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Year : 2020  |  Volume : 63  |  Issue : 1  |  Page : 161-163
Uncommon presentation of a common tropical infection

1 Department of Microbiology, Apollo Gleneagles Hospitals, 58, Canal Circular Road, Kolkata, West Bengal, India
2 Department of Internal Medicine, Apollo Gleneagles Hospitals, 58, Canal Circular Road, Kolkata, West Bengal, India

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Date of Web Publication31-Jan-2020

How to cite this article:
Ray U, Dutta S, Bandyopadhyay S, Mondal S. Uncommon presentation of a common tropical infection. Indian J Pathol Microbiol 2020;63:161-3

How to cite this URL:
Ray U, Dutta S, Bandyopadhyay S, Mondal S. Uncommon presentation of a common tropical infection. Indian J Pathol Microbiol [serial online] 2020 [cited 2022 Dec 8];63:161-3. Available from:


Hemophagocytic lymphohistiocytosis (HLH) is characterized by an unremitting activation of CD8+ T lymphocytes and macrophages that engulf erythrocytes, leucocytes, platelets, and their precursor cells. HLH is a distinct clinical entity characterized by fever, pancytopenia, splenomegaly, and hemophagocytosis in bone marrow, liver, or lymph nodes and is associated with high mortality rates. HLH may be familial or secondary to a variety of infections, collagen vascular disease, or malignancies. Although HLH is now being increasingly detected in clinical practice due to improved understanding on the part of physicians, pathologists, and microbiologists, much work remains to raise awareness, explore treatment options, and improve outcome of this complex condition. We report two cases of HLH secondary to a common tropical infection.

A 24-year-old woman presented with high-grade fever (temp. max 103°F) with chills and rigor for 5 days and loose stool for 1 day. On examination, he was febrile, pulse rate was 120/min, and blood pressure was 110/70 mmHg. Physical examination was remarkable for toxic look and moderate hepatosplenomegaly. Laboratory investigations were significant for leukopenia (white blood cell [WBC] count 2670 mm-3; reference value [RV]: 5000–13,000 mm-3), thrombocytopenia (platelet count 90,000 mm-3; RV: 1.7 × 105–4 × 105 mm-3), raised ferritin (10,250 ng/ml; RV: 30–400 ng/ml), and triglycerides (290 mg/dl; RV: up to 150 mg/dl). Serial monitoring of the hematological parameters revealed a falling leucocyte and platelet count [Figure 1]. Bone marrow aspiration done on day 4 of hospitalization showed features of marked hemophagocytosis [Figure 2]. Blood culture collected at the time of admission showed growth of gram-negative bacilli, which was subsequently identified as  Salmonella More Details typhi on the basis of biochemical tests and confirmed by serotyping. Following isolation of S. typhi, she was treated with ceftriaxone (1 g IV BD) to which the S. typhi showed susceptibility. The patient became afebrile and the counts started improving by day 8 of admission. At the time of discharge 11 days post admission, there was almost normalization of blood parameters and resolution of symptoms.
Figure 1: Trend of laboratory results. D: day of illness; WBC: total white blood count (mm3); PC: platelet count (mm3); AST: aspartate transaminase (IU/l); ALT: alanine transaminase (IU/l); Fe: ferritin (μg/l); TG: triglycerides (mg/dl). All units are converted to Log10 scale in the figure

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Figure 2: Leishman stain of bone marrow biopsy (in 40× magnification) showing macrophage with marked hemophagocytic activity. Nuclei of RBC and WBC precursor cells are seen within cytoplasm of macrophage

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A 15-year-old boy presented on day 5 of illness with high fever, anorexia, abdominal pain, and vomiting. Blood tests showed bicytopenia (low WBC and platelet counts), raised transaminases, hypertriglyceridemia, and high ferritin levels. Blood culture collected at the time of admission showed growth of S. typhi and initial antibiotics were substituted with ceftriaxone on day 3. Despite appropriate antibiotics and other supportive care, the patient remained unwell with spikes of temperature, abdominal pain, vomiting, and restlessness. On day 4 of hospitalization blood pressure dropped to 84/54 mmHg and the patient developed respiratory distress and was shifted to the intensive care unit. Blood tests showed progressive bicytopenia [Figure 3]. The patient was diagnosed as a case of secondary HLH triggered by S. typhi, although bone marrow study performed at day 4 of admission did not reveal any hemophagocytic activity. Dexamethasone (6.5 mg BD) was instituted in gradually tapering dose. The patient improved over the next few days and was discharged after 12 days in the hospital. At the time of discharge, the counts had improved and other inflammatory parameters had subsided.
Figure 3: Trend of laboratory results. D: day of illness; WBC: total white blood count (mm3); PC: platelet count (mm3); AST: aspartate transaminase (IU/l); ALT: alanine transaminase (IU/l); Fe: ferritin (μg/l); TG: triglycerides (mg/dl). All units are converted to Log10 scale in the figure

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Extensive workup for other common tropical infections such as malaria, cytomegalovirus, Epstein-Barr virus (EBV), dengue, leptospirosis, and rickettsiosis came back negative for both the patients.

HLH is a disease with major therapeutic and diagnostic difficulties. The diagnosis of HLH was based on five criteria: fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis.[1] In 2004, three additional criteria were introduced by the histiocyte society; low or absent natural killer (NK)-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor level.[2] Five of these eight criteria must be fulfilled for a diagnosis of HLH.

In both patients the following diagnostic criteria of HLH were fulfilled: fever, splenomegaly, bicytopenia (decrease in platelets and leucocytes), hyperferritinemia, and hypertriglyceridemia. Both patients tested negative for other infectious etiologies such as malaria, cytomegalovirus, EBV, leptospira, rickettsial disease, dengue, which are common triggers of HLH. In case of the first patient, there was presence of hemophagocytes in the bone marrow but bone marrow study was essentially normal in the second patient. Although hemophagocytosis is the hallmark of the disease, it is seldom found at presentation in case of secondary HLH and may not be apparent until late in the course of disease progression. Bone marrow biopsies performed in the initial stage of disease may be normal or demonstrate very nonspecific changes.[3]

HLH may be primary or secondary. Secondary HLH develops due to a strong immunological activation of the immune system. Secondary HLH has been associated with a variety of viral, bacterial, fungal, and parasitic infections as well as collagen vascular diseases and malignancies, particularly T-cell lymphomas.[4] The term reactive HLH has been suggested when HLH is associated with an identifiable infectious or noninfectious etiology, to distinguish it from the familial form. Infection has been found to be associated with HLH in half of all reported cases.[3]

Phagocytosis of blood cells and their precursors is a hallmark of hemophagocytic syndromes. Hemophagocytosis is accomplished mostly by monocytes and macrophages. Excessive activation of monocytes in HLH is due to stimulation by high levels of activating cytokines. It has been recognized that high levels of cytokines such as interferon-γ, soluble interleukin-2 receptor, tumor necrosis factor (TNF-α), interleukin-1, and interleukin-6 by T helper cells results in stimulation of macrophages leading to the cascade of events.[4]

Hemophagocytosis is associated with diverse and medically important infectious diseases and has been reported in patients with severe cases of intracellular microbial infection, including avian influenza, leishmaniasis, tuberculosis, typhoid fever, and others.[4],[5],[6] Among the bacterial pathogens activating HLH, there are some reports of S. typhi-triggered HLH in the literature.[7],[8] As early as the mid-1800s, hemophagocytic macrophages, which are macrophages that have consumed red blood cell (RBC) and WBC, were observed in the tissues and blood of recently deceased typhoid fever patients.[9]

The association with infections is particularly important because overwhelming HLH can obscure the typical clinical features of the primary disease, as has been described in case of leishmaniasis, or HLH may itself mimic infectious illnesses such as overwhelming bacterial sepsis and leptospirosis.[4]

The aim of infection-associated HLH is to treat the inciting infection but in around 30–40% of cases require specific HLH therapy. The only exception to this rule is leishmania-induced HLH, which is successfully treated with amphotericin B only. Glucocorticoids, cyclosporine intravenous immunoglobulin, and various other drugs have been used to suppress the immunological onslaught. Etoposide has been shown to be lifesaving in case of EBV-induced HLH. In the first case with the early institution of appropriate antibiotics there was resolution of the HLH. Immunomodulators were not required and the patient made an uneventful recovery. The second patient notwithstanding appropriate antibiotics deteriorated hemodynamically and dexamethasone was instituted following which the patient stabilized and gradually made a recovery. Thus, it is of paramount importance to recognize HLH early followed by close monitoring of the clinical, hematological and biochemical parameters as this condition might progress rapidly and may prove fatal. Institution of HLH-specific therapy is essential if the condition does not resolve following treatment of the underlying disease.

Thus, these cases highlight the serious immunological phenomenon triggered by a common tropical infection. Enteric fever, transmitted via the fecal-oral route, is endemic in the developing countries of Asia, Africa, Latin America, the Caribbean, and Oceania with an estimated 13.5 million episodes in 2010.[10] There are few cases of enteric fever-induced HLH reported in the literature, and it is possible that secondary HLH due to typhoid fever go unrecognized possibly due to lack of awareness about this entity. Leucopenia and splenomegaly, two of the diagnostic criteria of HLH, are also pathognomonic features of typhoid fever, and therefore, secondary HLH triggered by enteric fever may be difficult to identify. In enteric fever patients with progressive bicytopenia despite appropriate antibiotics, the diagnosis of HLH should be considered. Minimal diagnostic parameters to establish HLH are a complete hemogram, liver function test, serum triglycerides, and ferritin. Ferritin has been found to be particularly useful and elevated levels >10,000 μg/L has been found to be 90% sensitive and 96% specific for HLH.[4] The tests for quantification of NK cells and sIL2 receptor, two of the criteria included in 1997 for the diagnosis of HLH are not done in all hospitals and when performed the results are available after some time. These tests should not be crucial for the diagnosis, let alone the commencement of treatment provided there is a high index of suspicion.

Typhoid, a widespread tropical disease, can cause HLH as this report and other similar cases reported in the literature seem to suggest. Treatment of the bacterial pathogen is often not adequate and in certain cases it is important to start lifesaving therapy with immunomodulators and immunosuppressants sufficiently early. Awareness about clinical symptoms and diagnostic criteria of HLH are essential for successful outcome.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Henter JI, Elinder G, Ost A, The FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 1991;18:29-33.  Back to cited text no. 1
Henter JI, Horne A, Aricó M, Egeler M, Filipovich A, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124.  Back to cited text no. 2
George MR. Hemophagocytic lymphohistiocytosis: Review of etiologies and management. J Blood Med 2014;5:69-86.  Back to cited text no. 3
Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601-8.  Back to cited text no. 4
Janka GE. Haemophagocytic syndromes. Blood Rev 2007;21:245-53.  Back to cited text no. 5
La Gruta NL, Kedzierska K, Stambas J, Doherty PC. A question of self-preservation: Immunopathology in influenza virus infection. Immunol Cell Biol 2007;85:85-92.  Back to cited text no. 6
Non LR, Patel R, Esmaeeli A, Despotovic V. Typhoid fever complicated by hemophagocytic lymphohistiocytosis and rhabdomyolysis. Am J Trop Med Hyg 2015;93:1068-9.  Back to cited text no. 7
Singh ZN, Rakheja D, Yadav TP, Shome DK. Infection-associated haemophagocytosis: The tropical spectrum. Clin Lab Haematol 2005;27:312-5.  Back to cited text no. 8
Mallory FB. A histological study of typhoid fever. J Exp Med 1898;3:611-38.  Back to cited text no. 9
Buckle GC, Walker CLF, Black RE. Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010. J Glob Health 2012;2:010401.  Back to cited text no. 10

Correspondence Address:
Ujjwayini Ray
Apollo Gleneagles Hospitals, 58, Canal Circular Road, Kolkata - 700 054, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_306_18

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