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Cell Versus Cytokine - Directed Therapies for Hemophagocytic Lymphohistiocytosis (HLH) in Inborn Errors of Immunity.

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous hyperinflammatory syndrome with different pathways of pathogenesis resulting in similar clinical presentations. It is best defined and understood if presenting in the context of genetic immunodeficiencies associated with defects of lymphocyte cytotoxicity. In these "primary" forms of HLH, cellular and soluble immune effectors are relatively well characterized. While etoposide-based broad cell-directed therapies remain standard of care, more specific therapies targeting these effectors individually are increasingly available. Anti-CD52 as a cell-directed therapy and anti-IFN-gamma, IL-18BP, and JAK-inhibition as cytokine-directed therapies are expected to broaden the therapeutic options, but the precise role of these drugs in first-line and rescue treatment indications remains to be defined. A number of additional inborn errors of immunity are associated with episodes of immune activation fulfilling the clinical criteria of HLH. Impaired pathogen control is a key driver of hyperinflammation in some conditions, while others are characterized by a strong autoinflammatory component. This heterogeneity of disease-driving factors and the variable severity in disease progression in these conditions do not allow a simple adaptation of protocols established for "primary" HLH to HLH in the context of other inborn errors of immunity. Cytokine-directed therapies hold significant promise in these increasingly recognized disorders.

SUBMITTER: Wegehaupt O

PROVIDER: S-EPMC7225316 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cell Versus Cytokine - Directed Therapies for Hemophagocytic Lymphohistiocytosis (HLH) in Inborn Errors of Immunity.

Wegehaupt Oliver O Wustrau Katharina K Lehmberg Kai K Ehl Stephan S

Frontiers in immunology 20200508

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous hyperinflammatory syndrome with different pathways of pathogenesis resulting in similar clinical presentations. It is best defined and understood if presenting in the context of genetic immunodeficiencies associated with defects of lymphocyte cytotoxicity. In these "primary" forms of HLH, cellular and soluble immune effectors are relatively well characterized. While etoposide-based broad cell-directed therapies remain standard of care, ...[more]

PMID: 32457750

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Project description:BackgroundHemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied.ObjectiveThis systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management.MethodsA systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria.ResultsA comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups.ConclusionA comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Project description:Inborn errors of immunity (IEIs) are a heterogeneous group of inherited disorders of the immune system. Many IEIs have a severe clinical phenotype that results in progressive morbidity and premature mortality. Over 450 IEIs have been described and the incidence of all IEIs is 1/1,000–10,000 people. Current treatment options are unsatisfactory for many IEIs. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative but requires the availability of a suitable donor and carries a risk of graft failure, graft rejection and graft-versus-host disease (GvHD). Autologous gene therapy (GT) offers a cure whilst abrogating the immunological complications of alloHSCT. Gene editing (GE) technologies allow the precise modification of an organisms’ DNA at a base-pair level. In the context of genetic disease, this enables correction of genetic defects whilst preserving the endogenous gene control machinery. Gene editing technologies have the potential to transform the treatment landscape of IEIs. In contrast to gene addition techniques, gene editing using the CRISPR system repairs or replaces the mutation in the DNA. Many IEIs are limited to the lymphoid compartment and may be amenable to T cell correction alone (rather than haematopoietic stem cells). T cell Gene editing has the advantages of higher editing efficiencies, reduced risk of deleterious off-target edits in terminally differentiated cells and less toxic conditioning required for engraftment of lymphocytes. Although most T cells lack the self-renewing property of HSCs, a population of T cells, the T stem cell memory compartment has long-term multipotent and self-renewal capacity. Gene edited T cell therapies for IEIs are currently in development and may offer a less-toxic curative therapy to patients affected by certain IEIs. In this review, we discuss the history of T cell gene therapy, developments in T cell gene editing cellular therapies before detailing exciting pre-clinical studies that demonstrate gene editing T cell therapies as a proof-of-concept for several IEIs.

Project description:This study aimed to compare the serum levels of 34 cytokines of children with hemophagocytic lymphohistiocytosis (HLH) and explored the specific cytokine pattern of HLH subtypes and the relationship between cytokine levels and prognosis. This retrospective study assessed the clinical data and cytokine levels of newly diagnosed children with HLH in Beijing Children's Hospital, Capital Medical University, from January 2017 to December 2021. A total of 101 children were enrolled in the study. The levels of IFN-γ and IL-18 increased in more than 90% of patients, and MIP-1α, SDF-1α, IP-10, IL-6, IL-8, IL-10, IL-1 RA, and TNF-α increased at different levels in more than 50% of patients. The levels of IL-10 in EBV-HLH increased significantly, followed by IFN-γ and IL-18, while IL-10 and IFN-γ in CAEBV-HLH had a slight increase. Except for IL-10, the levels of IL-6, Eotaxin, IL-13, IL-18, IFN-γ, and MIP-1β in Rh-HLH increased significantly. F-HLH had significantly high IL-10 levels and a slight increase in IL-13. We showed that various cytokines could assist in differentiating HLH subtypes with ROC curve analysis. When IL-10/IL-6 was 1.37, the sensitivity and specificity of diagnosing EBV-HLH were higher than 80% (AUC = 0.837, p < 0.001). The effect of cytokine ratio on classifying HLH subtypes (17/22, 77.3%) was more significant than the single cytokine (5/22, 22.7%). The 3-year overall survival (OS) rate of children with F-HLH was the lowest during the follow-up. The 3-year OS of patients with EBV-HLH and CAEBV-HLH was significantly higher than that with F-HLH (88.1% ± 5.0% vs. 94.1% ± 5.7% vs. 57.1% ± 14.6%, p = 0.017). Cox proportional hazards model revealed that elevated GM-CSF and MCP-1, as well as CNS involvement, were independent risk factors for poor outcomes for patients with HLH. Various cytokines play important roles in HLH. Different subtypes of HLH have their specific cytokines pattern, and the ratio of cytokines may be more significant in differentiating HLH subtypes than the single one. Elevated GM-CSF and MCP-1 could be useful biomarkers for a poor prognosis for patients with HLH.

Project description:BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare though often fatal hyperinflammatory syndrome mimicking sepsis in the critically ill. Diagnosis relies on the HLH-2004 criteria and HScore, both of which have been developed in pediatric or adult non-critically ill patients, respectively. Therefore, we aimed to determine the sensitivity and specificity of HLH-2004 criteria and HScore in a cohort of adult critically ill patients.MethodsIn this further analysis of a retrospective observational study, patients ≥ 18 years admitted to at least one adult ICU at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with hyperferritinemia of ≥ 500 μg/L were included. Patients' charts were reviewed for clinically diagnosed or suspected HLH. Receiver operating characteristics (ROC) analysis was performed to determine prediction accuracy.ResultsIn total, 2623 patients with hyperferritinemia were included, of whom 40 patients had HLH. We found the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria (95.0% sensitivity and 93.6% specificity) and HScore cutoff of 168 (100% sensitivity and 94.1% specificity). By adjusting HLH-2004 criteria cutoffs of both hyperferritinemia to 3000 μg/L and fever to 38.2 °C, sensitivity and specificity increased to 97.5% and 96.1%, respectively. Both a higher number of fulfilled HLH-2004 criteria [OR 1.513 (95% CI 1.372-1.667); p < 0.001] and a higher HScore [OR 1.011 (95% CI 1.009-1.013); p < 0.001] were significantly associated with in-hospital mortality.ConclusionsAn HScore cutoff of 168 revealed a sensitivity of 100% and a specificity of 94.1%, thereby providing slightly superior diagnostic accuracy compared to HLH-2004 criteria. Both HLH-2004 criteria and HScore proved to be of good diagnostic accuracy and consequently might be used for HLH diagnosis in critically ill patients.Clinical trial registrationThe study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Project description:BackgroundEpstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common subtype of HLH with heterogeneous clinical presentations from self-limited to death, of which adults are worse than children.ObjectiveTo establish predictors of mortality risk in adult EBV-HLH patients for timely and appropriate treatment.MethodsPatients with confirmed EBV-HLH admitted to Beijing Friendship Hospital from January 2015 to December 2019 were enrolled and statistical analysis of their laboratory test results was performed.ResultsAmong 246 adult patients with EBV-HLH, the deceased were older (p < 0.05), with fewer blood cells (p < 0.05), poorer renal function (p < 0.01), higher levels of procalcitonin (PCT) (p < 0.01), as well as soluble interleukin-2 receptor (sCD25) (p < 0.01). The overall median survival time of patients was 135 days, 87 days for patients without transplantation and 294 days with transplantation (p < 0.001). A combined index of sCD25, PCT, and estimated glomerular filtration rate (eGFR) was obtained to predict prognosis, named the Improved HLH index (IH index), and patients were divided into three groups meeting IH- (i.e. sCD25 ≤ 18,000 pg/mL, PCT ≤ 1.8 ng/mL, eGFR ≥ 90 mL/min/1.73m2), IH1+ (i.e. only sCD25 > 18,000 pg/mL or only eGFR < 90 mL/min/1.73m2), and IH2+ (i.e. the rest), respectively. In patients with the HScore ≥ 169 or meeting HLH-04, those meeting IH2+ had significantly worse prognoses than those who met IH1+ or IH- (p < 0.001). In the group meeting IH + or IH2+, patients who received allo-HSCT had better prognoses than those who did not (p < 0.05), but there was still a significant difference in prognosis among the three groups in transplanted patients (p < 0.001).ConclusionThe IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.KEY MESSAGESA combined index of sCD25, PCT, and eGFR was obtained to predict prognosis, named the Improved Hemophagocytic Lymphohistiocytosis index (IH index).IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.

Project description:We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101.

Dataset Information

Cell Versus Cytokine - Directed Therapies for Hemophagocytic Lymphohistiocytosis (HLH) in Inborn Errors of Immunity.

Publications

Cell Versus Cytokine - Directed Therapies for Hemophagocytic Lymphohistiocytosis (HLH) in Inborn Errors of Immunity.

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