A Clinical Labyrinth: Diagnosis of Hemophagocytic Lymphohistyocytosis

Abstract

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare, non-malignant immune regulation disorder characterized by hemophagocytosis. The HLH 2004 study listed the widely accepted diagnostic model, which requires the presence of 5 out of 8 criteria (Fever; splenomegaly; cytopenia; hypertriglyceridemia or hypofibrinogenemia; hemophagocytosis, ferritin >500 mcg/L; Low/absent NK-cell activity; soluble CD25 elevation). The current management guidelines based on HLH-94 studies involve immunosuppression with weekly chemotherapy (etoposide) and glucocorticoids (dexamethasone), and intrathecal methotrexate is administered in patients with CNS involvement. CASE:A 4-month-old male patient with no known disease was admitted to our institution with a fever complaint. The physical examination and ultrasound (USG) revealed an enlarged spleen: WBC 2600, Hg 7.3, ANS 390, platelet count 26.000, ferritin 8.300, triglyceride 767, AST 48, ALT 21, total bilirubin 1.6, Na 133, and fibrinogen 70. Genetic tests were processed and intravenous immunoglobulin (IVIG) treatment was initiated with 10 mg/m2/day of Dexamethasone. The findings flared up again in the following period, and a complete treatment regimen was administered according to the HLH 2004 protocol (IVIG + Dexamethasone + Cyclosporine + Etoposide). DISCUSSION and CONCLUSION:HLH should be considered in patients with prolonged fever, cytopenia hepatosplenomegaly, and hemophagocytosis, which should be investigated by performing bone marrow aspiration first.

Keywords

• Hemophagocytic lymphohistiocytosis (HLH)
• hematopoietic stem cell transplantation (HSCT)
• hypertriglyceridemia
• hypofibrinogenemia
• hemophagocytosis

Klinik Bir Labirent: Hemofagositik Lenfohistiyositoz Tanısı

Abstract

Giriş: Hemofagositik lenfohistiyositoz (HLH), hemofagositoz ile karakterize nadir, malign olmayan bir bağışıklık regülasyon bozukluğudur. HLH 2004 çalışması, 8 kriterden 5'inin (ateş; splenomegali; sitopeni; hipertrigliseridemi veya hipofibrinojenemi; hemofagositoz, ferritin> 500 mcg/L; düşük/L; düşük/yok NK-hücre aktivitesi; CD25 Yüksekliği). HLH-94 çalışmalarına dayanan mevcut yönetim kılavuzları, haftalık kemoterapi (etoposid) ve glukokortikoidler (deksametazon) ile immünosupresyonu içerir ve CNS tutulumu olan hastalarda intratekal metotreksat uygulanır. Vaka: Bilinen hastalığı olmayan 4 aylık bir erkek hasta, kurumumuza ateş şikayeti ile kabul edildi. Fizik muayene ve ultrason (USG) genişlemiş bir dalak ortaya çıkardı: WBC 2600, HG 7.3, ANS 390, trombosit sayısı 26.000, AST 48, ALT 21, TOPLAM BİLirubin 1.6, Na 133 ve fibrinojen 70. Testler işlendi ve 10 mg/m2/gün deksametazon ile intravenöz immünoglobulin (IVIG) tedavisi başlatıldı. Bulgular bir sonraki dönemde tekrar alevlendi ve HLH 2004 protokolüne (IVIG + Deksametazon + siklosporin + etoposid) göre tam bir tedavi rejimi uygulandı. Tartışma ve Sonuç: Önce kemik iliği aspirasyonu yapılarak araştırılması gereken uzun süreli ateş, sitopeni hepatosplenomegali ve hemofagositozu olan hastalarda HLH düşünülmelidir.

Keywords

• Hemofagositik lenfohistiyositoz (HLH)
• hematopoietik kök hücre nakli (HSCT)
• hipertrigliseridemi
• hipofibrinojenemi
• hemofagositoz

References

1. 1. Janka GE. History of Hemophagocytic Lymphohistiocytosis. Adv Exp Med Biol. 2024;1448:9-19.
2. 2. Jordan MB. Hemophagocytic lymphohistiocytosis: A disorder of T cell activation, im-mune regulation, and distinctive immunopathology. Immunol Rev. 2024 Mar;322(1):339-350.
3. 3. Nyvlt P, Schuster FS, Ihlow J, Heeren P, Spies C, Hiesgen J, Schenk T, von Brünneck AC, Westermann J, Brunkhorst FM, La Rosée P, Janka G, Lachmann C, Lachmann G. Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients. Eur J Haematol. 2024;112(6):917-926.
4. 4. Zoref-Lorenz A, Ellis M, Jordan MB. Inpatient recognition and management of HLH. Hematology Am Soc Hematol Educ Program. 2023(1):259-266.
5. 5. Zhao C, Zhang Q, Zhang R, Lian H, Ma H, Zhao X, Li Z. Genetic and clinical characte-ristics of primary hemophagocytic lymphohistiocytosis in children. Ann Hematol. 2024;103(1):17-28.
6. 6. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic gui-delines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31.
7. 7. Cox MF, Mackenzie S, Low R, Brown M, Sanchez E, Carr A, Carpenter B, Bishton M, Duncombe A, Akpabio A, Kulasekararaj A, Sin FE, Jones A, Kavirayani A, Sen ES, Quick V, Dulay GS, Clark S, Bauchmuller K, Tattersall RS, Manson JJ; HiHASC group. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 Hyperinflammation and HLH Across Speciality Collaboration (Hi-HASC) consensus guideline. Lancet Rheumatol. 2024;6(1):e51-e62.
8. 8. Yang T, Chen R, Zhang M, Jing R, Geng J, Wei G, Luo Y, Xiao P, Hong R, Feng J, Fu S, Zhao H, Cui J, Huang S, Huang H, Hu Y. Relapsed/Refractory Peripheral T-Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis With UNC13D and CD27 Germline Mutations. Cell Transplant. 2024 Jan-Dec;33:9636897231221887.

9. 9. Ouachée-Chardin M, Elie C, de Saint Basile G, Le Deist F, Mahlaoui N, Picard C, Ne-ven B, Casanova JL, Tardieu M, Cavazzana-Calvo M, Blanche S, Fischer A. Hematopo-ietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center re-port of 48 patients. Pediatrics. 2006;117(4):e743-50.
10. 10. Yoon HS, Im HJ, Moon HN, Lee JH, Kim HJ, Yoo KH, Sung KW, Koo HH, Kang HJ, Shin HY, Ahn HS, Cho B, Kim HK, Lyu CJ, Lee MJ, Kook H, Hwang TJ, Seo JJ. The outcome of hematopoietic stem cell transplantation in Korean children with hemop-hagocytic lymphohistiocytosis. Pediatr Transplant. 2010;14(6):735-40.