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CASE REPORT Table of Contents   
Year : 2009  |  Volume : 52  |  Issue : 2  |  Page : 260-262
Hemophagocytic syndrome: A cause for fatal outcome in tuberculosis

Department of Pathology, Government Medical College, Nagpur, India

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Hemophagocytic syndrome is rare syndrome characterized by unregulated proliferation and activation of macrophages and phagocytosis of the platelet, erythrocytes, lymphocytes and their hematopoietic precursors in the bone marrow, resulting in cytopenias. It is associated with stimuli-like infections, malignancies and immunocompromised states. We present here a case of generalized lymphadenopathy, hepatosplenomegaly and progressive cytopenias in a 17-year-old male.

Keywords: hemophagocytosis, infections, tuberculosis

How to cite this article:
Gupta AP, Parate S N, Bobhate S K, Anupriya. Hemophagocytic syndrome: A cause for fatal outcome in tuberculosis. Indian J Pathol Microbiol 2009;52:260-2

How to cite this URL:
Gupta AP, Parate S N, Bobhate S K, Anupriya. Hemophagocytic syndrome: A cause for fatal outcome in tuberculosis. Indian J Pathol Microbiol [serial online] 2009 [cited 2022 Jan 18];52:260-2. Available from: https://www.ijpmonline.org/text.asp?2009/52/2/260/48939

   Introduction Top

Hemophagocytic syndrome is an infrequent disorder characterized by benign proliferation of mature histiocytes and uncontrolled phagocytosis of the platelet, erythrocytes, lymphocytes and their hematopoietic precursors in the bone marrow (BM). [1] Systemic manifestation in this syndrome is mainly because of cytopenias. [2] It is associated with various stimuli-like infections, malignancies and immunocompromised states. [2] We present here a case of generalized lymphadenopathy, hepatosplenomegaly and progressive cytopenias. The lymph node and BM demonstrated hemophagocytosis. On careful search, acid fast bacilli were demonstrated in the lymph node aspirate. Hence, it was diagnosed as a case of hemophagocytic syndrome associated with tuberculosis. The patient responded to steroids and anti-Koch's treatment.

   Case Report Top

A 17-year-old male presented with fever, edematous feet and distention of the abdomen of 15 days duration. His general condition was bad, with gross pallor and generalized lymphadenopathy, i.e. bilateral cervical, axillary and inguinal, ranging from 1 × 1cm to 4 × 4cm. He had sternal tenderness and macular rash over the body. An examination of the abdomen revealed ascitis.

Ultrasonography of the abdomen revealed free fluid, hepatosplenomegaly and hypoechoic mass in the right lobe of the liver and extensive intra-abdominal lymphadenopathy. X-ray of the chest showed bilateral pleural effusion.

Hematological investigations revealed hemoglobin of 7gm%.

Peripheral smear was normocytic and moderately hypochromic. The total leukocyte count was 6000 cells/mm 3 initially but decreased to 4000 cells/mm 3 4-5 days later and 3000cells/mm 3 within 10 days. The differential leukocyte count was within normal limits. Platelets were depleted, with a count of 70,000 cells/mm 3 . The red blood cell count was 3.5 × 10 6 /micro liter and the erythrocyte sedimentation rate by Wintrobe method was 40mm.

Random blood sugar was 89mg%, serum lactate dehydrogenase was 540U/L, triglycerides were 280mg/dL, serum ferritin was 960mcg/L, C-reactive proteins were positive, test for lupus erythematosus cells was negative, liver function tests were within normal limits and the Widal test and the enzyme-linked immunosorbant assay for human immunodeficiency virus (HIV) were negative.

Ascitic fluid cytology revealed lymphocytosis. Initial fine needle aspiration cytology from the cervical lymph nodes showed only acellular necrotic material. Acid fast bacilli could not be demonstrated on Ziehl Neelsen stain.

Cervical lymph node biopsy showed dilated sinuses containing macrophages. The lymphocytes were small and mature, with few reactive cells. The macrophages had abundant cytoplasm and eccentrically or centrally placed bland nuclei. The cytoplasm was stuffed with red blood cells and some contained vacuoles [Figure 1a] and [Figure 1b]. Red blood cells are better seen in the inset. Masson's trichrome stain was performed, which highlighted the red blood cells in the macrophages [Figure 2].

Because of the increasing cytopenias, generalized lymphadenopathy, hepatosplenomegaly and the high suspicion of lymphoreticular malignancy, BM aspiration was performed, which showed hypocellularity with focal necrotic areas. The myeloid-erythroid ratio was within normal limits. The myeloid and erythroid cells showed normal maturation. Smears showed few lymphocytes, reactive plasma cells and large histiocytes containing engulfed red blood cells, nuclear debris and platelets [Figure 3].

Because of a strong clinical suspicion of lymphoreticular malignancy, aspiration cytology was repeated from two other cervical lymph nodes, which again showed necrotic material, but after a careful search, acid fast bacilli were demonstrated on Ziehl Neelsen staining. Hence, the case was diagnosed as hemophagocytic syndrome associated with tuberculosis.

The patient was started on antitubercular therapy and dexamethasone. Significant response was noted in the form of absence of fever and increasing counts within one and a half months.

   Discussion Top

Hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (HLH) is a disorder characterized by benign proliferation of the mature histiocyte and uncontrolled phagocytosis of the platelet, erythrocytes, lymphocytes and their hematopoietic precursors in the BM giving rise to cytopenias. [1],[2],[3] It has an abrupt onset of systemic manifestations like pallor, fever, rash, lymphadenopathy, hepatosplenomegaly, neurological manifestations, raised lactate dehydrogenase (LDH) and serum bilirubin. Many patients present with fever of unknown origin. [4] It takes a fulminant course and has a fatal outcome. [1],[2]

According to the criteria laid down by the Histiocyte Society protocol entitled HLH 2004, the diagnosis of HLH, can be established if five of the following eight criteria are fulfilled: [5]

  1. Fever (≥7 days),
  2. splenomegaly,
  3. cytopenia (≥2 lineages), anemia (Hb <9.0g/dL), thrombocytopenia (<100,000 cells) and neutropenia (<1000),
  4. hypertriglyceridemia (≥ 265 mg/dL) and/or hypofibrinogenemia (<1.5g/L),
  5. hemophagocytosis (BM, spleen, lymph nodes),
  6. low/absent natural killer cell activity,
  7. hyperferritinemia (≥500mcg/L) and
  8. increased soluble CD25 > 2400units/mL.

In our case, six of the eight criteria were present. Hence, the case was diagnosed as hemophagocytic syndrome associated with tuberculosis.

HLH is subdivided into familial HLH, a familial disorder due to genetic mutations and secondary or acquired HLH. Secondary HLH is associated with various stimuli-like infections, [3],[5] T cell lymphoma and immunocompromised states. Among the infections, Epstein-Barr virus (EBV) is the most common. Others are cytomegalovirus, adenovirus, parvovirus B19, HIV, bacteria like Mycobacterium tuberculosis , some gram-positive and -negative bacteria, fungi and protozoa like  Babesia More Details microti . [2] On literature search, cases have been reported in association with collagen vascular disorders, [6] EBV infection and T cell lymphoma. [1],[2] Few cases of tuberculosis were associated with miliary tuberculosis, HIV and mycoplasma infection, respectively. [7],[8],[9]

Excessive hemophagocytosis is said to be due to release of chemokines and cytokines, i.e. interferon-γ, interleukins-1, 2 and 6 and tumor necrosis factor (TNF)-α. [1],[2] It is preceded in some patients by proliferation of activated or neoplastic EBV-infected T lymphocytes that produce TNF-2. [2]

All reactive hemophagocytic syndromes have a similar morphology. They may show phagocytosis in the lymph nodes, BM, spleen and liver and necrosis in the lymph nodes and cytopenias. [1],[2] A careful search for primary pathology is essential for effective treatment.

These patients need to be diagnosed early because they have shown a response to steroids, cyclosporine-A, etoposide and treatment of primary cause. [1],[2] Goto et al. [10] have reported a successfully treated case of disseminated tuberculosis who responded to acute blood purification. Early diagnosis of hemophagocytic syndrome as well as primary disease and treatment are essential to avoid a fatal outcome.

Our case was a hemophagocytic syndrome associated with tuberculosis and was put on steroids and anti-Koch's treatment and had started responding.

   References Top

1.Brunning RD. Bone Marrow. In: Rosai and Akerman's surgical pathology. 9 th ed. St. Louis, Missouri, USA: MOSBY Elsevier Inc; 2005. p. 2097-8.  Back to cited text no. 1    
2.Fisman DN. Hemophagocytic syndrome and infection. Emerg Infect Dis 2000;6:601-8.  Back to cited text no. 2  [PUBMED]  
3.Chan JK, Ng CS, Law Ck, Ng WF, Wong KF. Reactive hemophagocytic syndrome: A study of seven fatal cases. Pathology 1987;19:43-50.  Back to cited text no. 3  [PUBMED]  
4.Palazzi DL, Kenneth L, McClain KL, Kaplan SL. Hemophagocytic Syndrome in children. An important diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003;36:306-12.  Back to cited text no. 4    
5.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;48:124-31.  Back to cited text no. 5    
6.Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, et al. Reactive hemophagocytic syndrome in adult systemic disease: Report of twenty-six cases and literature review. Arthritis Rheum 2003;49:633-9.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Browett PJ, Varcoe AR, Fraser AG, Ellis-Pegler RB. Disseminated tuberculosis complicated by the Hemophagocytic syndrome. Aust NZ J Med 1988;18:79-80.  Back to cited text no. 7    
8.Campo E, Condom E, Mario MJ, Cinta M, Romagosa V. Tuberculosis-associated hemophagocytic syndrome: A systemic process. Cancer 1986;58:2640-5.  Back to cited text no. 8    
9.Subhash HS, Sowmya S, Sitaram U, Cherian AM. Tuberculosis-associated haemophagocytic syndrome. J Postgrad Med 2001;47:220.  Back to cited text no. 9  [PUBMED]  Medknow Journal
10.Goto S, Aoike I, Shibasaki Y, Morita T, Miyazaki S, Shimizu T, et al . A successfully treated case of disseminated tuberculosis-associated hemophagocytic syndrome and multiple organ dysfunction syndrome. Am J Kidney Dis 2001;38:E19.  Back to cited text no. 10  [PUBMED]  

Correspondence Address:
Anupama P Gupta
Flat No. 203, Shyam Dham, C.A.Road, Near Ambedkar Square, Babulban, Nagpur - 440 008
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.48939

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  [Figure 1a], [Figure 1b], [Figure 2], [Figure 3]

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