Prognostic Factors and Outcomes of Adults With Hemophagocytic Lymphohistiocytosis

doi:10.1016/j.mayocp.2013.12.012

Mayo Clinic Proceedings

Volume 89, Issue 4, April 2014, Pages 484-492

Previous Presentation: Presented at the 54th Annual American Society of Hematology Meeting; December 8, 2012; Atlanta, Georgia.

https://doi.org/10.1016/j.mayocp.2013.12.012 Get rights and content

Abstract

Objective

To describe the prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis (HLH), a rare disorder caused by pathologic activation of the immune system.

Patients and Methods

The study population consisted of a consecutive cohort of adult (age ≥18 years) patients treated at Mayo Clinic in Rochester, Minnesota, from January 1, 1996, through December 31, 2011, in whom a diagnosis of HLH was suspected and subsequently confirmed by retrospective review using the HLH-04 diagnostic criteria.

Results

Of 250 adult patients suspected of having HLH, 62 met the HLH-04 diagnostic criteria and were included in the final analysis. The median age was 49 years (range, 18-87 years), and 42 (68%) were male. The underlying cause of HLH was malignant tumor in 32 patients (52%), infection in 21 patients (34%), autoimmune disorder in 5 patients (8%), and idiopathic disease in 4 patients (6%). After a median follow-up of 42 months, 41 patients (66%) had died. The median overall survival of the entire cohort was 2.1 months. The median overall survival of patients with tumor–associated HLH was 1.4 months compared with 22.8 months for patients with non-tumor–associated HLH (P=.01). The presence of a malignant tumor and hypoalbuminemia were significant predictors of inferior survival on multivariate analysis.

Conclusion

In this large series of adults with secondary HLH treated at a single tertiary care center, patients with low serum albumin levels and tumor–associated HLH had a markedly worse survival. Hemophagocytic lymphohistiocytosis remains elusive and challenging to clinicians who must maintain a high index of suspicion. The recent discovery of several novel diagnostic and therapeutic modalities may improve outcomes of adult patients with HLH.

Section snippets

Methods

The Mayo Clinic electronic medical record database was queried for the terms hemophagocytic syndrome, hemophagocytosis, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome from January 1, 1996, through December 31, 2011. All adult patients (age ≥18 years) whose medical records contained these terms were manually reviewed. The Mayo Clinic hematopathology database was also cross-referenced for the terms hemophagocytic syndrome and hemophagocytosis during the same period. All

Baseline Clinical and Laboratory Characteristics

Of 250 medical records reviewed in which the diagnosis was listed, 62 patients met the stringent eligibility criteria for inclusion in the study. Table 1 outlines the baseline characteristics of our study population. The median age of patients was 49 years (range, 18-87 years), and 42 (68%) were male. Thirty-two patients (52%) were diagnosed with tumor–associated HLH. Of the remaining patients (n=30) with non-tumor–associated HLH, 21 (34%) had an infection, 5 (8%) had an autoimmune condition,

Discussion

Adult HLH is a rare disease, and most of our understanding of this complex disorder comes from small retrospective case series or individual patient case reports.29, 30, 31, 32, 33, 34, 35, 36, 37, 38 To the best of our knowledge, this study is the largest single-institution retrospective analysis of adult HLH patients. In our series of adult HLH patients, 52% of patients had an underlying malignant cause, and their outcomes were markedly inferior to HLH patients with a nonmalignant cause. In

Conclusion

Our study is one of the largest retrospective studies comparing the clinical characteristics and outcomes of adult HLH patients with a variety of secondary causes. A high index of suspicion for HLH should be maintained for adults who present with unexplained fever, cytopenias, and hyperferritinemia. The underlying cause of HLH is the most important determinant of outcome in this heterogeneous population of patients. Unfortunately, the median OS of adult patients with HLH remains poor, in

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Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival
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We evaluated malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) in Sweden regarding population-based incidence, clinical features, and survival. From 1997 to 2018, we identified 307 adults (≥18 years old) and 9 children (209 males, 107 females; P < .001) with both an HLH-related diagnosis and malignant disease, corresponding to 0.19 per 100 000 adults annually (0.15/100 000 for the entire population), increasing from 0.026 (1997-2007) to 0.34 (2008-2018) (P < .001). In the latest 7-year period (2012-2018), the annual incidence was 0.45 per 100 000 adults (n = 246). This incidence varied between the 6 health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100 000 adults annually (P < .001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies, with the highest proportion (2.5%) in young males. Among the 316 patients, the 1-month probability of survival, likely representing the HLH episode, increased significantly from 52% (95% confidence interval [CI], 40-63) (1997-2007) to 71% (95% CI, 65-76) (2008-2018), whereas 2-year survival remained poor (25%; 95% CI, 20-30). Altogether, 52% were lymphomas, 29% leukemias, 8% other hematological malignancies, and 11% solid tumors. Males were more affected than females by mal-HLH, also taking the over-representation of males with hematological malignancies into account (P = .0012). Validation by medical-file reviews revealed 13% over-reporting of HLH. We conclude that the annual mal-HLH incidence has increased 10-fold and was at least 0.71 per 100 000 adults from 2012 to 2018, that is, 0.62 per 100 000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.
Extensive Hemophagocytic Lymphohistiocytosis Associated With Aggressive Natural Killer Cell Leukemia
2023, Mayo Clinic Proceedings
The predictive value of hematological inflammatory markers for acute kidney injury and mortality in adults with hemophagocytic Lymphohistiocytosis: A retrospective analysis of 585 patients
2023, International Immunopharmacology
Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological hyperactivation-related disease with a high mortality rate. The purpose of this study was to examine the relationship between complete blood count parameters and the occurrence of acute kidney injury (AKI) and mortality in patients with HLH.
We included 585 adult patients with HLH. Logistic regression models for AKI and 28-day mortality were developed.
Multivariate logistic regression models revealed that hemoglobin (HB) ≤ 7.3 g/dl (adjusted OR, 1.651; 95% CI, 1.044–2.612), hemoglobin-to-red blood cell distribution width ratio (HRR) < 0.49 (adjusted OR, 1.692), neutrophil-to-lymphocyte ratio (NLR) ≥ 3.15 (adjusted OR, 1.697), and neutrophil-to-lymphocyte-platelet ratio (NLPR) ≥ 11.0 (adjusted OR, 1.608) were independent risk factors for the development of AKI. Moreover, lower platelet levels (31 × 10⁹/L < platelets < 84 × 10⁹/L, adjusted OR, 2.133; platelets ≤ 31 × 10⁹/L, adjusted OR, 3.545) and higher red blood cell distribution width-to-platelet ratio (RPR) levels (0.20 < RPR < 0.54, adjusted OR, 2.595; RPR ≥ 0.54, adjusted OR, 4.307), lymphocytes ≤ 0.34 × 10⁹/L (adjusted OR, 1.793), NLPR ≥ 11.0 (adjusted OR, 2.898), and the aggregate index of systemic inflammation (AISI) ≤ 7 (adjusted OR,1.778) were also independent risk factors for 28-day mortality. Furthermore, patients with AKI had a worse prognosis than those without AKI (P < 0.05).
In patients with HLH, hematological parameters are of great value for the early identification of patients at high risk of AKI and 28-day mortality.
Ocular Phenotypes in Patients With Hemophagocytic Lymphohistiocytosis: A Retrospective Analysis in a Single Center Over 7 Years
2023, American Journal of Ophthalmology
To investigate the presence and type of ocular abnormalities in patients with hemophagocytic lymphohistiocytosis (HLH).
A retrospective cross-sectional study.
Observational report of ocular findings and their associations with age, sex, underlying disease, and hematologic parameters. HLH was defined according to the 2004 criteria, and the patients were enrolled from March 2013 to December 2021. Analysis began in July 2022 and ended in January 2023. The main outcome measures were ocular abnormalities associated with HLH and their potential risk factors.
Of 1525 HLH patients, 341 had ocular examinations, and 133 (133 of 341, 39.00%) had ocular abnormalities. Mean age at presentation was 30.21 ± 14.42 years. The multivariate analysis indicated that old age, autoimmune disorders, decreasing red blood cell count, decreasing platelet count, and increasing fibrinogen level were independent risk factors of ocular involvement in HLH patients. The most common presenting ocular findings were posterior segment abnormalities (66 patients, 49.62%), including retinal and vitreous hemorrhage, serous retinal detachment, cytomegalovirus retinitis, and optic disc swelling. Other HLH-associated ocular abnormalities included ocular surface infection (conjunctivitis, 34 patients, 25.56%; keratitis, 16 patients, 12.03%), subconjunctival hemorrhage (11 patients, 8.27%), chemosis (5 patients, 3.76%), anterior uveitis (11 patients, 8.27%), glucocorticoid-induced glaucoma (5 patients, 3.76%), radiation cataract (1 patient, 0.75%), dacryoadenitis (2 patients, 1.50%), dacryocystitis (1 patients, 0.75%), orbital cellulitis (2 patients, 1.50%), orbital pseudotumor (2 patients, 1.50%), and strabismus (2 patients, 1.50%).
Eye involvement is not uncommon in HLH. Better awareness among both ophthalmologists and hematologists is necessary for prompt diagnosis and institution of appropriate management strategies with potential to save sight and life.
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome
2023, Transplantation and Cellular Therapy
T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term “immune effector cell-associated HLH-like syndrome (IEC-HS)” to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.
Disseminated tuberculosis in rare association with hemophagocytic lymphocytosis - A case report from central India
2023, Heliyon
Hemophagocytic Lymphohistiocytosis (HLH) is an uncommon, diverse and rare genetic hyper-inflammatory syndrome. HLH associated with tuberculosis (TB-HLH) has been described as a clinical and diagnostic quandary. The co-existence leads to significantly higher morbidity and mortality. Our case highlights the presence of disseminated tuberculosis and worsening of the case due to underlying hemophagocytic syndrome leading to rapid deterioration of patient prognosis. Prompt diagnosis and treatment remains help to improve patient management.

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Original articlePrognostic Factors and Outcomes of Adults With Hemophagocytic Lymphohistiocytosis

Abstract

Objective

Patients and Methods

Results

Conclusion

Section snippets

Methods

Baseline Clinical and Laboratory Characteristics

Discussion

Conclusion

Blood

Cell

Am J Hum Genet

Blood

ASH Annual Meeting Abstracts

ASH Annual Meeting Abstracts

ASH Annual Meeting Abstracts

J Microbiol Immunol Infect

J Am Acad Dermatol

J Infect Chemother

J Clin Virol

Leuk Res

Blood

J Microbiol Immunol Infect

Joint Bone Spine

ASH Annual Meeting Abstracts

Blood

Blood

Familial and acquired hemophagocytic lymphohistiocytosis

Annu Rev Med

Familial haemophagocytic reticulosis

Arch Dis Child

Perforin gene defects in familial hemophagocytic lymphohistiocytosis

Science

Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11

Hum Mol Genet

Approach to hemophagocytic syndromes

Hematology Am Soc Hematol Educ Program

Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature

Hematol Oncol

A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases

Int J Hematol

Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center

Leukemia Lymphoma

Lymphoma-associated hemophagocytic syndrome: clinical features and treatment outcome

Ann Hematol

A clinicopathological study of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma

Int J Hematol

Clinical characteristics of T-cell lymphoma associated with hemophagocytic syndrome: comparison of T-cell lymphoma with and without hemophagocytic syndrome

Leukemia Lymphoma

Original article
Prognostic Factors and Outcomes of Adults With Hemophagocytic Lymphohistiocytosis