725 mg/dL (mean 421 mg/dL). Marked inflammation was present (max CRP 2.6 - 44.9 mg/dL, max ferritin 1,091 - 90,219 ng/mL). All were treated with dexamethasone, doses ranging from 5 to 11 mg/m2/day and duration from 2 to 70 days. Most (90%) received parenteral nutrition (PN) with a mean max GIR of 8 mg/kg/min (SD=2.7). Intravenous infusions of regular insulin were used in 80% of patients, though 2 patients were later transitioned to long and short acting subcutaneous insulin. Mean duration of IV insulin therapy was 9.5 days (2–24 days); however, 2 patients died while on IV insulin therapy. The majority (70%) needed insulin within 5 days of starting steroids. Two patients (20%) were treated with subcutaneous insulin only (no IV). Only 1 patient was discharged home on insulin therapy. Mean hospital stay was 60 days (10–202 days). Mortality was 50% (n=5). Conclusions: One-third of pediatric HLH patients required insulin during their hospitalization for severe hyperglycemia likely secondary to multiple factors including glucocorticoid use, parenteral nutrition, inflammation, and severe illness. Insulin is typically started within 5 days of initiating steroid therapy, limited to IV infusions, and often is not needed by the time of discharge. Risk of mortality is very high.

scholarly journals SAT-LB93 Rapid Reduction of Insulin Requirement in a Hyperglycemic Patient Treated for Hemophagocytic Lymphohistiocytosis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Cintya Schweisberger ◽  
Lauren Amos ◽  
Nicole Wood ◽  
Kelsee Halpin
Keyword(s):  
Insulin Resistance ◽  
Insulin Therapy ◽  
T Cell Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Ferritin Level ◽  
Cytokine Release ◽  
Rapid Reduction ◽  
Post Transplant ◽  
Insulin Requirements

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is life-threatening disorder of immune dysregulation involving macrophage and T-cell activation resulting in massive cytokine release causing multi-organ dysfunction. Similar release of cytokine products from fat tissue is associated with obesity-related insulin resistance. Our case presentation is an example of HLH and insulin resistance, two conditions with overlapping pathophysiology, occurring simultaneously. Clinical Presentation: A 17-year-old male, with no history of hyperglycemia, underwent renal transplant due dysplastic kidneys. He received 500mg IV methylprednisolone during surgery followed by a prednisone taper starting at 70mg daily. Serum glucoses post-transplant ranged from 97 to 129 mg/dL. Three weeks post-transplant he was admitted for fever and dehydration. BMI on admission was the 85th percentile. Serum glucose was 371 mg/dL without ketosis. He started on insulin therapy, requiring 60 units per day (0.8 units/kg). It was suspected his new-onset diabetes was due to his immunosuppressant regimen (prednisone 50mg daily, tacrolimus) and/or acute illness. With persistent fevers and negative infectious workup, there was concern for HLH. The diagnosed was confirmed with ferritin level of 65,962 ng/mL (27-265), hemoglobin 6.5 gm/dL, platelets 88,000, triglycerides 765 mg/dL, soluble IL-2 receptor 2,717 u/mL (45 - 1,105). For HLH treatment, he received methylprednisolone 800 mg daily x 3 doses. During this time his insulin requirements increased to 188 units per day (3.6 units/kg). He was transitioned to dexamethasone 20mg daily. His insulin requirements increased over the next 72 hours to 388 units per day (5.2 units/kg). He was found to be positive for Ehrlichiosis, a known precipitant of HLH. Doxycycline therapy was initiated for a 14 day course. One week into his doxycycline course his ferritin had decreased to 999 ng/mL. He remained on dexamethasone 20 mg daily but developed severe hypoglycemia to 29 mg/dL with altered mental status. All insulin therapy was held. Fasting glucoses over the next 4 days ranged from 94-154 mg/dL and post-prandial glucoses 116-288 mg/dL. He discharged home with only short acting insulin for glucoses above 250 mg/dL, which he did not require. Case Lessons: Cytokine release from macrophages is implicated in the pathology of both HLH and insulin resistance associated with obesity. Glucocorticoids used to treat HLH can also exacerbate insulin resistance. Providers should be aware of the risk of hyperglycemia and large insulin requirements in patients with HLH, and the potential for rapid reduction of insulin needs as HLH is successfully treated.

Excessive Anti-Viral CD8 T Cell Activation Inverts the IL-2 Consumptive Hierarchy Triggering Regulatory T Cell Collapse in Mouse Model for Hemophagocytic Lymphohistiocytosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1025-1025
Author(s):  
Stephanie Humblet-Baron ◽  
Dean Franckaert ◽  
Simon Bornschein ◽  
Bénédicte Cauwe ◽  
Susann Schonefeldt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Life Threatening ◽  
Deficient Mice

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8+ T cell activation. HLH occurs in both acquired and familial (FHL) forms, with mutations in Perforin being a common cause of FHL. In both conditions a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent advances using experimental FHL triggered by lymphocytic choriomeningitis virus (LCMV) in Perforin-deficient mice have attributed the key distal event to be excessive IFNγ production, however the proximal events driving immune dysregulation have remained undefined. We investigated the role of regulatory T cells (Tregs) in the pathophysiology of experimental FHL. While we found no primary Treg defects in Perforin-deficient mice, Treg numbers collapsed following LCMV inoculation. The collapse of Treg numbers in LCMV-triggered Perforin-deficient, but not wildtype, mice was driven by the combination of lower IL-2 secretion by conventional CD4+ T cells, increased IL-2 consumption by activated CD8+ T cells and secretion of competitive sCD25 (IL-2 receptor). Together, these data demonstrate that excessive CD8+ T cell activation rewires the IL-2 homeostatic network away from Treg maintenance and towards feed-forward inflammation. In addition, reduced Treg number may contribute to the massive inflammation found in FHL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Blood ◽  
2019 ◽  
Vol 134 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Sabrin Albeituni ◽  
Katherine C. Verbist ◽  
Paige E. Tedrick ◽  
Heather Tillman ◽  
Jennifer Picarsic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Proinflammatory Cytokines ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Interferon Γ ◽  
Lymphocytic Choriomeningitis ◽  
Dependent Manner ◽  
Ifn Γ

Abstract Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-γ (IFN-γ). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1−/−) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-γ, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-γ signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-γ–neutralizing antibody (αIFN-γ) in 2 murine HLH models. In both models, ruxolitinib and αIFN-γ reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-γ–dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-γ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1−/− mice exhibited enhanced survival compared with mice in which αIFN-γ was discontinued. This protective effect could be mimicked by transient treatment with αIFN-γ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-γ–dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.

scholarly journals The Role of Soluble Interleukin-2 Receptor (sIL-2r) in Diagnosis of Adult Hemophagocytic Lymphohistiocytosis (HLH): A Single Center Retrospective Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 999-999
Author(s):  
Anna Hayden ◽  
Molly Lin ◽  
Sujin Park ◽  
Andre Mattman ◽  
Morris Pudek ◽  
...  
Keyword(s):  
Retrospective Study ◽  
T Cell ◽  
Disease Activity ◽  
T Cell Activation ◽  
Immune Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Interleukin 2 Receptor ◽  
Soluble Interleukin 2 Receptor

Abstract Purpose: Serum soluble interleukin-2 receptor (sIL-2r) is considered an important disease marker in hemophagocytic lymphohistiocytosis (HLH). High levels of sIL2r are indicative of T-cell activation, and sIL2r > 2400 U/mL was 93% sensitive and 100% specific for pediatric HLH in the HLH-2004 diagnostic criteria. [1] There are no published data on its performance characteristics in adults and very limited data in children. [2] We conducted a retrospective study to examine the diagnostic sensitivity and specificity of sIL-2r in diagnosing HPS/HLH, to assess how it varies with disease severity, determine its prognostic significance and ability to discriminate between subgroups of HPS/HLH. Methods: Retrospective data was collected on adult patients with at least one sIL-2r level at Vancouver General Hospital in Vancouver, Canada between March 2012 and April 2017. Patients were subdivided into HLH and non-HLH groups. Sensitivity, specificity, prognosis associated with sIL-2r >10,000U/ml, utility as a marker of disease activity and mean sIL-2r between subgroups of HLH were evaluated. Non-HLH patients did not have convincing evidence to suggest HLH and did not receive HLH-specific therapy. Serum sIL-2r levels were enzyme-linked immunosorbent assay (ELISA; Siemens IMMULITE Immunoassay platform, adult reference range 241-846 U/ml). Results: 81 patients were included, 41 with HLH and 40 with an alternate diagnosis (non-HLH). Non-HLH diagnoses included sepsis, histiocyte disorders, multiple transfusions, liver disease, cardiac disease, autoimmune disease/vasculitis, and other inflammatory diseases. The sensitivity of sIL-2r >2400 U/ml was 93% (95% CI 0.79 - 0.98) and specificity 63% (95% CI 0.46 - 0.77). Specificity improved to 93% (95% CI 0.79 - 0.98) with a threshold of sIL-2r >10,000U/ml. Based on ROC curves, sIL2r is a good diagnostic test (AUC of 0.86) with a threshold that optimizes sensitivity and specificity of 2785U/ml and ferritin is a fair test (AUC 0.78) with an optimal threshold of 5775 ug/L. Similar to ferritin, sIL-2r levels correlated with disease activity in seven HLH patients that had multiple sIL-2r levels drawn during their disease course. Within the HLH group, sIL-2r >10,000U/ml was not associated with worse prognosis. Higher sIL-2r levels were seen in malignancy associated HLH (MAHS) as compared to infection associated HLH (IAHS) and macrophage activation syndrome (MAS). Conclusion: sIL-2r >2,400U/ml is a sensitive test for diagnosis of adult HPS/HLH and has utility in monitoring disease activity. At higher levels (sIL-2r >10,000U/ml), this biomarker loses sensitivity but gains specificity in diagnosing HPS/HLH. Higher sIL-2r levels may indicate MAHS when the underlying etiology is unclear. In adults, secondary HPS/HLH is much more common than primary HLH, and all patients in this study were presumed to be secondary. The defining features of secondary HPS/HLH are pathologic immune activation and hypercytokinemia leading to end organ damage. SIL-2r is elevated in numerous conditions associated with T-cell activation and inflammation, such as lymphoma and autoimmune lymphoproliferative syndrome (ALPS), and larger prospective studies of adults with these and other conditions are needed to better define the specificity of increased sIL-2r for HPS/HLH. Since adult secondary HPS/HLH is increasingly diagnosed and treated in many centers, diagnostic criteria for adult secondary HPS/HLH should incorporate markers of hypercytokinemia and immune activation. References: 1. Janka, G.E. and E.M. Schneider, Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol, 2004. 124(1): p. 4-14. 2. Lin, M., et al., Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review. Ann Hematol, 2017. 96(8): p. 1241-1251. Disclosures No relevant conflicts of interest to declare.

scholarly journals T cell-Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis (HLH) occurs in Non-Asians and is associated with a T cell activation state that is comparable to primary HLH

2021 ◽  
Author(s):  
Oded Shamriz ◽  
Deepak Kumar ◽  
Jenny Shim ◽  
Michael Briones ◽  
Maa-Ohui Quarmyne ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Severity ◽  
T Cell Activation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Barr Virus ◽  
Epstein Barr

Abstract PurposeT cell-Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of this disease is limited and literature regarding prevalence in North America is scarce. Herein, we summarize our experience. MethodsA retrospective analysis of T cell-EBV-HLH patients admitted to Children's Healthcare of Atlanta (GA, USA) from 2010-2020 was conducted. Additional immune studies were completed in a subset of patients. ResultsWe report 15 patients (10 months-19 years of age) diagnosed with T cell-EBV-HLH. Nine patients were Hispanic and the majority without primary HLH (p-HLH) gene defects. Soluble interleukin-2 receptor levels in T cell-EBV-HLH were significantly higher than other forms of secondary-HLH but comparable to p-HLH, and it correlated with disease severity at presentation. Natural-Killer cell function was decreased in most patients despite a negative workup for p-HLH. Depending on disease severity, initial therapy included dexamethasone or dexamethasone and etoposide. Refractory patients were managed with blended regimens that included one or more of these therapies - combination chemotherapy, alemtuzumab, emapalumab and nivolumab. Rituximab did not appreciably decrease EBV viremia in most patients. Alemtuzumab resulted in inflammation flare in 2 of the 3 patients. Two patients underwent allogeneic hematopoietic cell transplantation, with disease relapse noted in one. At a median follow-up of 3 years, 10 of the 15 patients are alive.ConclusionT cell-EBV-HLH occurs in the US among the non-Asian population, especially in those who are Hispanic. The amplitude of T cell activation noted in T cell-EBV-HLH is comparable to p-HLH.

T cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis

Blood ◽  
2020 ◽  
Author(s):  
Vandana Chaturvedi ◽  
Rebecca A Marsh ◽  
Adi Zoref Lorenz ◽  
Erika Owsley ◽  
Vijaya Chaturvedi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Cytokine Storm ◽  
Activated T Cells ◽  
Suspected Infection ◽  
Early Sepsis

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation which has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. While clinical similarities between these syndromes suggests similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38high/HLADR+ effector cells, with activation of CD8+ T cells being most pronounced. Activated T cells were polarized towards Tc1/Th1 differentiation, were proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38high/HLADR+ cells among CD8+ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T cell activation while sepsis is not, and that these two syndromes can be readily distinguished by T cell phenotypes.

scholarly journals Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients

2021 ◽  
Vol 17 (9) ◽  
pp. e1009804
Author(s):  
Jonathan Youngs ◽  
Nicholas M. Provine ◽  
Nicholas Lim ◽  
Hannah R. Sharpe ◽  
Ali Amini ◽  
...  
Keyword(s):  
T Cell ◽  
Critically Ill ◽  
T Cell Activation ◽  
Critically Ill Patients ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Severe Illness ◽  
Γδt Cells ◽  
Depth Analysis ◽  
Mait Cell

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49–14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08–18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

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