Are You Confident of the Diagnosis?

What you should be alert for in the history

Inquire about the patient’s area of residence or recent travel to endemic areas. In North America, histoplasmosis is especially common in the Ohio and Mississippi River Valley. The disease is also present in Central and South America, and parts of Asia and Africa

Also ask about the patient’s occupation. Those exposed to high loads of histoplasma partake in activities that cause disruption of soil, such as farming and excavation. People at risk for histoplasmosis include those who work in chicken coops, old barns, houses and attics.

Immunosuppressed patients, especially those HIV/AIDS or lymphoreticular malignancies are at higher risk. Immunosuppressive drugs (eg, cytotoxics, corticosteroids and immunosuppressive agents) predispose patients to infection with the disease

Patients who have initiated HAART may be predisposed to immmune reconstitution syndrome. Patients who are HIV positive and initiating antiretroviral therapy are prone to develop histoplasmosis as a manifestation of the immune reconstitution inflammatory syndrome (IRIS) due to successful antiretroviral therapy.

Ask about systemic symptoms including fever, headache, malaise, weight loss, weakness, and a non-productive cough.

Characteristic findings on physical examination

General features include pyrexia, pallor, lymphadenopathy, and possible hypotension. Check for hepatosplenomegaly. Dermatologically, the patient may display features of pancytopaenia (eg, pallor, purpura, ecchymoses and petechiae). Specific skin lesions can present as a range of lesions, most commonly papules, plaques and nodules involving the face, neck, trunk, and less often the limbs and mucosae. Other possible, but less common lesions appear acneiform, ulcerated, rupiod, vasculitic, follicular, or molluscum-like (Figure 1, Figure 2, Figure 3, Figure 4)

Figure 1.

Erythematous papules on upper arm, some molluscum-like and others excoriated.

Figure 2.

Papulonodular lesions with scaling.

Figure 3.

Varying sizes on nodules; note large nodules with hemorrhagic crust.

Figure 4.

Annular plaques with central clearing and advancing verrucous edge.

Figure 5.

Parasitised macrophages stippled with small organisms (H&E, X400)

Figure 6.

PAS stain highlighting organisms within macrophages (X400).

Expected results of diagnostic studies

General tests include:

Blood count: anemia, leukopenia, thrombocytopenia

Liver function test: abnormal liver function tests


Chest radiograph: diffuse or nodular opacities, diffuse interstitial infiltrates, hilar or mediastinal lymph nodes

Ultrasound of abdomen: enlarged liver, splten and lymph nodes

Computed tomography (CT)/magnetic resonance imaging (MRI): for the chest and abdomen to further define any abnormalities found on chest x-ray or ultrasonography.

Specific tests for histoplasmosis include:

Urine: urine detection, deleted serum; antigen detection: the most rapid test for diagnosing disseminated disease. High sensitivity; cross reactivity is rare for other fungi thereby resulting in fewer false positive tests. Urine has higher sensitivity compared to serum.

Histopathology: parasitized macrophages with 2-4um organisms that can be confirmed with special stains (PAS, Grocott, Methenamine Silver); parasitized macrophages with 10-15um organisms for the H capsulatum var duboisii variant of disease. The above will be found in any of the systems involved (eg skin, lung, bone marrow, or adrenals)

Culture: Culture of H capsulatum and H duboisii (delay of 2-4 weeks)

Serology: rapid test which detects antibodies to H capsulatum. Although sensitive, false negatives may be observed in immunocompromised patients and up to 6 weeks post exposure. False posivives may be due to cross reaction with other fungi (eg, Blastomycosis and Aspergillosis)

Diagnosis confirmation

For the patient with the predominantly systemic features above one must rule out tuberculosis (TB). Similarities between histoplasmosis and TB include pyrexia, weight loss, cough, haemoptysis, headache, night sweats, lymphadenopathy, hepatospelomegaly, and chest pathology.

Differences between the two disorders are as follows. Patients with disseminated TB usually are often moribund with a lower incidence of skin involvement. In histolplasmosis, there is no response to antituberculous therapy; patients have unresolving pyrexia and rash as described above.

Patients with predominantly cutaneous features must be diffentiated from other systemic/disseminated fungal infections including cryptococcosis, blastomycosis, sporotrichosis, and coccidiodomycosis. Other disorders to consider in the differential diagnosis are secondary syplilis and leishmaniasis.

To differentiate any of these diseases from histoplasmosis, the use of urine antigen detection, histopathology, and culture are the gold standards for diagnosis.

Who is at Risk for Developing this Disease?

Histoplasmosis is endemic in North America (especially the Ohio and Mississippi River Valley regions), South America, and parts of Asia and Africa. Four percent of the population in endemic areas are affected. Those involved in certain occupations that involve disruption of soil (eg, farming and excavation) and those exposed to high loads of histoplasma in chicken coops, old barns, houses and attics are at risk. Other at risk are immunosuppressed patients (especially those with HIV/AIDS or lymphoreticular malignancies) and those on immunosuppressive drugs (eg, cytotoxics, corticosteroids, and biologic agents).

What is the Cause of the Disease?


The disease is caused by Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var duboisii.


The mycelial forms of H capsulatum produce spores that become airborne and are inhaled and deposited in the alveoli. In vivo, these germinate into yeasts that become engulfed by pulmonary macrophages. These become parasitic and multiply in the macrophages; they then travel to lymph nodes from which they enter the circulation, disseminating to various organs. Macrophages in the reticulo-endothelial system subsequently ingest and sequester the organism.

Immunocompetent hosts will be cleared of the infection within 10-14 days. Necrosis develops at the infected sites, leading to caseation, fibrosis and calcium deposition. The calcified granulomas develop within a few years of infection. If there is a defect in cell mediated immunity, there will be progressive dissemination of infection. In 99% of patients, the infection is restricted to the lungs.

Systemic Implications and Complications

The following complications might develop in immunocompromised patients or immunocompetent patients with high histoplasmal exposure. Infants and children are more prone to disease because of an immature cell mediated immune response.

-Acute pulmonary histoplasmosis

-Chronic pulmonary histplasmosis (especially in those with pre-existing lung disease such as emphysema)

-Disseminated histoplasmosis (this occurs mainly in the setting of patients who are immunocompromised with HIV/AIDS with CD4 counts < 150-200 and is therefore an AIDS-defining illness)

Investigation to confirm the diagnosis above will be blood count, bone marrow aspirate, abdominal ultrasound, CT, and liver or adrenal biopsy. Other organs affected (eg, brain or skin) will require appropriate imaging (CT or MRI, depending on availability and cost), and tissue biopsy diagnosis.

Treatment Options

The therapy of choice is amphotericin B intravenously 0.75-1mg/kg/day for 14 days.

The next option is oral Itraconazole 400mg daily until clinical resolution and H capsulatum antigen levels normalize. Itraconazole 200mg daily lifelong prophylaxis is indicated for immuncompromised individuals to prevent relapse. For those on HAART, prophylaxis is continued for 3 months after the CD4 count is above 150cell/mm3, thereafter prophylaxis can be stopped.

Fluconazole is less effective than amphotericin and itraconazole; however, it crosses the central nervous system (CNS) and is reserved for patients with meningitis and/or those with mild to moderate disease where Itraconazole is contraindicated

Optimal Therapeutic Approach for this Disease

Although the treatment of choice for rapid control of disseminated disease is intravenous amphotericin, oral therapy is safe and effective in patients with mild disease (eg, immunocompetent patients, or even immunocompromised patients with mild or moderate disease).

Patients with HIV/AIDS who are on concomitant NNRTIs will require monitoring of itraconazole levels, which may be reduced due to induction of the CYP3A4 pathway. Patients may require itrazconazole doses to be increased depending on the levels. Protease inhibitors may be preferred as HAART therapy in patients with disseminated histoplasmosis concurrently on azole antifungals.

Patients with HIV/AIDS on HAART and azole antifungals will be more prone to hepatotoxicity, hence this will have to be monitored carefully. Patients with HIV/AIDS may also have underlying renal involvement, hence care will have to be taken to ensure optimal renal function while adminstering amphotericin B.

Patient Management

Baseline monitoring should include CBC, liver function tests, urea and electrolytes, urine histoplasma antigen, HIV and CD4 count. Urea and electrolytes shoule be obtained every 2 days to monitor for hypokalemia while the patient is on intravenous amphotericin B. Potassium supplementation may be required for persistent hypokal.emia while on amphotericin B. If a patient has amphotericin toxicity, itraconazole can be substituted after 3 days of intravenous amphotericin.

Liver function tests should be obtained monthly for the first 3 months, then every 3 months subsequently. CD4 counts should be checked every 3 months in those who are HIV infected. For those on HAART, underline the importance of maintaining prophylactic therapy until CD4 remains above 150 for 3 months.

If the patient has contraindications to itraconazole, fluconazole can be used. In the future, agents like voriconazole may be available which may have sufficient fungicidal activity to replace amphotericin B.

Unusual Clinical Scenarios to Consider in Patient Management

Although uncommon, patients initiating HAART may present with unmasking of the immune reconstitution syndrome. These patients will require timeous diagnosis and initiation of antifungal therapy.

What is the Evidence?

Kurowski, R, Ostapchuk, M. "Overview of Histoplasmosis". Am Fam Physician. vol. 66. 2002. pp. 2255-6.

(This is a comprehensive review on histoplasmosis and highly recommended for those healthcare professionals in endemic areas or those treating patients with histoplasmosis.)

De Lavaissière, M, Manceron, V, Bourée, P, Garçon, L, Bisaro, F, Delfraissy, JF, Lambotte, O, Goujard, C. "Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection". J Infec. vol. 58. 2009 Mar. pp. 245-7.

(This is an interesting reference which documents the occurrence of histoplasmosis as an IRIS phenomenon.)

Hills-Nieminen, C, Hughes, CA, Houston, S, Shafran, SD. "Drug-drug interaction between itraconazole and the protease inhibitor lopinavir/ritonavir". Ann Pharamacother. vol. 43. 2009 Dec. pp. 2117-20.

(This important reference discusses the decrease of fluconazole levels due to NNRTIs, which are enzyme inducers. It suggests protease inhibitors as the therapy of choice in patients on long-term prophylactic fluconazole therapy.)

Ruhnke, M. "Mucosal and systemic fungal infections in patients with AIDS: prophylaxis and treatment". Drugs. vol. 64. 2004. pp. 1163-80.

(This is an important reference to guide clinicians on long-term follow-up and prophylaxis of patients with histoplasmosis on antifungals.)

Anderson, AM, Mehta, AK, Wang, YF, Qian, J, Easly, K, Nguyen, MT. "HIV-associated histoplasmosis in a nonendemic area of the United States during the HAART era: role of migration from endemic areas and lack of antiretroviral therapy". JIAPAC. vol. 9. 2010. pp. 296.

(This reference warns healthcare professionals of the possibility of histoplasmosis even in nonendemic areas and to have a high index of suspicion in those who are traveling from endemic areas.)
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