Published: 2016-12-16

Hemophagocytic lymphohistiocytosis secondary to infections:a tertiary care experience

Swaroopa Deme, Bhaskar Kakarla, Naval Chandra, Subbalaxmi M. V. S., Shetty Mallikharjuna, Satyanarayana Raju Yadati


Background: Hemophagocytic lymphohistiocytosis is an uncommon complication of various conditions. It is characterized by immune dysregulation and massive cytokine release causing multiorgan dysfunction. It is classified as primary and secondary to various etiologies like infections, malignancies and autoimmune disease. As it has high mortality, clinician awareness is important for early diagnosis and improved outcome. Aim of the study was to study the etiologies, clinical manifestations, complications and laboratory features in patients diagnosed with infection associated hemophagocytic syndrome (IAHS).

Methods: We have done retrospective analysis of all cases diagnosed to have Infection Associated Hemophagocytic Syndrome (IAHS) between March 2012 to November 2015 in a 1000 bedded tertiary care hospital in south India.

Results: Total five cases detected. Most of the cases are related to tropical infections (80%). All of them presented with fever, cytopenias and organomegaly. Ferritin and Triglycerides were elevated in all patients. Bone marrow hemophagocytosis was observed in 80% of cases. Diagnostic protocol of HLH 2004 was followed. Only 20% survival observed.

Conclusions: IAHS is a rare fulminant complication associated with diagnostic and therapeutic challenges because of overlapping clinical features with sepsis. Increased physician awareness, early diagnosis and therapeutic interventions may improve survival.


Hemophagocytic lymphohistiocytosis, Infections, Tertiary care

Full Text:



Rajagopala S, Singh N. Diagnosing and treating Hemophagocytic Lymphohistiocytosis in the tropics: systematic review from the Indian subcontinent. Acta Med Acad. 2012;41(2):161-74.

Henter JI, Horne A, Aricó 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.

Sharma N, Clark J, Pham H, Efron D, MacGregor D, O'Keefe R, et al. TEN‐like eruption in setting of EBV positive TCell lymphoproliferative disease with HLH, in a child. Australas J Dermatol. 2014;55(3):e44‐7.

Olaya M, Alsina L, de Sevilla MF, Catal A, López‐Ramos MG, Martín Mateos MA, et al. Epstein Barr virus infection triggering a haemophagocytic syndrome. Allergol Immunopathol (Madr). 2014;42(6):627‐9.

Vladescu IA, Browning WL, Thomsen IP. Massive Ferritin Elevation in Neonatal Herpes Simplex Virus Infection: Hemophagocytic Lymphohistiocytosis or Herpes Simplex Virus Alone? J Pediatric Infect Dis Soc. 2015;4(3):e48‐52.

Sharp TM, Gaul L, Muehlenbachs A, Hunsperger E, Bhatnagar J, Lueptow R, et al. Centers for Disease Control and Prevention (CDC). Fatal hemophagocytic lymphohistiocytosis associated with locally acquired dengue virus infection ‐ New Mexico and Texas, 2012. MMWR Morb Mortal Wkly Rep. 2014;63(3):49‐54.

Ab‐Rahman HA, Rahim H, AbuBakar S, Wong PF. Macrophage Activation Syndrome‐Associated Markers in Severe Dengue. Int J Med Sci. 2016;13(3):179‐86.

Usman M, Thapa SD, Hadid H, Yessayan LT. HIV infection presenting proliferation of CD8+ T lymphocyte and hemophagocytic lympho-histiocytosis. Int J STD AIDS. 2016;27(5):411.

Hui YM, Pillinger T, Luqmani A, Cooper N. Haemophagocytic lymphohistiocytosis associated with Mycobacterium tuberculosis infection. BMJ Case Rep. 2015;2015. pii: bcr2014208220.

Padhi S, Ravichandran K, Sahoo J, Varghese RG, Basheer A. Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis. Lung India. 2015;32(6):593‐601.

Rathnayake PV, Kularathne WK, De Silva GC, Athauda BM, Nanayakkara SN, Siribaddana A, et al. Disseminated tuberculosis presenting as hemophagocytic lymphohistiocytosis in an immunocompetent adult patient: a case report. J Med Case Rep. 2015;9:294.

Otsuki S, Iwamoto S, Azuma E, Nashida Y, Akachi S, Taniguchi K, et al. Hemophagocytic Lymphohistiocytosis Due to Rickettsia Japonica in a 3‐Month‐old Infant. J Pediatr Hematol Oncol. 2015;37(8):627‐8.

Shah PA, Rashid A, Maqbool M, Yaseen Y, Shiekh FA. Enteric Fever Presenting as Hemophagocytic Lymphohistiocytosis (Macrophage Activation Syndrome). Webmed Central infectious diseases 2011;2(10):WMC002331.

Georgiadou SP, Stefos A, Spanakos G, Skrimpas S, Makaritsis K, Sipsas NV, et al. Current clinical, laboratory, and treatment outcome characteristics of visceral leishmaniasis: results from a seven year retrospective study in Greece. Int J Infect Dis. 2015;34:46‐50.

Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428-35.

Gürgey A, Göğüş S, Ozyürek E, Aslan D, Gümrük F, Cetin M, et al. Gurgey A Turkey Pediat hemato oncol 2003. Primary hemophagocytic lymphohistiocytosis in Turkish children. Pediatr Hematol Oncol. 2003;20(5):367-71.

Tothova Z, Berliner N. Hemophagocytic Syndrome and Critical Illness: New Insights into Diagnosis and Management. J Intensive Care Med. 2015;30(7):401-12.

Egeler RM, Shapiro R, Loechelt B, Filipovich A. Characteristic immune abnormalities in hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 1996;18(4):340-5.

George, Melissa R. “Hemophagocytic Lymphohistiocytosis: Review of Etiologies and Management.” J Blood Med. 2014;5:69-86.

Zhang Z, Wang J, Ji B, Bahr Greenwood Tv, Zhang Y, Wang Y, et al. Clinical presentation of hemophagocytic lymphohistiocytosis in adults is less typical than in children. Clinics. 2016;71(4):205-9.

Goel S, Polski JM, Imran H. Sensitivity and specificity of bone marrow hemophagocytosis in hemophagocytic lymphohistiocytosis. Ann Clin Lab Sci. 2012;42(1):21-5.

Kodan P, Chakrapani M, Shetty M, Pavan R, Bhat P. Hemophagocytic lymphohistiocytosis secondary to infections: a tropical experience! J Postgrad Med. 2015 ;61(2):112-5.

Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227-35.

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.

Okamoto M, Yamaguchi H, Isobe Y, Yokose N, Mizuki T, Tajika K, et al. Analysis of triglyceride value in the diagnosis and treatment response of secondary hemophagocytic syndrome. Intern Med. 2009;48(10):775-81.

Sankhyan SN, Saptharishi LG, Sasidaran K, Kanga A, Singhi SC. Clinical profile of scrub typhus in children and its association with hemophagocytic lymphohistiocytosis. Indian Pediatr. 2014;51(8):651-3.

Cattaneo C, Oberti M, Skert C, Passi A, Farina M, Re A, Tozzi P, et al. Adult onset hemophagocytic lymphohistiocytosis prognosis is affected by underlying disease and coexisting viral infection: analysis of a single institution series of 35 patients. Hematol Oncol. 2016.

Chen TL, Wong WW, Chiou TJ. Hemophagocytic syndrome: an unusual manifestation of acute human immunodeficiency virus infection. Int J Hematol. 2003;78(5):450-2.

Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults. Chest. 2011;140(4):933-8.

Maheshwari N, Mandal AK, Sahni N. Sepsis of unknown origin with multiorgan failure syndrome: Think of hemophagocytic lymphohistiocytosis. Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine. 2015;19(7):419-21.

Rivière 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.

Li Jing. Hemophagocytic Lymphohistiocytosis: Clinical Analysis of 103 Adult Patients. Medicine. 2014;93(2):100-5.

Li F, Yang Y, Jin F, Dehoedt C, Rao J, Zhou Y, et al. Clinical characteristics and prognostic factors of adult hemophagocytic syndrome patients: a retrospective study of increasing awareness of a disease from a single-center in China. Orphanet J Rare Dis. 2015;10:20.

Lambotte LO, Cacoub P, Costedoat N, Le Moel G, Amoura Z, Piette JC. High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation. J Rheumatol. 2003;30(5):1027-8.

Fardet L, Coppo P, Kettaneh A, Dehoux M, Cabane J, Lambotte O. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum. 2008;58(5):1521-7.

Iqbal W, Raza M, Mughal F. Infection Associated Hemophagocytic Histiocytosis and Its Effect on Hematological Parameters, American Journal of Medicine and Medical Sciences. 2014;4(2):72-8.

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

Tseng YT, Sheng WH, Lin BH, Lin CW, Wang JT, Chen YC, et al. Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults. J Microbiol Immunol Infect. 2011;44(3):191-7.