Triple threat: pregnancy, SLE, EBV as potential triggers in secondary hemophagocytic lymphohistiocytosis


  • Aiswarya Rajendran Department of Medicine, Amrita Institute of Medical Sciences, Kerala, India
  • Akil Adrian Sherif Department of Medicine, Amrita Institute of Medical Sciences, Kerala, India
  • Arun Divakar Department of Medicine, Amrita Institute of Medical Sciences, Kerala, India
  • Sandeep Surendran Department of Medicine, Amrita Institute of Medical Sciences, Kerala, India
  • Jyothi Visalakshy Department of Medicine, Amrita Institute of Medical Sciences, Kerala, India
  • Madhavan Pillai Gopalakrishna Pillai Department of Medicine, Amrita Institute of Medical Sciences, Kerala, India



Hemophagocytic lymphohistiocytosis, Immunological changes in pregnancy, Macrophage activation syndrome


We present a case of hemophagocytic lymphocytosis (HLH) that occurred secondary to a combination of Epstein Barr virus (EBV) infection and systemic lupus erythematosus (SLE) in early pregnancy. A 29-years-old lady presented with complaints of fever, vomiting and loose stools. She underwent successful in-vitro fertilization (IVF) and embryo transfer 20 days prior to the onset of these symptoms. Her blood investigations revealed anemia, neutropenia, hyperferritinemia and hypertriglyceridemia, eventually resulting in a diagnosis of HLH further substantiated by bone marrow examination. Additional investigations revealed positive anti-dsDNA and EBV IgM antibodies amongst other findings, adding SLE and EBV to the diagnoses. They were considered potential triggers for HLH. However, the occurrence of these events following IVF poses the question of whether pregnancy played a role in the development of HLH. Our patient responded well to pulse steroid therapy and has had an uneventful course till date.


Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31.

Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol Hoboken NJ. 2014;66(9):2613-20.

Petri M, Orbai A-M, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-86.

Bruu A-L, Hjetland R, Holter E, Mortensen L, Natas O, Petterson W, et al. Evaluation of 12 Commercial Tests for Detection of Epstein-Barr virus-specific and Heterophile antibodies. Clin Diagn Lab Immunol. 2000;7(3):451-6.

Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care. 2009;10(3):387-92.

Spergel AR, Walkovich K, Price S, Niemela JE, Wright D, Fleisher TA, et al. Autoimmune lymphoproliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis. Ped. 2013; 1;132(5):e1440-4.

Kim JM, Kwok SK, Ju JH, Park KS, Park GS, Kim HY, et al. Macrophage activation syndrome resistant to medical therapy in a patient with systemic lupus erythematosus and its remission with splenectomy. Rheumatol Int. 2013;33(3):767-71.

Tumian NR, Wong CL. Pregnancy-related hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection: A diagnostic and therapeutic challenge. Taiwan J Obstet Gynecol. 2015;54(4):432-7.

Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-52.

Bracaglia C, Gatto A, Pardeo M, Lapeyre G, Ferlin W, Nelson R, et al. Anti-interferon-gamma (IFNγ) monoclonal antibody treatment in a patient carrying an NLRC4 mutation and severe hemophagocytic lymphohistiocytosis. Pediatr Rheumatol. 2015;13(S1):O68.

Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer. 2011;56(1):154-5.

Gupta A, Tyrrell P, Valani R, Benseler S, Weitzman S, Abdelhaleem M. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;51(3):402-4.

Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221-30.

Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014;127(11):1118-25.

Falini B, Pileri S, De Solas I, Martelli MF, Mason DY, Delsol G, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood. 1990;75(2):434-44.

Ménard F, Besson C, Rincé P, Lambotte O, Lazure T, Canioni D, et al. Hodgkin lymphoma-associated hemophagocytic syndrome: a disorder strongly correlated with Epstein-Barr virus. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008;47(4):531-4.

Okuda T, Sakamoto S, Deguchi T, Misawa S, Kashima K, Yoshihara T, et al. Hemophagocytic syndrome associated with aggressive natural killer cell leukemia. Am J Hematol. 1991;38(4):321-3.

Miyahara M, Sano M, Shibata K, Matsuzaki M, Ibaraki K, Shimamoto Y, et al. B-cell lymphoma-associated hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol. 2000;79(7):378-88.

Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic syndrome with Kaposi’s sarcoma-associated herpesvirus-related primary effusion lymphoma. Br J Haematol. 2000;111(4):1112-5.

Chang TY, Jaffray J, Woda B, Newburger PE, Usmani GN. Hemophagocytic lymphohistiocytosis with MUNC13-4 gene mutation or reduced natural killer cell function prior to onset of childhood leukemia. Pediatr Blood Cancer. 2011;56(5):856-8.

Nikiforow S, Berliner N. The unique aspects of presentation and diagnosis of hemophagocytic lymphohistiocytosis in adults. ASH Educ Program Book. 2015;2015(1):183-9.

Santhakumara RP, Boyella PK, Vidyadharan G, Indu RN, Munirathnam V, Rema G, et al. HLH, Lymphoma, CMV and HLH: Heterogeneous presentation of HLH in Lymphoma. Indian J Cancer Educ Res. 2015;3(2):71.

Trottestam H, Horne A, Aricò M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577-84.

Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. ASH Educ Program Book. 2009;2009(1):127-31.

Luppi P. How immune mechanisms are affected by pregnancy. Vaccine. 2003;21(24):3352-7.

Yamaguchi K, Yamamoto A, Hisano M, Natori M, Murashima A. Herpes simplex virus 2-associated hemophagocytic lymphohistiocytosis in a pregnant patient. Obstet Gynecol. 2005;105(5):1241-4.

Whitacre CC, Reingold SC, O’looney PA, Blankenhorn E, Brinley F, Collier E, et al. A gender gap in autoimmunity. Sci. 1999;283(5406):1277-8.

Ota K, Kawahara K, Banno H, Nishijima K, Yoshida Y. Hemophagocytic lymphohistiocytosis caused by pyogenic liver abscess during pregnancy: a case report and literature review. Open J Obstet Gynecol. 2016;6(05):287.

Gill DS, Spencer A, Cobcroft RG. High-dose gamma-globulin therapy in the reactive haemophagocytic syndrome. Br J Haematol. 1994;88(1):204-6.

Mihara H, Kato Y, Tokura Y, Hattori Y, Sato A, Kobayashi H, et al. Epstein-Barr virus-associated hemophagocytic syndrome during mid-term pregnancy successfully treated with combined methylprednisolone and intravenous immunoglobulin. Rinsho Ketsueki. 1999;40(12):1258-64.

Dunn T, Cho M, Medeiros B, Logan A, Ungewickell A, Liedtke M. Hemophagocytic lymphohistiocytosis in pregnancy: a case report and review of treatment options. Hematol Amst Neth. 2012;17(6):325-8.

Mayama M, Yoshihara M, Kokabu T, Oguchi H. Hemophagocytic lymphohistiocytosis associated with a parvovirus B19 infection during pregnancy. Obstet Gynecol. 2014;124(2):438-41.

Arewa OP, Ajadi AA. Human immunodeficiency virus associated with haemophagocytic syndrome in pregnancy: a case report. West Afr J Med. 2011;30(1):66-8.

Nakabayashi M, Adachi T, Izuchi S, Sugisaki A. Association of hypercytokinemia in the development of severe preeclampsia in a case of hemophagocytic syndrome. Semin Thromb Hemost. 1999;25(5):467-71.

Hannebicque-Montaigne K, Le Roc’h A, Launay D, Coulon C, Deruelle P, Langlois S. Haemophagocytic syndrome in pregnancy: a case report. Ann Fr Anesth Reanim. 2012;31(3):239-42.

Pérard L, Costedoat-Chalumeau N, Limal N, Hot A, Cohen J, Vauthier-Brouzes D, et al. Hemophagocytic syndrome in a pregnant patient with systemic lupus erythematosus, complicated with preeclampsia and cerebral hemorrhage. Ann Hematol. 2007;86(7):541-4.

Teng CL, Hwang GY, Lee BJ, Wang RC, Chou MM. Pregnancy-induced hemophagocytic lymphohistiocytosis combined with autoimmune hemolytic anemia. J Chin Med Assoc JCMA. 2009r;72(3):156-9.

Hanaoka M, Tsukimori K, Hojo S, Abe Y, Mutou T, Muta K, et al. B-cell lymphoma during pregnancy associated with hemophagocytic syndrome and placental involvement. Clin Lymphoma Myeloma. 2007;7(7):486-90.

Chien CT, Lee FJ, Luk HN, Wu CC. Anaesthetic management for cesarean delivery in a parturient with exacerbated hemophagocytic syndrome. Int J Obstet Anesth. 2009;18(4):413-6.

Goulding EA, Barnden KR. Disseminated herpes simplex virus manifesting as pyrexia and cervicitis and leading to reactive hemophagocytic syndrome in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2014;180:198-9.

Zaibi H, Azzabi S, Ourari-Dhahri B, Ben Amar J, Ali Baccar M, Aouina H, et al. Rare cause of fever in pregnant women: Hemophagocytic syndrome. Tunis Med. 2015;93(5):331-2.

Pawar S, Ragesh R, Nischal N, Sharma S, Panda PK, Sharma SK. Unique triad of “Pregnancy, Kala Azar and Hemophagocytic Lymphohistiocytic Syndrome from a non-endemic region.” J Assoc Physicians Ind. 2015;63(6):65-8.

Chmait RH, Meimin DL, Koo CH, Huffaker J. Hemophagocytic syndrome in pregnancy. Obstet Gynecol. 2000;95(6):1022-4.

Klein S, Schmidt C, La Rosee P, Pletz M, Harz S, Dirsch O, et al. Fulminant gastrointestinal bleeding caused by EBV-triggered hemophagocytic lymphohistiocytosis: report of a case. Z Für Gastroenterol. 2014;52(04):354-9.

Yoshida S, Takeuchi T, Itami Y, Hata K, Watanabe K, Shoda T, et al. Hemophagocytic syndrome as primary manifestation in a patient with systemic lupus erythematosus after parturition. Nihon Rinsho Meneki Gakkai Kaishi. 2009;32(1):66-70.

Tsuda H, Shirono K, Shimizu K, Shimomura T. Postpartum parvovirus B19-associated acute pure red cell aplasia and hemophagocytic syndrome. Rinsho Ketsueki. 1995;36(7):672-6.

Komaru Y, Higuchi T, Koyamada R, Haji Y, Okada M, Kamesaki T, et al. Primary Sjögren syndrome presenting with hemolytic anemia and pure red cell aplasia following delivery due to Coombs-negative autoimmune hemolytic anemia and hemophagocytosis. Intern Med. 2013;52(20):2343-6.




How to Cite

Rajendran, A., Sherif, A. A., Divakar, A., Surendran, S., Visalakshy, J., & Pillai, M. P. G. (2017). Triple threat: pregnancy, SLE, EBV as potential triggers in secondary hemophagocytic lymphohistiocytosis. International Journal of Research in Medical Sciences, 5(8), 3758–3766.



Case Reports