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 Table of Contents  
Year : 2022  |  Volume : 12  |  Issue : 3  |  Page : 128-130

A case of PUO in diabetes mellitus

1 Department of Medicine, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Pathology, Sir Ganga Ram Hospital, New Delhi, India

Date of Submission14-Jan-2022
Date of Decision21-Mar-2022
Date of Acceptance04-Apr-2022
Date of Web Publication30-Jun-2022

Correspondence Address:
Dr. Shipra Gulati
Room 1417, Sir Ganga Ram Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmrp.cmrp_2_22

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Histoplasma capsulatum, a thermal dimorphic fungus, is the agent of histoplasmosis. It is a common cause of endemic mycosis. We report the case of a 64-year-old female, a known case of diabetes mellitus, hypertension, beta-thalassemia trait who presented with persistent fever, decreased appetite and weight loss for a period of 1 month and found to have anaemia and hepatosplenomegaly. She was diagnosed with histoplasmosis on liver biopsy. She was started on amphotericin 'B' liposomal for 14 days. She showed marked improvement symptomatically and later put on tablet itraconazole 200 mg twice a day for 1 year and was advised for follow-up.

Keywords: Fever, hepatosplenomegaly, histoplasmosis, itraconazole

How to cite this article:
Agarwal P K, Gulati S, Garg A, Jain S. A case of PUO in diabetes mellitus. Curr Med Res Pract 2022;12:128-30

How to cite this URL:
Agarwal P K, Gulati S, Garg A, Jain S. A case of PUO in diabetes mellitus. Curr Med Res Pract [serial online] 2022 [cited 2022 Aug 12];12:128-30. Available from: http://www.cmrpjournal.org/text.asp?2022/12/3/128/349290

  Introduction Top

A progressive granulomatous disease caused by intracellular dimorphic fungus Histoplasma capsulatum is known as disseminated histoplasmosis (DH).[1] It is typically seen in immunocompromised individuals, which accounts for ~70% of cases. In immunocompromised individuals, most infections are either asymptomatic or mild and self-limiting. Two varieties are known to infect humans, namely: H. capsulatum var. capsulatum H. capsulatum var. farciminosum and H. capsulatum var. duboisii (found in Africa). The disease in many cases may be asymptomatic or may manifest clinically as acute primary pulmonary type, chronic cavitatory or progressive DH (PDH).

The PDH is seen in immunocompromised individuals with risk factors such as AIDS (CD4 <20/μL), extremities of age, immunosuppressive medication, anti-tumour necrosis factor-alpha agents, methotrexate or other biologic response modifiers.[2] It can manifest as acute/subacute or chronic depending upon the duration and type of symptoms and extent of organ involvement.

  Case Report Top

A 64-year-old, female, a resident of Delhi NCR, India, homemaker by occupation a known case of diabetes mellitus, hypertension and beta-thalassemia trait, was admitted with complaints of fever for 20 days, decreased appetite and weight loss. On examination, she had pallor, tachycardia (120/min), fever (102°F) and blood pressure of 100/63 mmHg. On systemic examination, she had normal vesicular breath sounds, S1S2 heard, and per abdomen examination revealed hepatosplenomegaly. There were no palpable lymph nodes.

On investigation, her laboratory workup showed haemoglobin (7.2 g/dl), total leucocyte count (4200/cu.mm), platelet count (1.87 lakhs) and erythrocyte sedimentation rate (58). Bilirubin and transaminase levels were within normal limits while alkaline phosphatase was 221 IU/L. Renal functions were normal. Her HbA1c was 7.9%. Chest X-ray reported to be normal. Mantoux test was negative. Blood and urine cultures were sterile. Abdominal ultrasound showed hepatosplenomegaly. Tests for Widal, malaria antigen, scrub typhus IgM,  Brucellosis More Details, Leptospira IgM, viral markers for hepatitis, Weil–Felix, HIV, influenza, CMV, EBV and RK-39 were all negative. Collagen markers and anti-immune markers were all negative. Serum angiotensin-converting enzyme levels were raised 107.7 μ/L.

Given the negative infections workup and persistent fever, positron emission computed tomography (CT) was performed which showed fluorodeoxyglucose (FDG)-avid gross hepatosplenomegaly with unhomogeneous FDG uptake of the skeleton [Figure 1]. Later, a bone marrow aspiration biopsy was performed, which showed evidence of iron-deficiency anaemia with no evidence of granuloma or malignancy. Liver biopsy was positive for fungal stain and reported to be histoplasmosis [Figure 2].
Figure 1: PET scan showing increase FDG uptake in the liver and spleen. PET: Positron emission tomography, FDG: Fluorodeoxyglucose

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Figure 2: Liver biopsy with special stain (methenamine silver stain)

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Histoplasma capsular antigen was 22.8 ng/ml (raised) and Histoplasma antibody showed a titre of 1:16 (raised). The patient was treated with injection amphotericin-B and the patient showed marked improvement. Later, she was discharged on oral itraconazole 200 mg twice daily for 1 year and advised for follow-up.

  Discussion Top

The infectious form of Histoplasma, Mycelia has a characteristic appearance with microconidial and macroconidial forms. After inhalation, the microconidia settle in alveoli followed by ingestion by alveolar macrophages and are then converted to yeast form, which replicates within macrophages and spreads to the lymph node and the reticuloendothelial system. Infected macrophages then release cytokines and monocytes to fight the organism, which coalesces together to form a granuloma.[3]

The activation of T-cell-mediated immune response usually takes 2 weeks for completion, failure of which results in a spread of infection to other organ systems. Thus, PDH indicates impairment of the cell-mediated immune response.[4]

Histoplasmosis can manifest as any of three main types: acute prepulmonary type, chronic cavitary or progressive disseminated. PDH is rarest of all three types. People involved in the various types of occupation including exposure to soil rich in birds excretion and rehabilitation of building inhabited by birds have been found to be at higher risk of getting infected. DH can have multiorgan involvement, most commonly affecting the bone marrow, spleen, liver, adrenal glands and mucocutaneous system.[5] Latent histoplasmosis reactivation is rare.

Fever and weight loss are persisting symptoms in about 70% of cases. Physical findings include hepatosplenomegaly, anaemia, lymphadenopathy and others.

Many patients diagnosed with acute histoplasmosis may not require specific treatment and show spontaneous recovery. However, the treatment is recommended in all cases of PDH. Among severe case, the mortality rate of 50% has been reported, even when treatment with amphotericin has been administered. However, 98% of milder cases respond well to treatment.

DH is not uncommon aetiology of fever of prolonged duration even in immunocompetent as well as immunocompromised individuals. PDH should also be kept as differential diagnosis for pyrexia of unknown origin.

Differential diagnosis includes leishmaniasis/tuberculosis/toxoplasmosis/other fungal infections such as Cryptococcus/Candida and coccidioidomycosis.

In a study done by Lamps et al., they evaluated 52 patients and found that 43% presented with gastrointestinal rather than pulmonary symptoms, of which 10% had liver lesions. Of these, portal lymphohistiocytic inflammation was the most common hepatic lesion and discrete hepatic granulomas were seen in <20% of involved livers.[5]

In another study Radin retrospectively evaluated 16 abdominal CT scans of DH patients reported hepatomegaly (63%) and splenomegaly (38%) most commonly. Other findings included diffuse splenic hypoattenuation (19%), bilateral adrenal enlargement or hypoattenuating masses (13%), lymphadenopathy with homogeneous soft-tissue density (44%) or diffuse or central low density (13%) or both (19%). Thus, they concluded that histoplasmosis should be included in the differential diagnosis when abdominal CT scans of specifically immunocompromised patients show such nonspecific findings as hepatomegaly, splenomegaly, enlarged soft-tissue density or hypoattenuating lymph nodes or adrenal enlargement or masses.[6]

A similar case was reported by Rihana et al. in a 66-year-old female who was a known case of rheumatoid arthritis and was on immunosuppressive therapy, presented with prolonged fever and was diagnosed to have granulomatous hepatitis.[7]

Mahajan, et al. reported a series of four cases of histoplasmosis from Himachal Pradesh, India. Out of the 4 patients, 3 patients were immunocompetent and 1 patient was HIV positive. Of the cases reported, 3 patients suffered from a disseminated disease and 1 patient had a local cutaneous disease. They concluded that in their experience, IV amphotericin B should be preferred in the initial treatment till the investigation regarding the extent of the disease is awaited. However, owing to the diverse presentation of the disease, selecting an appropriate treatment regimen is the discretion of the treating physician.[8]

Thus, emphasis is laid on considering histoplasmosis as an important differential diagnosis in granulomatous hepatitis in patients of fever of unknown origin in the immunodeficient population.

  Conclusion Top

PDH should be considered a differential diagnosis in patients with a history of prolonged fever, particularly when dealing with an immunodeficient population. Primary liver involvement though uncommon is potentially life threatening. A timely diagnosis and initiation of treatment is associated with a favourable outcome.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Deepe GS Jr. Histoplasma capsulatum. In: Mandell GL, Benett JE, Dolin R, editors. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol. 2. Philadelphia: Churchill Livingstone; 2000. p. 2718-32.  Back to cited text no. 1
McKinsey DS, Gupta MR, Riddler SA, Driks MR, Smith DL, Kurtin PJ. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;111:655-9.  Back to cited text no. 2
Subramanian S, Abraham OC, Rupali P, Zachariah A, Mathews MS, Mathai D. Disseminated histoplasmosis. J Assoc Physicians India 2005;53:185-9.  Back to cited text no. 3
Goodwin RA Jr., Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: Clinical and pathologic correlations. Medicine (Baltimore) 1980;59:1-33.  Back to cited text no. 4
Lamps LW, Molina CP, West AB, Haggitt RC, Scott MA. The pathologic spectrum of gastrointestinal and hepatic histoplasmosis. Am J Clin Pathol 2000;113:64-72.  Back to cited text no. 5
Radin DR. Disseminated histoplasmosis: Abdominal CT findings in 16 patients. AJR Am J Roentgenol 1991;157:955-8.  Back to cited text no. 6
Rihana NA, Kandula M, Velez A, Dahal K, O'Neill EB. Histoplasmosis presenting as granulomatous hepatitis: Case report and review of the literature. Case Rep Med 2014;2014:879535.  Back to cited text no. 7
Mahajan VK, Raina RK, Singh S, Rashpa RS, Sood A, Chauhan PS, et al. Case report: Histoplasmosis in Himachal Pradesh (India): An emerging endemic focus. Am J Trop Med Hyg 2017;97:1749-56.  Back to cited text no. 8


  [Figure 1], [Figure 2]


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