Case Report

By Prof. Parvaiz A Koul , Dr. Umar Khan , Dr. Sonaullah Shah , Mr. Rafi Jan , Dr. Abdul Wani , Dr. Abdul Baseer Qadri , Dr. Zarka Amin Masoodi
Corresponding Author Prof. Parvaiz A Koul
Internal & Pulmonary Medicine, SKIMS, - India 190011
Submitting Author Prof. Parvaiz A Koul
Other Authors Dr. Umar Khan
Internal , Soura, Srinagar (India) - India 190011

Dr. Sonaullah Shah
INternal , Soura, Srinagar (India) - India 190011

Mr. Rafi Jan
Internal , Soura, Srinaagr (India) - India 190011

Dr. Abdul Wani
Internal , Soura, Srinagar (India) - India 190011

Dr. Abdul Baseer Qadri
Internal , Soura, Srinagar (India) - India 190011

Dr. Zarka Amin Masoodi
Internal , Soura, Srinagar (India) - India 190011


Fever, Cytopenia, Hemophagocytosis, Salmonella, Epstein Barr virus

Koul PA, Khan U, Shah S, Jan R, Wani A, Qadri A, et al. Adult Hemophagocytic Lymphohistiocytosis: A 25-Year Experience at a Tertiary Care Hospital. WebmedCentral INFECTIOUS DISEASES 2010;1(9):WMC00674
doi: 10.9754/journal.wmc.2010.00674
Submitted on: 20 Sep 2010 04:53:26 AM GMT
Published on: 20 Sep 2010 04:28:28 PM GMT


Five patients of acquired Hemophago Lymphohistiocytosis (HLH) were seen in a tertiary care hospital over a period of 25 years. Three of the patients had a culture proved Salmonella typhi infection and one had evidence of Epstein Barr virus infection. The three patients with Enteric fever were managed with antibiotic therapy and the one with EBV associated HLH received etoposide, cyclosporine and steroids. The other patient was treated with pulsed steroid therapy. One patient died of sepsis during his relapse. HLH must be considered in patients with fever with prolonged cytopenias.


Hemophagocytosis is the pathologic finding of activated macrophages, engulfing erythrocytes, leukocytes, platelets, and their precursor cells (1), and constitutes an important finding in patients with hemophagocytic syndrome, more properly referred to as hemophagocytic lymphohistiocytosis (HLH) (2). HLH is a distinct clinical entity characterized by fever, pancytopenia, splenomegaly, and hemophagocytosis in bone marrow, liver, or lymph nodes. Initially the syndrome was thought of a sporadic disease resultant on neoplastic proliferation of histiocytes but subsequently, a familial form of the disease (3) (now referred to as familial hemophagocytic lymphohistiocytosis [4]) was described and the nearly simultaneous development of fatal HLH by a father and son in 1965 indicated that infection might play a role (5). HLH has since been associated with a variety of viral, bacterial, fungal, and parasitic infections, as well as collagen-vascular diseases (6-10) and malignancies, particularly T-cell lymphomas (11). There is, however, a  paucity of literature, especially from our part of the world. The present case series describes five patients seen over a 19-year period who presented with prolonged cytopenias and subsequently were proved to have hemophagocytosis on bone marrow examination.

Case Report(s)

In the present case series, we describe five patients who presented with prolonged cytopenias. Table 1 depicts the clinical features of these patients. Three out of the four patients had a diagnosis of salmonellosis confirmed by isolation of Salmonella typhi. All the patients presented with fever of varying duration with evidence of clinical bleeding (n=2). Clinical features included splenomegaly. Pancytopenia of varing severity was evidenced upon hematological investigation. Serum lactic dehydrogenase was elevated in all the patients whereas elevated ferritin and triglyceride in 2 of the five in whom it was available. Cultures form blood, urine and bone marrow aspirate were sterile.. Serologies for EBV, CMV HAV, HAB and HIV were negative in 4 of the cases and was positive in patient no 5. Bone marrow aspiration revealed evidence of hemophagocytosis (Fig 1,2). NK cell activity was normal in 2 of the patients in whom it was done. Patients with a diagnosis of enteric fever were treated with antibiotics as per culture sensitivity reports. They responded to antibiotics and their blood counts returned to normal values. Patient no 4 was treated with intravenous pulses of methyl prednisolone following which her fever subsided and counts returned to normal. Serum ferritin and LDH levels also normalized. She continues to have normal counts and is asymptomatic over a followup of 12 months.

Patient no 5 was put on steroids, etoposide and cyclosporine. The patient responded with response of fever, counts, ferritin and LDH. However he was readmitted after 4 months of his initial illness with a sepsis syndrome with recurrence of the pancytopenia. He was planned for a bone marrow transplantation but he succumbed to his sepsis.


Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life threatening condition characterized by uncontrolled activation of macrophages and lymphocytes. The syndrome, which affects mainly the pediatric population but can involve any age, has also been referred to as histiocytic medullary reticulosis and  was first described in 1939. (12) The disorder was initially belived to exist in sporadic form only but subsequently a familial form has been reported which is referred to as familial hemophagocytic lymphohistiocytosis (FHLH) (4). Familial HLH is an autosomal recessive disorder first described by Farquhar and Claireaux in 1952, (3) and is also termed variously as familiar hemophagocytic reticulosis, Farquhar's disease, familiar erythrophagocytic lymphohistiocytosis, lymphohistiocytic reticulosis with phagocytosis, or lymphohistiocytosis. Its incidence is 1.2 cases per million children under 15 years as reported in Sweden (13). Most cases are no older than three years. Evolution is similar to a septic picture but with no detectable etiologic agent. The diagnosis of FHLH is made based on the presence of clinical criteria and is confirmed by molecular genetic testing. Four disease subtypes (FHL1, FHL2, FHL3, and FHL4) are described and three genes have been identified and characterized: PRF1 (FHL2), UNC13D (FHL3), and STX11 (FHL4 (14)

Secondary HLH (acquired HLH) occurs after strong immunologic activation such as that occurs with a variety of viral, bacterial, fungal, and parasitic infections, as well as collagen-vascular diseases (7-10) and malignancies, particularly T-cell lymphomas. (11-15) Virus-associated hemophagocytic syndrome was first described in  immunodeficient patients receiving organ transplantation.(16). Subsequently, it was shown to be present even in immunocompetent patients. The main viruses involved are Epstein- Barr virus, cytomegalovirus, adenovirus and parvovirus B 19. The hemophagocytic syndrome, described in HIV positive patients, is generally associated with other viruses, especially the Epstein~Barr virus, or to other infections (1,16,17). The reactive forms of HLH are difficult to distinguish from the hereditary forms especially as patients with familial HLH may have hemophagocytic syndrome after a documented viral infection (18).  HLH has also been described in Weber-Christian's disease (as a histiocytic cytophagic panniculitis) (16); in the advanced phase of Chediak- Higashi's syndrome (1); in systemic lupus erythematosus (7) and in patients receiving parenteral feeding with high lipid content (1, 19).

The pathological hallmark of the syndrome is aggressive proliferation of macrophages and histiocytes which phagocytose other blood cells leading to the clinical symptoms. This uncontrolled growth is nonmalignant and in contrast to the lineage of cells in Langerhans cells Histiocytosis does not appear clonal. The preferential sites of involvement include spleen, lymph nodes, bone marrow, liver, skin and membranes that surround the spinal cord. (20)

Although the processes underlying the pathophysiology of HLH are not entirely understood, a current accepted theory involves an inappropriate immune reaction caused by activated T cells associated with macrophage activation and inadequate apoptosis of

immunogenic cells.(21). Perforins and NK cells have been proposed to play crucial roles in the causation of HLH even as the exact mechanisms are unclear (22-24).

Upon activation, NK cells release granules containing granzymes and perforins which form pores in the target cell membrane and causes osmotic lysis and protein degradation respectively. An impairment of the cytotoxic function of NK cells and cytotoxic T lymphocytes has been demonstrated which in turn results in increased T cell activation and expansion resulting in production of large quantities of inflammatory cytokines, including interferon α(IFN α ), tumor necrosis factor α (TNF α) and granulocyte macrophage colony stimulating factor (GM-CSF). A sustained macrophage activation and tissue infiltration as well as production of interleukins, IL-1  and IL-6, results and causes extensive damage with associated clinical and biochemical features including cytopenias, coagulopathy and high triglycerides (20).     Factors leading to cytolytic defects in acquired HLH are less clear. Viruses have been reported to interfere with T cell activity by specific proteins or cytokines (25,26).

The diagnosis of HLH is based upon finding typical clinical and biochemical features (27,28).  Five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis) were proposed to be satisfied for a definite diagnosis of HLH in the HLH-94 study (28).  In HLH-2004 three additional criteria were introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH (29). Measurement of natural killer (NK) cell activity has been shown to be useful in distinguishing primary from secondary HLH. Children with confirmed familial disease have been reported to have persistently low or absent NK cell activity. Those with secondary HLH may have low NK cell activity at presentation, but this typically normalizes with remission of illness (20, 30, 31).

Untreated, familial disease is fatal in all cases. Stem cell transplantation (SCT) is the only curative treatment.. Since many patients do not have a family history or a proven genetic defect a surrogate marker for genetic disease is persistent disease activity or relapses on or off treatment. In patients without family history and complete resolution of all symptoms, elective cessation of therapy is recommended to prevent an unnecessary SCT for transient, acquired HLH. This, however,  is not without risk since a relapse may be accompanied by severe symptoms. Thus these patients have to be closely monitored to restart therapy in time.

Also, acquired infection associated HLH has a high fatality rate of 50% in children. (32). If a treatable organism is found, appropriate therapy should be given but anti-infectious therapy may not sufficient to control HLH. The immediate aim of treatment is to suppress hypercytokinemia that is responsible for the life-threatening symptoms. Three of our cases had a antibiotics associated response of the biochemical and clinical features of HLH. There are only few reports of Salmonella infection induced HLH and has been reported to result in varied clinical and hematological features like jaundice and pancytopenia (33-41). All of our patients with typhoid fever had pancytopenia at presentation and thus hemophagocytosis could be contributory to the development of pancytopenia in patients with typhoid fever.

Standard treatment for HLH is a combination of corticosteroids, cyclosporin A and etoposide. All patients with known familial disease, suspected genetic disease, age below 1 year and patients with life-threatening symptoms such as coagulopathy, profound cytopenia or neurological disease should receive therapy according to the present HLH 2004 protocol. Etoposide may be life-saving especially in patients with EBV-associated HLH (42) and the benefit outweighs the possible side effects of etoposide.


We conclude that physicians must possess a high index of suspicion for diagnosing HLH amongst patients presenting with fever and cytopenias as appropriately administered therapy can be life saving in this potentially fatal disease.


1. Favara B. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol 1992; 9:63-74.
2. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol991 ; 18:29-33.
3. Farquhar J, Claireaux A. Familial hemophagocytic reticulosis. Arch Dis Child 1952;27:519-25.
4. Janka G. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983;140:221-30.
5. Boake W, Card WH, Kimmey JF. Histiocytic medullary reticulosis: concurrence in father and son. Arch Intern Med 1965;116:245-52.
6. Onishi R, Namiuchi S. Hemophagocytic syndrome in a patient with rheumatoid arthritis. Intern Med1994;33:607-11.
7. Wong KF, Hui PK, Chan JK, Chan YW, Ha SY. The acute lupus hemophagocytic syndrome. Ann Intern Med 1991;114:387-90.
8. Kumakura S, Ishikura H, Munemasa S, Adachi T, Murakawa Y, Kobayashi S. Adult onset Still’s disease associated hemophagocytosis. J Rheumatol 1997;24:1645-8.
9. Morris JA, Adamson AR, Holt PJ, Davson J. Still’s disease and the virus-associated haemophagocytic syndrome. Ann Rheumatol Dis 1985;44:349-53.
10. Yasuda S, Tsutsumi A, Nakabayashi T, Horita T, Ichikawa K, Ieko M, et al. Haemophagocytic syndrome in a patient with dermatomyositis. Br J Rheumatol 1998;37:1357-8.
11. Chang CS, Wang CH, Su IJ, Chen YC, Shen MC. Hematophagic histiocytosis: a clinicopathologic analysis of 23 cases with special reference to the association with peripheral T-cell lymphoma. J Formos Med Assoc 1994;93:421-8.
12. Scott R, Robb-Smith A. Histiocytic medullary reticulosis. Lancet 1939;2:194-8.
13.Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991;80:428-35.
14. Zhang K, Fillipovich AH, Johnson J. Hemophagocytic lymphochistiopcytosis, familial. In: Pagon R A, Bird TC, Dolan CR,  Stephens K, eds. Gene Reviews.Seattle (WA): University of Washington; c1993-2009. Available from∂=hlh
15. Kadin ME, Kamoun M, Lamberg J. Erythrophagocytic T gamma lymphoma: a clinicopathologic entity resembling malignant histiocytosis. N Engl J Med 1981;304:648-53.
16. Risdall RJ, Mckenna RW,Nesbit ME, et aI. Virus-associated Hemophagocytic Syndrome. A Benign histiocytic proliferation distinct from malignant histiocytosis. Cancer1979;44:993-1002.
17. Shirono K, Isuda H. Parvovirus B 19-associated haemophagocytic syndrome in healthy adults. Br J Haematol 1995;89:923-926.
18. Henter J, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr 1993;82:369-72.
19. Goulet O, Girot R, Maier-Redelsperger M, Bougle D, Virelizier JL, Ricour C. Hematologic disorders following prolonged use of intravenous fat emulsions in children.  J Parenter Enteral Nutr 1986;10:284-8
20. Arico M, Allen m, Brusa S, et al. Hemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Br J Haematol 2002;119:180-8.
21. Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of hemophagocytic lymphohistiocytosis. Expert Opin Pharmacother 2001;2: 1437-48.
22. Risma KA, Frayer RW, Fillipovich AH, Sumegi J. Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest 2006; 116:182- 92.
23. Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br j Haematol 2005;128:739-50.
24. Rieux-Laucat F, Le deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med 2005;352:306-7.
25. Jerome KR, Tait JF, Koelle DM, Corey L. Herpes simplex virus type 1 renders infected cells resistant to cytotoxic T cell induced apoptosis. J Virol 1998;72:436-41.
26. Poggi A, Costa p, Tomassaello E, Moretta L. IL-12 induced up regulation of NKRPIA expression in human NK cells and consequent NKRPIA mediated downregulation ofNK cell activation. Eur J Immunol 1998;28:1611-16.
27. Henter JI, Arico M, Elinder G, Imashuku S, et al. Familial hemophagocytic lymphohistiocytosis.Primary hemophagocytic lymphohistiocytosis.Hematol Oncol Clin North Am 1998;12:417-33.
28. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. - Henter JI - Med Pediatr Oncol - 01-MAY-1997; 28(5): 342-7
29. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Henter JI et al. Pediatr Blood Cancer. 2007 Feb;48(2):124-31.
30. Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996;10:197-203.
31.  Sullivan KE, Delaat CA, Douglas SD, Filipovich AH. Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first-degree relatives. Pediatr Res 1998;44:465-8.              &n bsp;                                 &nbs p;     32.  Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 1998;/12:/435-/444.
33. Albert A, Azgui Z, Buisine J, Ciaudo M, Fenneteau O, Fillola G, et al. Macrophage activation syndromes. Nouv Rev Fr Hematol 1992;34:435-41.
34. Fame TM, Engelhard D, Riley HD Jr. Hemophagocytosis accompanying typhoid fever. Pediatr Infect Dis 1986;5:367-9.
35. Fernandes-Costa F, Eintracht I. Histiocytic medullary reticulosis. Lancet 1979;2:204-5.
36. Lien-Keng K, Odang O, Tumbelaka W. Diagnostic value of bone marrow and blood picture in salmonellosis. Ann Pediatr 1960;194:141-9.
37. Mallory F. A histological study of typhoid fever. J Exp Med 1898;3:611-38.
38. Mallouh A, Saadi A. Hemophagocytosis with typhoid fever. Ped Infect Dis 1986;5:720.
39. Ramanathan M, Karim N. Haemophagocytosis in typhoid fever. Med J Malaysia 1993;48:240-3.
40. Udden MM, Banez E, Sears DA. Bone marrow histiocytic hyperplasia and hemophagocytosis with pancytopenia in typhoid fever. Am J Med Sci 1986;291:396-400.
41. Uzuner N, Arici A, Yilmaz E, Oren H, Kavukcu S. Typhoid fever with sever pancytopenia. Gazi Med J 2002;13:191-3.
42. Imashuku S, Kuriyama K, Teramura T, Ishii E, Kinugawa N, Kato M, Sako M, Hibi S. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol 2001;/19:/2665-2673.

Source(s) of Funding

Funded by the SheriKashmir Institute of Medical Sciences, Srinagar

Competing Interests

No conflict of interest involved for any of the authors 


This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

1 review posted so far

Critical Review on HLH
Posted by Prof. Luis Marcelo A Camargo on 14 Dec 2011 05:05:44 PM GMT

0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.


Author Comments
0 comments posted so far


What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)