Disseminated histoplasmosis and tuberculosis: dual infection in a non-endemic region

Abstract

Histoplasmosis is a systemic fungal infection caused by Histoplasma capsulatum, a dimorphic fungus that spreads commonly by contamination of soil with bird and bat droppings. The infection remains latent in most patients until manifested by reduced immune status, for example, HIV/AIDS, corticosteroid/immunosuppressive therapy or in solid organ transplant recipients. Tuberculosis and histoplasmosis may cooccur rarely in HIV and the clinical resemblance of both diseases may hinder identification of patients’ harbouring dual infection, especially in regions non-endemic for histoplasmosis. We report a case of disseminated histoplasmosis with disseminated tuberculosis in an incidentally detected patient with HIV-positive who presented with reports of fever and skin rash for 10 days. The Mantoux positivity and CT of chest and abdomen revealing multiple necrotic lymph nodes coupled with bone marrow and skin biopsy divulging histoplasmosis and tuberculosis helped us clinch the concurrent infection.

Background

Histoplasmosis is usually acquired via inhalation of microconidia or hyphae in soil contaminated with bird and bat droppings. It is a systemic fungal disease endemic in Ohio and Mississippi river valleys of North America with reports from the whole of America.¹ Histoplasmosis is also a major cause of progressive extrapulmonary opportunistic infection (OI) in several Latin American countries.²

The clinical manifestations are quite varied; patients may remain totally asymptomatic or develop a self-limiting infection when immunocompetent. However, immunocompromised patients such as those with HIV–AIDS and a CD4 count <200 cell/µL may show progressive, severe and disseminated course of the disease which is usually mistaken as tuberculosis (TB) before a final diagnosis of histoplasmosis is achieved. As a result of the HIV–AIDS pandemic, disseminated histoplasmosis has become prevalent not only in endemic regions but also in areas that are not considered endemic. In India, the disease is not endemic, however, many cases have been reported.

The primary infection can lead to acute, subacute or chronic disseminated histoplasmosis. During acute dissemination, immunosuppressed patients are unable to develop effective cell-mediated immunity against the causative organism and, hence, are likely to manifest symptomatic disease.³ Dual infection with Histoplasma capsulatum and Mycobacterium tuberculosis is even rarer as both mimic each other’s presentation and the diagnosis may be missed. The skin lesions in histoplasmosis are non-specific and usually arise after dissemination from a primary focus of disease, however, they may provide a useful clue.⁴

Case presentation

A 50-year-old man, resident of Solan district, Himachal Pradesh and a farmer by profession, presented with high-grade fever (102°F–103°F) and nodular skin lesions over face, neck and trunk for 10 days. The skin lesions were reddish in colour, non-tender, papulonodular with no pruritus. The facial lesion measured 5×5 mm with no active bleeding and no obvious umbilication. There was no history to suggest any anorexia, weight loss or any organ-based localisation. Previous medical history did not suggest TB or any other chronic illness, any blood transfusions, needle prick injury or promiscuous behaviour; the only available history was of getting intramuscular pain killer injections from a local practitioner for generalised body aches.

On general physical examination, he had normal vitals except for a temperature of 101°F. In addition, pallor was noted along with multiple enlarged palpable cervical and inguinal lymph nodes, largest measuring 2×2 cm, without any matting or softening or sinus. There was no icterus, oral candidiasis or sternal tenderness. He had multiple discrete papulonodular skin lesions over face, neck, arms and trunk measuring 5×5 mm with similar discrete lesions over the back (figure 1). The respiratory and cardiovascular system examination was normal. On abdominal examination, moderate hepatosplenomegaly was recorded but no free fluid. Higher mental functions were normal and meningeal signs were absent. Choroidal tubercles were absent on funduscopy.

Figure 1.

Clinical photograph showing papulonodular lesions on the forehead (above) with similar discrete lesions over the back (below).

Investigations

On presentation, patient was found to have bicytopenia with haemoglobin of 77 g/L, normocytic normochromic type, platelet count of 28×10⁹/L and total leucocytes count 7.7×10⁹/L with 91% neutrophils. There was a progressive fall in platelet count with a nadir of 6×10⁹/L on day 3 of admission, for which single-donor platelet transfusion was done. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels were 295, 286 and 273 IU/L, respectively, with a normal bilirubin. Tropical fever workup in form of dengue nonstructural protein 1 (NS1) Ag and IgM, malaria antigen and scrub typhus serology were negative. Venereal disease research laboratory (VDRL), hepatitis B and hepatitis C serologies were non-reactive, however, patient was detected to be seropositive for HIV with CD4 counts of 29. Mantoux test (tuberculin test) revealed 10×10 mm induration.

Chest radiography did not reveal any lung parenchymal/pleural lesions or mediastinal widening. Abdomen sonography revealed a liver and spleen measuring 17.5 cm and 13.5 cm, respectively, without any obvious infiltration. Contrast-enhanced CT of chest and abdomen suggested bilateral nodular infiltration in lungs with necrotic retroperitoneal, retrocrural, mesenteric, mediastinal and cervical lymphadenopathy with a strong likelihood of disseminated TB (figure 2). Skin biopsy from the nodular facial lesions revealed a mild acanthosis in epidermis, with dermis showing numerous macrophages and intracellular and extracellular organisms conforming to morphology of Histoplasma (figure 3). These organisms were highlighted on Periodic acid–Schiff (PAS) and Giemsa stain. The patient then underwent a bone marrow examination which revealed hypercellular marrow spaces (cellularity: 85%–90%), megakaryocytic hypolobation, increased histiocytes showing numerous intracellular organisms (oval to spherical, uniform yeast-like cells surrounded by a clear halo) confirming the diagnosis of disseminated histoplasmosis (figure 4). Focal areas showed increase in lymphoid cells along with occasional foci of necrosis and ill-defined collections of epitheloid histiocytes. Though no acid-fast bacilli were detected, bone marrow aspirate was positive for TB by PCR.

Figure 2.

Multiple mesenteric and para-aortic necrotic and matted lymph nodes on contrast-enhanced CT abdomen.

Figure 3.

Skin biopsy showing Histoplasma in upper dermis high-power view (40×).

Figure 4.

Intrahistocytic Histoplasma organism in bone marrow biopsy.

Differential diagnosis

In view of fever associated with peripheral lymphadenopathy, hepatosplenomegaly, skin lesions and associated pancytopenia in a severely immunosuppressed patient, we considered the diagnosis of multiple disseminated OIs. Besides the highly endemic TB, the other conditions that were considered as strong contenders were histoplasmosis, visceral leishmaniasis, Mycobacterium avium complex and disseminated nocardiosis. Lymphoma, sarcoidosis were the other diagnostic possibilities. Rare differential diagnoses considered were primary HIV lymphadenopathy, Castleman’s disease, Kaposi’s sarcoma, disseminated cryptococcosis and bacillary angiomatosis/strongyloidiasis.

Treatment

The patient was started on trimethoprim/sulfamethoxazole, fluconazole, azithromycin initially as prophylaxis for OIs. After the radiology and histopathological confirmation of dual diagnosis, he was initiated on antitubercular treatment and liposomal amphotericin B 3 mg/kg/day for 2 weeks. After this, he was started on oral itraconazole 200 mg three times a day with meals for first 3 days followed by 200 mg twice a day (BD). Rifampicin was replaced with moxifloxacin due to its interactions with itraconazole.

Outcome and follow-up

Five days into the treatment protocol, patient started responding to the treatment and became afebrile. Skin lesions started resolving and the complete blood counts started recovering. The patient was then discharged in a stable condition with normal platelet count, renal function tests and resolving transaminases. The patient was planned to continue on antitubercular therapy for 6 months and itraconazole for a year. Antiretroviral therapy was initiated after 4 weeks of antitubercular therapy. Since there is a significant drug interaction among the above agents, tenofovir, lamivudine and efavirenz were prescribed. We monitored the serum levels of itraconazole two times, once at 2 weeks of initiating itraconazole and then after another 4 weeks and the levels were 1.14 µg/mL and 1.19 µg/mL, respectively. The positive bone marrow cultures for H. capsulatum were obtained after 8 weeks of inoculation, confirming the dimorphic fungi.

Discussion

Developing countries still observe the presence of multiple OIs in their HIV/AIDS treatment-naïve population in up to 33% cases.⁵ TB in India and histoplasmosis in Latin America are among the most common OI encountered. It is estimated that TB coinfection may occur in 8%–15% of HIV-infected patients afflicted with histoplasmosis.⁶ Histoplasmosis and TB share several clinical manifestations including fever, weight loss, night sweats, fatigue, lymphadenopathy and hepatosplenomegaly that it may become absolutely impossible to clinically attribute it to either of them in an individual patient.⁷ However, certain features may be interesting to observe in disseminated histoplasmosis; first is that, though, pulmonary infiltrates may be present in >75%, the corresponding symptoms are minimal.⁶ Skin lesions appear to be higher in frequency than in TB and often yield the histopathological diagnosis. Pancytopenia, granulomatous infiltration of liver or spleen and elevated acute phase reactants are often non-specific findings, although some opine that markedly elevated serum ferritin levels might be more suggestive of histoplasmosis.⁸ Histopathological evaluation, both for fungal elements and acid-fast organisms, is the most successful mean for establishing either or dual diagnosis.

The first case of histoplasmosis in India was reported in 1954 by Panja and Sen from Calcutta.⁹ Randhawa and Khan reviewed 37 cases from 1954 to 1994.¹⁰ The study suggested preponderance of the disease in the western states of India. In 2013, Kathuria et al published a series of cases diagnosed between 1995 and 2011.¹¹ Kashyap et al, in 2014, established the case report of a diagnosed case in the state of Himachal Pradesh.¹² In 2016, another case was reported from Himachal Pradesh by Raina et al which depicted primary cutaneous histoplasmosis in an immunocompetent host from a non-endemic area.¹³ Two previously reported and two new cases of histoplasmosis by Mahajan et al, indigenous to Himachal Pradesh, were described with an objective of documenting an emerging focus.¹⁴ None of these cases, however, had dual infection of histoplasmosis and TB.

Although worldwide series have been reported, data on dual infection in India are scarce. Gutierrez et al looked at 104 histoplasmosis patients with AIDS in Panama and concluded that 15.4% cases had dual infection of TB and histoplasmosis.¹⁵ Huber et al, retrospectively, studied 200 cases of AIDS-related histoplasmosis diagnosed in French Guiana between 1982 and 2007.¹⁶ The authors reported a histoplasmosis and tuberculosis coinfection frequency of 8% in the study. Agudelo et al conducted a retrospective review of 14 HIV-infected patients who had been diagnosed and treated for both TB and histoplasmosis.⁶ The authors recommended that the diagnosis of TB should be considered first when both infections occur simultaneously and histoplasmosis should be evaluated further when the patient has unsatisfactory response to antitubercular agents. They also suggested moxifloxacin as an alternative to rifampicin as it does not interact with itraconazole, allowing a satisfactory response to therapy for histoplasmosis.

Adenis et al tested whether histoplasmosis and TB are discernible in HIV-infected patients by identifying epidemiological, clinical, biological and radiological characteristics.¹⁷ They concluded that symptoms of pleuropulmonary sphere were more frequent in persons with TB, whereas abnormal imagery in the abdominal sphere was more frequent in histoplasmosis. Most cases of histoplasmosis were from rural background, had more disseminated disease, lymphadenopathy >2 cm in size and had higher frequency of inflammatory markers.

Patient’s perspective.

I was so afraid when I was diagnosed with so many dreaded diseases and I thought I will not survive. I am grateful to be alive with the treatment provided to me.

Learning points.

• Immunosuppressed individuals may have multiple coexisting opportunistic infections.

• Literature is scanty on tuberculosis and histoplasmosis opportunistic coinfection in India. Despite the scarcity of reports, dual infection should be suspected especially when clinical features are unusual or treatment response is unsatisfactory.

• Histopathological evaluation and microbiological confirmation are important in establishing the diagnosis of histoplasmosis and tuberculosis.

• The cooccurrence of disseminated forms of tuberculosis and histoplasmosis in treatment-naïve HIV-infected patients has important implications for diagnosis and treatment especially in context of drug–drug interactions.