Clinical case of hemophagocytic lymphohistiocytosis: rare or undiagnosed syndrome?

Authors

DOI:

https://doi.org/10.14739/2310-1210.2023.1.261972

Keywords:

hemophagocytic syndrome, macrophage activation syndrome, cytokine storm, hyperferritinemia, coagulopathy

Abstract

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.

Author Biographies

O. B. Yaremenko, Bogomolets National Medical University, Kyiv, Ukraine

MD, PhD, DSc, Professor, Head of the Department of Internal Medicine 3

A. O. Sydorova, Bogomolets National Medical University, Kyiv, Ukraine

MD, Assistant of the Department of Internal Medicine 3, Bogomolets National Medical University; Rheumatologist, General Practitioner, Medical Center “Universal Clinic “Oberig”, Kyiv, Ukraine

O. Ya. Antoniuk, Bogomolets National Medical University, Kyiv, Ukraine

MD, Assistant of the Department of Social Medicine and Public Health, Bogomolets National Medical University; Endocrinologist, General Practitioner, Medical Center “Universal Clinic “Oberig”, Kyiv, Ukraine

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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Published

2023-02-15

How to Cite

1.
Yaremenko OB, Sydorova AO, Antoniuk OY. Clinical case of hemophagocytic lymphohistiocytosis: rare or undiagnosed syndrome?. Zaporozhye Medical Journal [Internet]. 2023Feb.15 [cited 2024Nov.22];25(1):81-6. Available from: http://zmj.zsmu.edu.ua/article/view/261972