A case series of endemic infections associated hemophagocytic lymphohistiocytosis (HLH) mimicking severe sepsis syndrome.
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ABSTRACT:
SUBMITTER: Kollipara V
PROVIDER: S-EPMC6529707 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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A case series of endemic infections associated hemophagocytic lymphohistiocytosis (HLH) mimicking severe sepsis syndrome.
Kollipara Venkateswara V Hussain Shahzad S Franco-Palacios Domingo D Sofi Umar U
Respiratory medicine case reports 20190514
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Project description:ObjectivesSome 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.DesignA retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014.SettingEmergency department and PICU at a single academic children's hospital.PatientsConsecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen < 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.InterventionsNone.Measurements and main resultsThe 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 < 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 < 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).ConclusionsHypofibrinogenemia 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.
| S-EPMC9630256 | biostudies-literature
Project description:Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. First-line therapeutic regimens directed against activated immune cells or secreted cytokines show limited efficacy since they do not target the underlying immunological problem: defective lymphocyte cytotoxicity causing prolonged immune stimulation. A potential rescue strategy would be the adoptive transfer of ex vivo gene-corrected autologous T cells. However, transfusion of cytotoxicity-competent T cells under conditions of hyperinflammation may cause more harm than benefit. As a proof-of-concept for adoptive T cell therapy (ATCT) under hyperinflammatory conditions, we transferred syngeneic, cytotoxicity-competent T cells into mice with virally triggered active primary HLH. ATCT with functional syngeneic trigger-specific T cells cured Jinx mice from active HLH without life-threatening side effects and protected Perforin-deficient mice from lethal HLH progression by reconstituting cytotoxicity. Cured mice were protected long-term from HLH relapses. A threshold frequency of transferred T cells with functional differentiation was identified as a predictive biomarker for long-term survival. This study is the first proof-of-concept for ATCT in active HLH.
| S-EPMC9728053 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis is a clinic pathologic entity characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. It is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent. HPS may be primary, or secondary to malignancy, infections, auto-immune diseases, and pharmacotherapy. HPS is a rare, but life-threatening complication. Herein, we described a female patient with HPS with secondary sepsis. Our objective was to raise the importance of early diagnosis of HFS by presenting a representative case.
| S-EPMC4502496 | biostudies-literature
Project description:PurposeGATA2 deficiency is an autosomal dominant disease that manifests with a range of clinical symptoms, including increased susceptibility to viral, bacterial, and fungal infections. Furthermore, the increased susceptibility to infections in GATA2 deficiency can trigger hemophagocytic lymphohistiocytosis (HLH) in these patients. Our systematic review evaluates reported cases of GATA2 deficiency and HLH in the literature.MethodsA systematic review of case reports was conducted following PRISMA 2020 guidelines, encompassing studies retrieved from Ovid MEDLINE ALL, Embase via Ovid SP, Scopus, Web of Science, and Google Scholar from inception until June 14, 2024. This review included studies reporting patients diagnosed with GATA2 deficiency or having a documented history of the condition, who subsequently developed or were concurrently diagnosed with HLH. Various study types were considered, such as case reports, case series, letters to editors, original articles, correspondences, and commentaries, without any restrictions on language.ResultsIn our systematic review, 15 studies from 2016 to 2024 were analyzed, encompassing 23 patients with GATA2 deficiency and HLH. the mean (SD) age of patients was 23.48 (10.54) years, ranging from 7 to 57 years. These patients exhibited diverse genetic mutations and a spectrum of infections, particularly Mycobacterium avium (M. avium), Mycobacterium kansasii (M. kansasii), Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), herpes simplex virus (HSV), and influenza A, often leading to HLH. Family histories of GATA2-deficient patients with HLH occasionally reveal confirmed GATA2 mutations or suspicious cases among first-degree relatives. Hematopoietic stem cell transplantation (HSCT) was performed in 8 patients with GATA2 deficiency and HLH. Among them, 6 patients survived post-therapy, while 2 patients died following HSCT. Currently, 1 patient is being considered for HSCT. The overall mortality rate among GATA2 deficiency patients who experienced HLH was 39.13%.ConclusionsThis systematic review highlights GATA2 deficiency's association with diverse infections triggering HLH, emphasizing early infection management to mitigate mortality risks. This comprehensive analysis contributes to scientific knowledge, offering important insights for clinicians and researchers in diagnosing and managing this rare condition.
| S-EPMC11536883 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.
| S-EPMC3208276 | biostudies-literature
Project description:Although COVID-19 vaccines are an effective public health tool to combat the global pandemic, serious adverse events, such as hemophagocytic lymphohistiocytosis (HLH), caused by them are a concern. In this systematic review, cases of HLH reported after COVID-19 vaccination have been examined to understand the relationship between the two and propose effective therapeutic strategies. Furthermore, ruxolitinib's potential as a cytokine inhibitor and its affinity for CD25 were initially assessed through molecular docking, aiming to aid targeted HLH therapy. PubMed and Web of Science databases were searched for published individual case reports on the occurrence of HLH after the administration of any COVID-19 vaccine. A total of 17 articles (25 patients) were included in this qualitative analysis. Furthermore, molecular docking was employed to investigate the therapeutic potential of ruxolitinib for HLH after COVID-19 vaccination. The mean age of patients who developed HLH after COVID-19 vaccination was 48.1 years. Most HLH episodes occurred after the BNT162b2 mRNA COVID-19 vaccination (14/25 cases) and to an extent after the ChAdOx1 nCov-19 vaccination (5/25 cases). Almost all affected patients received steroid and antibiotic therapy. Three patients died despite treatment because of esophagus rupture, neutropenic fever, bacteroides bacteremia, refractory shock, and encephalopathy and shock. Visual docking results of IL-2 Rα and ruxolitinib using the Discovery Studio 2019 Client software yielded a model score of 119.879. The findings highlight the importance of considering and identifying the adverse effects of vaccination and the possibility of using ruxolitinib for treating HLH after COVID-19 vaccination.
| S-EPMC10563610 | biostudies-literature
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.
| S-EPMC9766494 | biostudies-literature
Project description: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.
| S-EPMC7225316 | biostudies-literature
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.
| S-EPMC7245825 | biostudies-literature
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.
| S-EPMC7422132 | biostudies-literature