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Year : 2017  |  Volume : 6  |  Issue : 3  |  Page : 197-199


Department of Medicine, S. N. Medical College, Agra, Uttar Pradesh, India

Date of Web Publication25-Sep-2017

Correspondence Address:
Prabhat Agrawal
d-1, Sulahkul Nagar, Bodla Road, Agra - 282 010, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2277-8632.215527

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Hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition characterized by uncontrolled hyperinflammation caused by various inherited or acquired immunodeficiency states. Cardinal symptoms are prolonged fever, hepatosplenomegaly, lymphadenopathy, rash, and central nervous system symptoms. Laboratory findings include high triglycerides, ferritin, transaminases, bilirubin and alpha chain of the soluble IL2 receptor, and decreased fibrinogen. A hallmark of HLH is impaired or absent function of natural killer cells and cytotoxic T cells. Hemophagocytosis, which has given the disease its name, is found in only a minority of cases at presentation, and its occurrence increases as the disease progresses.

Keywords: Etoposide, hemophagocytic lymphohistiocytosis, NK cells

How to cite this article:
Agrawal P, Raj A, Bansal M, Agrawal A, Upadhyay S. Lymphohistiocyosis. J NTR Univ Health Sci 2017;6:197-9

How to cite this URL:
Agrawal P, Raj A, Bansal M, Agrawal A, Upadhyay S. Lymphohistiocyosis. J NTR Univ Health Sci [serial online] 2017 [cited 2022 Jan 26];6:197-9. Available from: https://www.jdrntruhs.org/text.asp?2017/6/3/197/215527

  Introduction Top

Fever is a common complaint in the Indian subcontinent, the true cause of which is often ignored. Poor hygiene and the high prevalence of diseases like malaria, dengue and typhoid, mostly leads to a treatment without investigating the true nature or the cause of the febrile illness. The patient on his part keeps switching doctors if he does not get relief. Through this article we would like to emphasize that, if a patient is not responding to therapy and presents with prolonged fever associated with hepatosplenomegaly, pancytopenia, and/or rash, the diagnosis of hemolymphocytosis (HLH) should be considered.

  Case Report Top

A 42-year-old male Muslim, restaurant owner by occupation, came to our emergency department with the chief complaints of nausea, loss of appetite, pain in the abdomen, night sweats, and high grade fever, which was occasionally associated with chills and rigors, for the past 2 weeks. There was no fixed pattern of the fever, no diurnal variations, and it was not associated with cough or expectoration. On inquiry, the patient did not give any history suggestive of a urinary tract infection, no history of rash, jaundice, blood transfusion, recent vaccination, loose motion, headache, joint pain, any sexual contact hematuria, bleeding from any other site, arthralgia, dryness of eyes, mouth ulcers, or any regular drug intake. There was no history of any recent foreign travel or eating raw meat or consuming unpasteurized milk.

On examination, the patient's vitals were stable and he did not have pallor, icterus, clubbing, cyanosis, lympadhenopathy, or edema. Systemic examination was normal, except that on abdomen examination, there was mild splenomegaly. His investigations revealed haemoglobin 12.4 gm%, total leucocyte count 4500 (N-60, L-31, E-3, M-6), platelet count 1.31 lakh/mm3, erythrocyte sedimentation rate 68, serum creatinine 1.1 mg/dl, serum bilirubin (T) 1.4, serum lipase 34.2, and serum amylase 36. Enzyme-linked immunosorbent assay (ELISA) and Widal and typhidot were negative. The patient was put on injection ceftriaxone and mikacin, tab paracetamol, and was given artesunate coverage for malaria. The patient did not improve and was subsequently put on injectable chloroquine 4 days later. Ultrasonography (USG) revealed mild hepatosplenomegaly, but his chest X-ray was normal. Urine examination revealed occasional pus cells with alb 1+. However, the culture was sterile.

The patient still did not improve and repeat counts were done 4 days later. His hemoglobin was 9.6 gm%, total leucocyte count was 4100 (N-87, L-13), platelet count was 1.22 lakh, erythrocyte sedimentation rate was 50, SGPT was 85, serum bilirubin (T) was 0.6, serum creatinine was 1.5 and blood Urea was 43.8; serum lactate dehydrogenase (LDH) was elevated 2240 U/L (300–620 U/L). Serum electrolytes were within normal limits, and his blood culture was sterile for bacteria and fungus. Human immunodeficiency virus (HIV) and serology for hepatitis A and B were negative. Dengue serology testing and quantiferon testing for tuberculosis was also nonreactive. As before, our efforts bore no fruit and the patient began to deteriorate. Three days later, he became icteric and his liver function test (LFT) showed a serum bilirubin of 4.8 (D-4.3, I-0.5), SGPT of 232.2, and alkaline phosphatase of 522.0. A repeat HIV testing and ANA, RA factor, ANCA were also negative. Direct coomb's test was also negative. A repeat USG abdomen showed moderate hepatosplenomegaly, with a thickened and edematous gall bladder wall. Mild ascites and mild right-sided pleural effusion was also noted.

Despite aggressive treatment, the general condition of the patient did not improve, and in the following days he started to complain of generalized weakness. His hemoglobin reduced to 8.8 gm%, total leucocyte was 3300 (N-54, L-44, E-1, M-1), R count was 4.2%, platelet count was 54,000 per cubic mm, and erythrocyte sedimentation rate was 60. Peripheral blood smear showed microcytic hypochromic red blood cells with mature white blood cells with little shift to left side along with few pencil and target cells were also visible. Although his serum bilirubin had also increased to 5.7 (D-5.0, I-0.7), his SGPT levels came back to normal. Serum protein was 6.31, serum albumin was 2.87, and serum globulin was 3.44. His renal function tests and other liver function tests (LFTs) were within normal limits, and his sputum acid fast stain examination did not reveal any pathologic organism. All electrolyte tests were normal and filarial antigen tests were negative. Again dengue and ELISA were repeated, which were both negative. Serology for  Brucella More Details and Leptospirosis were also negative.

Repeat testing was done on subsequent days, which showed improvements in his serum bilirubin, but the patient had persistent pancytopenia. Following this, two units of fresh whole blood were transfused to the patient. Post blood transfusion, his blood profile was hemoglobin 11.2, total leucocyte count 2700 (N-56, L-39, E-1, M-4), platelet count 2.5 lakh, and serum bilirubin (T) 1.89. Serum fibrinogen level decreased to 98 mg/dl (150–400 mg/dl), and serum trigycerides were high (288 mg/dl); ferritin was 106 mg/dl. Urine analysis was normal. Echocardiography showed normal ventricular functions. Screening for TORCH organisms was done the next day, which came out positive for Herpes. Herpes IgM titre was 1.36 (>1.10). Polymerase chain reaction (PCR) for herpes was advised, which was positive (>3.5). Bone marrow aspiration and biopsy showed a hypercellular marrow with presence of many monocytes and marked hemophagocytosis, with no evidence of any malignant or immature cells. On the basis of PCR findings of herpes and bone marrow examination, a diagnosis of acquired HLH was made and the appropriate therapy with acyclovir, dexamethasone, and cyclosporin A (CSA) was started. The patient started showing signs of improvement and is in our regular follow-up every 15 days.

  Discussion Top

HLH is not a single disease but can be encountered in association with a variety of underlying conditions leading to the same hyperinflammatory phenotype.[1] Both genetic and acquired forms are triggered by infections,[2] mostly viruses, or other stimuli. Epstein bar virus (EBV) was found to be the triggering virus in 74% of the children in whom an infectious agent could be identified.[3]

Diagnostic criteria:[4]

  1. Familial disease/known genetic defect
  2. Clinical and laboratory criteria (5/8 criteria should be present)
    • Fever
    • Splenomegaly
    • Cytopenia (involving 2 or more cell lines)
      • Hemoglobin <9 gm/dl
      • Neutrophils <1000 cells/dl
      • Platelet count <100,000/dl
    • Hypertriglyceridemia and/or hypofibrinogenemia
      • Fasting triglycerides ≥3 mmol/l
      • Fibrinogen <1.5gm/l
    • Ferritin ≥500 μg/l
    • sCD25 ≥2400 U/ml
    • Decreased or absent NK cell activity
    • Hemophagocytosis in the bone marrow, lymph nodes, or CSF

Supportive evidence is the presence of cerebral symptoms with moderate pleocytosis and/or elevated proteins, elevated transaminases, and bilirubin, LDH of >1000 U/L.

The immediate aim of therapy is suppression of the increased inflammatory response and to kill pathogen-infected, antigen-presenting cells. In patients with less severe symptoms, corticosteroids and immunoglobulin infusions are sometimes sufficient to control the symptoms. However, if the symptoms progress, etoposide and CSA should be instituted.[5] The symptoms and laboratory abnormalities usually show improvement within 2–3 weeks of treatment. Familial cases and those with recurrences (presumed to be genetic in origin) subsequently received bone marrow transplantation and the probability of survival at 3 years was found to be 55% for all cases and 51% for familial cases.[6]

Our patient of prolonged febrile illness was diagnosed as a case of acquired HLH (Herpes induced) and responded well to therapy. Here, we suggest that in all cases of unexplained fever of long duration, a diagnosis of HLH be considered as prompt diagnosis and treatment can greatly enhance the patient's life expectancy.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601-8.  Back to cited text no. 1
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;12:435-44.  Back to cited text no. 2
Jin-Seok Lee, Jin-Han Kang, Geon-Kook Lee, Hyeon-Jin Park J. Successful Treatment of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis with HLH-94 Protocol. Korean Med Sci 2005;20:209-14.  Back to cited text no. 3
Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am 2008;28:293-313.  Back to cited text no. 4
Imashubu S, Kuriyama K, Teramura T, Ishu T, Kinugawa N, Koto M, et al. Requirement for Etoposide in the Treatment of Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis. J Clin Oncol 2001:2665-73.  Back to cited text no. 5
Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M, Haddad E, Le Deist F, Benkerrou M, et al. Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors. Blood 1997;90:4743-8.  Back to cited text no. 6


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