Case Report: Histoplasmosis Accompanying Disseminated Tuberculosis in an Immunocompetent Adolescent Boy

INTRODUCTION

The incidence of tuberculosis in India is around 204 per 100,000 population per year.¹ Diagnostically proven cases of tuberculosis with typical symptoms are seldom explored for coexistence of other infections, especially in an immunocompetent host. We present the case of an adolescent boy who presented with a fever with lymphadenopathy, splenomegaly, and pancytopenia. Although initially diagnosed as tuberculosis, persistence of fever despite antitubercular therapy (ATT) led us to further investigate the patient, which resulted in the detection of coexistent histoplasmosis.

CASE REPORT

A 15-year-old boy from Azamgarh city in the eastern part of Uttar Pradesh state of northern India presented with a high-grade fever (up to 103.5°F) for one and a half months. He also complained of easy fatigability and exertional breathlessness on less than normal exertion, but no cough. On examination, a single firm and freely mobile, non-tender right lower jugular lymph node of size 1 × 1 cm was palpable. The spleen was also palpable 2 cm below the left costal margin.

At presentation, he had a hemoglobin level of 9.2 g/dL, a mean cell volume of 101 fL, a total leukocyte count of 1,590/µL (55% neutrophils and 39% lymphocytes), and a manual platelet count of 67,000/µL. The peripheral blood smear microscopy revealed marked leucopenia and moderate thrombocytopenia with no blast cells, toxic granules, or malarial parasites, and his corrected reticulocyte count was 1.02. No abnormalities were observed in the morphology of white blood cells on microscopy. Further diagnostic workup for febrile illnesses with pancytopenia was performed. HIV serology was negative. Ultrasonography of the abdomen revealed mild hepatomegaly and moderate splenomegaly. An ostium secundum type of atrial septal defect was evident on transthoracic echocardiography but without any evidence of vegetations. Four blood cultures performed were sterile. Histological examination of bone marrow biopsy specimen revealed numerous caseating granulomas in the intra-trabecular spaces (Figure 1). Histopathology of the biopsied enlarged cervical lymph node showed extensive caseation necrosis with epitheloid histiocytes with Langhans giant cells. Ziehl–Neelsen staining of the lymph nodal tissue was performed and was positive for acid-fast bacilli. Three samples from the patient were sent for cartridge-based nucleic acid amplification test (CBNAAT)–bone marrow aspirate, lymph node biopsy specimen, and pus from lymph node. The CBNAAT is highly sensitive and specific for Mycobacterium tuberculosis (MTB).^2,3 Whereas the first two samples were negative for MTB, the pus sample was positive for MTB which was sensitive to rifampicin. Mycobacterium tuberculosis culture was performed using liquid culture system only for bone marrow sample, which was negative. A diagnosis of disseminated tuberculosis was made as per operational guidelines of the Indian Tuberculosis Control Programme, and ATT was started with standard four-drug regimen of rifampicin, isoniazid, pyrazinamide, and ethambutol.⁴ Vitamin B12 deficiency was ascribed to the patient’s almost entirely vegetarian food habit. Injectable vitamin B12 was started for macrocytic anemia. The pancytopenia responded within 1 week, and the patient was discharged on ATT and oral vitamin B12.

Histopathology of bone marrow biopsy specimen (Hematoxylin & Eosin stain, ×40 magnification) showing caseating granuloma with arrow showing Langhans-type giant cell.

Citation: The American Journal of Tropical Medicine and Hygiene 102, 2; 10.4269/ajtmh.19-0421

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Histopathology of bone marrow biopsy specimen (Hematoxylin & Eosin stain, ×40 magnification) showing caseating granuloma with arrow showing Langhans-type giant cell.

Citation: The American Journal of Tropical Medicine and Hygiene 102, 2; 10.4269/ajtmh.19-0421

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Histopathology of bone marrow biopsy specimen (Hematoxylin & Eosin stain, ×40 magnification) showing caseating granuloma with arrow showing Langhans-type giant cell.

Citation: The American Journal of Tropical Medicine and Hygiene 102, 2; 10.4269/ajtmh.19-0421

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After 2 months of follow-up, the boy again presented with a fever (measured up to 102°F) with evening rise of temperature and significant loss of weight. Multidrug-resistant tuberculosis was suspected. A repeat bone marrow aspiration was performed, and the aspirate was subjected to CBNAAT again. Mycobacterium tuberculosis culture, fungal staining, and fungal culture were also performed. Tests for MTB were all negative, presumably because the patient had received 2 months of ATT. Fungal staining of bone marrow aspirate revealed few budding yeast forms. Microscopy of the bone marrow fungal culture revealed spiked spherical conidia suggestive of Histoplasma capsulatum (Figure 2). The mold phase was successfully cultured in the brain heart infusion agar with blood, to isolate the yeast phase of the fungus. The patient was administered injectable lipid amphotericin B 5 mg/kg body weight per day for 2 weeks. The fever responded in 1 week along with dramatic improvement in the general condition of the patient. The patient was discharged on oral itraconazole 200 mg twice daily and ATT. The patient has been on follow-up for more than 14 months. He has been free from any illness during this period and has gained weight.

Lactophenol cotton blue mount from bone marrow culture with thick black arrows showing tuberculate macroconidia indicative of Histoplasma capsulatum (×40 magnification).

Citation: The American Journal of Tropical Medicine and Hygiene 102, 2; 10.4269/ajtmh.19-0421

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Lactophenol cotton blue mount from bone marrow culture with thick black arrows showing tuberculate macroconidia indicative of Histoplasma capsulatum (×40 magnification).

Citation: The American Journal of Tropical Medicine and Hygiene 102, 2; 10.4269/ajtmh.19-0421

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Lactophenol cotton blue mount from bone marrow culture with thick black arrows showing tuberculate macroconidia indicative of Histoplasma capsulatum (×40 magnification).

Citation: The American Journal of Tropical Medicine and Hygiene 102, 2; 10.4269/ajtmh.19-0421

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DISCUSSION

The incidence of histoplasmosis in India is underappreciated. Reports of H. capsulatum being isolated from the soil of the Gangetic plain exist since 1975.⁵ Many cases have been reported from the eastern part of India such as the state of West Bengal, traversed by the river Ganges.⁶ Incidentally, the patient in the current case belonged to Azamgarh in the eastern part of Uttar Pradesh in northern India, which also lies on the Ganges plain. Histoplasmosis is of late being reported as an endemic infection in developing Asian countries such as China, and hence endemicity of this fungus in India is a strong possibility.⁷ It has been suggested that histoplasmosis in India may not be rare but instead just underdiagnosed.⁸ The predominant presentation of histoplasmosis in the Indian subcontinent is as progressive disseminated histoplasmosis.^8,9 Most patients present with fever, weight loss, oral ulcerations, hepatosplenomegaly, and lymphadenopathy. Adrenal insufficiency may occur in some.^8,9 The clinical similarity of tuberculosis and histoplasmosis is probably the strongest reason for underdiagnosis of the latter. In previous retrospective case series, it was noticed that often patients had been empirically started on ATT and the suspicion of non-tubercular infection arose only after failure to respond.⁹ This is true for most low- and middle-income countries. Misdiagnosis as tuberculosis and late suspicion of histoplasmosis have been reported from Cameroon, where awareness and facilities for fungal detection are quite low.¹⁰ A study from northern Tanzania reported seven of 870 febrile inpatients to be positive for Histoplasma by urine antigen testing. These included both persons living with HIV and immunocompetent individuals. Poor physician awareness and failure to make a definitive diagnosis because of unavailability of resources were also highlighted.¹¹ Even in geographical areas hyper-endemic for histoplasmosis such as Guatemala, diagnosis is often compromised, despite histoplasmosis and tuberculosis being the most important AIDS-defining illnesses.¹² It is quite natural that in zones endemic for tuberculosis, histoplasmosis either mimicking the features of the former or coexisting with it may be a missed diagnosis, especially in apparently immunocompetent individuals. Apart from diagnostic dilemma, coinfection also affects therapeutic strategy. Rifampicin is an inducer of itraconazole metabolism through CYP3A4 activation and results in decreased therapeutic concentrations. Treating physicians need to watch out for signs of therapeutic failure. Furthermore, serum itraconazole concentration needs to be monitored in setups where such facilities exist.¹³

Coexistence of histoplasmosis and tuberculosis is common in people living with HIV and patients on biological therapy.^14,15 In the current case, the patient tested negative for HIV, had not received any immunosuppressant medications, and had never had a major illness or frequent minor infections till the current hospitalization. Even on follow-up over 14 months, he stayed asymptomatic. Microscopic evaluation of his blood smear for abnormalities in neutrophil morphology was unremarkable at initial hospitalization. Additional testing for possibly undetected immune dysfunction was performed at 14 months follow-up. Table 1 shows his lymphocyte counts.¹⁶ His total serum immunoglobulin level (IgG + IgA + IgM) was 858 mg/dL (cutoff for immunodeficiency states < 600 mg/dL), with a normal distribution of individual subtypes.^17,18 Thus, the patient could be considered immunocompetent, with reasonable certainty.¹⁹ It is possible that disseminated tuberculosis itself is a risk factor for histoplasmosis. Disseminated tuberculosis is a common entity in India, even among immunocompetent individuals, and it may have created a state of temporary immunocompromise, which predisposed the patient to develop histoplasma infection.

The current case highlights that rarely even an apparently immunocompetent patient may have tuberculosis coexisting with histoplasmosis, making it easy to miss the rarer diagnosis. The utility of bone marrow examination in patients with HIV who have pyrexia of unknown origin has been emphasized.²⁰ This may hold true even in immunocompetent individuals and should be backed up by fungal culture facilities. Although not possible at the periphery, a fungal culture of easily accessible biological samples such as sputum or tissue aspirate may be routinely performed, at least in referral medical centers, so that the few cases are not missed.