Clinical case of hemophagocytic lymphohistiocytosis: rare or undiagnosed syndrome?
DOI:
https://doi.org/10.14739/2310-1210.2023.1.261972Keywords:
hemophagocytic syndrome, macrophage activation syndrome, cytokine storm, hyperferritinemia, coagulopathyAbstract
Hemophagocytic lymphohistiocytosis (hemophagocytic syndrome, HLH) is a life-threatening hyperinflammatory condition associated with a high mortality rate; it is characterized by hyperstimulation of histiocytes and cytotoxic T-cells, which leads to cytokine storm and multisystemic injury.
Aim. To present our own clinical case of the HLH development at the key aspects of pathogenic mechanisms, differential diagnosis, and therapeutic management of this syndrome.
Materials and methods. This article provides information on the HLH development in a 69-year-old man with the onset of this syndrome prior to a diagnosis of the underlying disease – splenic marginal zone lymphoma. The article summarizes the current literature data on clinical manifestations, diagnosis, and treatment of HLH.
Results. This article describes a case of secondary HLH from our clinical practice. The most common causes of HLH are malignant neoplasm, infectious factors and rheumatic diseases (when associated with the latest, HLH is called “macrophage activation syndrome”). The main clinical symptoms are prolonged high fever and hepatosplenomegaly, typical laboratory changes such as cytopenia, hyperferritinemia, hypertriglyceridemia, elevated liver enzymes and low fibrinogen levels.
Conclusions. Despite typical clinical features, HLH is a condition that often remains unrecognized and it is characterized by a poor prognosis. Prompt prescription of adequate treatment can improve patients’ prognoses and increase the survival rate.
References
Al-Samkari, H., & Berliner, N. (2018). Hemophagocytic Lymphohistiocytosis. Annual review of pathology, 13, 27-49. https://doi.org/10.1146/annurev-pathol-020117-043625
Bhatt, N. S., Oshrine, B., & An Talano, J. (2019). Hemophagocytic lymphohistiocytosis in adults. Leukemia & lymphoma, 60(1), 19-28. https://doi.org/10.1080/10428194.2018.1482543
Campo, M., & Berliner, N. (2015). Hemophagocytic Lymphohistiocytosis in Adults. Hematology/Oncology Clinics of North America, 29(5), 915-925. https://doi.org/10.1016/j.hoc.2015.06.009
Carter, S. J., Tattersall, R. S., & Ramanan, A. V. (2019). Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology, 58(1), 5-17. https://doi.org/10.1093/rheumatology/key006
Daver, N., McClain, K., Allen, C. E., Parikh, S. A., Otrock, Z., Rojas-Hernandez, C., Blechacz, B., Wang, S., Minkov, M., Jordan, M. B., La Rosée, P., & Kantarjian, H M. (2017). A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer, 123(17), 3229-3240. https://doi.org/10.1002/cncr.30826
De Saint Basile, G., Moshous, D., & Fischer, A. (2017). Genetics and pathogenesis of hemophagocytic lymphohistiocytosis. In Histiocytic Disorders (pp. 197-214). Springer International Publishing. https://doi.org/10.1007/978-3-319-59632-7_11
Ehl, S., Astigarraga, I., von Bahr Greenwood, T., Hines, M., Horne, A., Ishii, E., Janka, G., Jordan, M. B., La Rosée, P., Lehmberg, K., Machowicz, R., Nichols, K. E., Sieni, E., Wang, Z., & Henter, J. I. (2018). Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society. The journal of allergy and clinical immunology. In practice, 6(5), 1508-1517. https://doi.org/10.1016/j.jaip.2018.05.031
Emile, J. F., Abla, O., Fraitag, S., Horne, A., Haroche, J., Donadieu, J., Requena-Caballero, L., Jordan, M. B., Abdel-Wahab, O., Allen, C. E., Charlotte, F., Diamond, E. L., Egeler, R. M., Fischer, A., Herrera, J. G., Henter, J. I., Janku, F., Merad, M., Picarsic, J., Rodriguez-Galindo, C., … Histiocyte Society (2016). Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood, 127(22), 2672-2681. https://doi.org/10.1182/blood-2016-01-690636
Esteban, Y. M., de Jong, J., & Tesher, M. S. (2017). An Overview of Hemophagocytic Lymphohistiocytosis. Pediatric annals, 46(8), e309-e313. https://doi.org/10.3928/19382359-20170717-01
George, M. R. (2014). Hemophagocytic lymphohistiocytosis: review of etiologies and management. Journal of blood medicine, 5, 69-86. https://doi.org/10.2147/JBM.S46255
Griffin, G., Shenoi, S., & Hughes, G. C. (2020). Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy. Best practice & research. Clinical rheumatology, 34(4), 101515. https://doi.org/10.1016/j.berh.2020.101515
Henderson, L. A., & Cron, R. Q. (2020). Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management. Paediatric drugs, 22(1), 29-44. https://doi.org/10.1007/s40272-019-00367-1
Henter, J. I., Horne, A., Aricó, M., Egeler, R. M., Filipovich, A. H., Imashuku, S., Ladisch, S., McClain, K., Webb, D., Winiarski, J., & Janka, G. (2007). HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer, 48(2), 124-131. https://doi.org/10.1002/pbc.21039
Hutchinson, M., Tattersall, R. S., & Manson, J. J. (2019). Haemophagocytic lymphohisticytosis-an underrecognized hyperinflammatory syndrome. Rheumatology, 58(Suppl 6), vi23-vi30. https://doi.org/10.1093/rheumatology/kez379
Janka, G. E., & Lehmberg, K. (2013). Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology. American Society of Hematology. Education Program, 2013, 605-611. https://doi.org/10.1182/asheducation-2013.1.605
Jordan, M. B., Allen, C. E., Greenberg, J., Henry, M., Hermiston, M. L., Kumar, A., Hines, M., Eckstein, O., Ladisch, S., Nichols, K. E., Rodriguez-Galindo, C., Wistinghausen, B., & McClain, K. L. (2019). Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatric blood & cancer, 66(11), e27929. https://doi.org/10.1002/pbc.27929
Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H., & McClain, K. L. (2011). How I treat hemophagocytic lymphohistiocytosis. Blood, 118(15), 4041-4052. https://doi.org/10.1182/blood-2011-03-278127
Kleynberg, R. L., & Schiller, G. J. (2012). Secondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy. Clinical advances in hematology & oncology : H&O, 10(11), 726-732.
La Rosée, P., Horne, A., Hines, M., von Bahr Greenwood, T., Machowicz, R., Berliner, N., Birndt, S., Gil-Herrera, J., Girschikofsky, M., Jordan, M. B., Kumar, A., van Laar, J., Lachmann, G., Nichols, K. E., Ramanan, A. V., Wang, Y., Wang, Z., Janka, G., & Henter, J. I. (2019). Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood, 133(23), 2465-2477. https://doi.org/10.1182/blood.2018894618
Larroche, C. (2012). Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment. Joint bone spine, 79(4), 356-361. https://doi.org/10.1016/j.jbspin.2011.10.015
Lerkvaleekul, B., & Vilaiyuk, S. (2018). Macrophage activation syndrome: early diagnosis is key. Open access rheumatology : research and reviews, 10, 117128. https://doi.org/10.2147/OARRR.S151013
Machowicz, R., Janka, G., & Wiktor-Jedrzejczak, W. (2017). Similar but not the same: Differential diagnosis of HLH and sepsis. Critical reviews in oncology/hematology, 114, 112. https://doi.org/10.1016/j.critrevonc.2017.03.023
Madkaikar, M., Shabrish, S., & Desai, M. (2016). Current Updates on Classification, Diagnosis and Treatment of Hemophagocytic Lymphohistiocytosis (HLH). Indian journal of pediatrics, 83(5), 434-443. https://doi.org/10.1007/s12098-016-2037-y
Marsh, R. A., Allen, C. E., McClain, K. L., Weinstein, J. L., Kanter, J., Skiles, J., Lee, N. D., Khan, S. P., Lawrence, J., Mo, J. Q., Bleesing, J. J., Filipovich, A. H., & Jordan, M. B. (2013). Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatric blood & cancer, 60(1), 101-109. https://doi.org/10.1002/pbc.24188
McClain, K. L. (2020). Treatment of hemophagocytic lymphohistiocytosis in the era of new biologics. Pediatric blood & cancer, 67(10), e28631. https://doi.org/10.1002/pbc.28631
Morimoto, A., Nakazawa, Y., & Ishii, E. (2016). Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatrics international, 58(9), 817-825. https://doi.org/10.1111/ped.13064
Okamoto, M., Yamaguchi, H., Isobe, Y., Yokose, N., Mizuki, T., Tajika, K., Gomi, S., Hamaguchi, H., Inokuchi, K., Oshimi, K., & Dan, K. (2009). Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. Internal medicine, 48(10), 775-781. https://doi.org/10.2169/internalmedicine.48.1677
Osińska, I., Popko, K., & Demkow, U. (2014). Perforin: an important player in immune response. Central-European journal of immunology, 39(1), 109-115. https://doi.org/10.5114/ceji.2014.42135
Otrock, Z. K., Daver, N., Kantarjian, H. M., & Eby, C. S. (2017). Diagnostic Challenges of Hemophagocytic Lymphohistiocytosis. Clinical lymphoma, myeloma & leukemia, 17S, S105-S110. https://doi.org/10.1016/j.clml.2017.02.017
Parikh, S. A., Kapoor, P., Letendre, L., Kumar, S., & Wolanskyj, A. P. (2014). Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clinic proceedings, 89(4), 484-492. https://doi.org/10.1016/j.mayocp.2013.12.012
Risma, K. A., & Marsh, R. A. (2019). Hemophagocytic Lymphohistiocytosis: Clinical Presentations and Diagnosis. The journal of allergy and clinical immunology. In practice, 7(3), 824-832. https://doi.org/10.1016/j.jaip.2018.11.050
Rosado, F. G., & Kim, A. S. (2013). Hemophagocytic lymphohistiocytosis: an update on diagnosis and pathogenesis. American journal of clinical pathology, 139(6), 713-727. https://doi.org/10.1309/AJCP4ZDKJ4ICOUAT
Sen, E. S., Clarke, S. L., & Ramanan, A. V. (2016). Macrophage Activation Syndrome. Indian journal of pediatrics, 83(3), 248-253. https://doi.org/10.1007/s12098-015-1877-1
Sen, E. S., Steward, C. G., & Ramanan, A. V. (2017). Diagnosing haemophagocytic syndrome. Archives of disease in childhood, 102(3), 279-284. https://doi.org/10.1136/archdischild-2016-310772
Soy, M., Atagündüz, P., Atagündüz, I., & Sucak, G. T. (2021). Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic. Rheumatology international, 41(1), 7-18. https://doi.org/10.1007/s00296-020-04636-y
Soy, M., Keser, G., Atagündüz, P., Tabak, F., Atagündüz, I., & Kayhan, S. (2020). Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clinical rheumatology, 39(7), 2085-2094. https://doi.org/10.1007/s10067-020-05190-5
Thomas, W., Veer, M. V., & Besser, M. (2016). Haemophagocytic lymphohistiocytosis: an elusive syndrome. Clinical medicine, 16(5), 432-436. https://doi.org/10.7861/clinmedicine.16-5-432
Valade, S., Mariotte, E., & Azoulay, E. (2020). Coagulation Disorders in Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome. Critical care clinics, 36(2), 415-426. https://doi.org/10.1016/j.ccc.2019.12.004
Verma, M., Gupta, N., Dass, J., Kotwal, J., & Sharma, A. (2020). HLH Masquerading Lymphoma: Diagnostic Dilemma and Treatment Outcomes. Indian journal of hematology & blood transfusion, 36(4), 635-639. https://doi.org/10.1007/s12288-019-01250-2
Zhou, M., Li, L., Zhang, Q., Ma, S., Sun, J., Zhu, L., Lu, D., Zhu, J., Zhou, D., Zheng, Y., Yang, X., Xie, M., Zhu, M., Ye, X., & Xie, W. (2018). Clinical features and outcomes in secondary adult hemophagocytic lymphohistiocytosis. QJM : monthly journal of the Association of Physicians, 111(1), 23-31. https://doi.org/10.1093/qjmed/hcx183
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