Histoplasmosis

I. What every physician needs to know.

Histoplasma capsulatum (H. capsulatum), the etiologic organism for histoplasmosis, infects humans via the respiratory tract. After the organism reaches the alveolar space, it replicates in macrophages and spreads in the reticuloendothelial system. As an intracellular pathogen, the organism can remain viable for years; reactivation of the infection can thus occur at a later time.

Histoplasmosis is endemic in the United States, with the highest prevalence of infection in the Ohio and Mississippi valleys. The organism lives in the soil and the highest concentrations are found in bird and bat droppings.The organism lives as mold in the soil and as yeast in the tissues (dimorphic fungus).

Most immunocompetent individuals are asymptomatic, or report a mild influenza-like illness.

II. Diagnostic Confirmation: Are you sure your patient has histoplasmosis?

No specific clinical criteria are available to confirm the diagnosis.

A. History Part I: Pattern Recognition:

The clinical manifestations of histoplasmosis varies widely.

Pulmonary infection – acute

Over 90% of patients with an acute primary infection are undiagnosed – patients complain of a mild influenza-like illness that resolves spontaneously. Complaints include fever, headache, non-productive cough, and chest pain (usually retrosternal – presumed to be due to lymphadenopathy). The infection resolves after 1-2 weeks. For patients who seek medical attention, an atypical pneumonia is often diagnosed – instead of histoplasmosis.

During the primary infection, patients at risk for disseminated infection are the very young (<2 years old), the elderly, and immunocompromised individuals (such as patients with HIV/AIDS). Individuals exposed to a large inoculum are also at increased risk. Severe pneumonia manifests by hypoxemia, progressive pulmonary infiltrates, and may progress to acute respiratory distress syndrome (ARDS).

A positive skin test is seen in most patients (over 90%). Antibody to H. capsulatum is present in 20-90% of patients and antigen is detected in the urine in 75%; the organism grows in up to 25% of lung samples; and, histology demonstrates caseating and non-caseating granulomas, with few yeasts and giant cells.

Pulmonary infection – acute cavitary

Fever with productive cough and chest pain are characteristic. A positive skin test is seen in 70%-90% of patients. Antibody to H. capsulatum is present in 70-95% of patients and antigen is detected in the urine in 40%; the organism grows in 5-70% of lung samples; and, histology demonstrates non-caseating granulomas, interstitial fibrosis, necrosis, cavities and few to moderate yeasts.

Pulmonary infection – chronic cavitary

Usually presents among the elderly with emphysema. The presentation resembles reactivation of tuberculosis. Findings include fever, fatigue, decreased appetite, productive cough, and hemoptysis. Imaging reveals upper lobe infiltrates with fibrosis of the lower fields.

Disseminated histoplasmosis

Hematogenous spread is frequent and disseminated infection almost always occur in the immunocompromised individual. Fever and other systemic findings are characteristic (chills, fever, anorexia, malaise, diarrhea, weight loss, hepatosplenomegaly, anemia, leukopenia, thrombocytopenia). Sepsis syndrome with ARDS can be seen. In this setting, diffuse mucosal ulcerations, pancytopenia, increased alkaline phosphatase, and profound elevation of serum ferritin are noted. Hemophagicytic syndrome has been reported. In AIDS patients, histoplasmosis has been noted to cause fever of unknown origin (FUO) in approximately 7% of patients.

A positive skin test is seen in approximately 50% of patients. Antibody to H. capsulatum is present in 70-90% and antigen is detected in the urine in 60-90%; the organism grows in about half of lung samples; and, histology demonstrates diffuse and significant macrophage infiltration and giant cells (the lymphocytic response is limited).

A chronic progressive form has been described in immunocompetent elderly and middle aged men.

Other, less common manifestations seen in less than 10% of patients, include erythema nodosum, erythema multiforme, arthralgias, and meningitis.

Complications of histoplasmosis include:

a) Granulomatous mediastinitis, due to persistent enlarged lymph nodes that may caseate and calcify. The clinical presentation may include recurrent pneumonia due to bronchial obstruction, or be completely asymptomatic (with areas of calcification in previously necrotic areas).

b) Fibrosing mediastinitis, a prominent fibrotic response to the organism is usually unilateral. The fibrosis, which rarely occurs, may present as superior vena cava syndrome, respiratory distress, pulmonary emboli, or bronchial constriction.

c) Pericardial effusion, usually in response to pulmonary infection.

Table I.

Immune Defect	Site of Infection	Pathogens
B cells / Immunoglobulin deficiency(ex. Common variable immunodeficiency)			Sinopulmonary tract, GI tract, joints, CNS		Encapsulated bacteria: Streptococcus pneumonia, Hemophilus influenzae type b Mycoplasma species, Campylobacter species
Enteroviruses: Echovirus, coxsackie, polio
Parasites: Giardia lamblia
T cell immune deficiency(ex. AIDS, chronic mucocutaneous candidiasis)				Sepsis, lung, GI tract, skin infections		Bacteria: encapsulated bacteria (see above), gram negative bacteria, Mycobacterial organisms
Viruses: CMV, adenovirus, measles, molluscum
Protozoa: Cryptosporidium species
Fungi: Candida, Aspergillus, Pneumocystis jiroveci
Complement deficiency (ex. Terminal complement deficiency, early complement deficiency)	Meningitis, systemic infections	Neisseria species infections Encapsulated bacteria (see above)
Phagocytes dysfunction (ex. Neutropenia, chronic granulomatous disease)	Skin infections, GI tract lymphadenitis, liver, lung, bone, periodontitis	Bacteria: Staphylococcus species, Nocardia species Gram negative infections including Serratia, Burkholderia, Klebsiella, E. coli, Salmonella, Proteus Fungi: Candida and Aspergillus

Table II.

Medication	Immune mechanisms affected	Comments
Steroids (example, prednisone)	Neutrophil function T cell function Humoral function only affected at high doses	Generally doses of 20mg / day or more will result in a two fold increased risk of infection. Doses of 10mg/day or less does not show a difference in infection rates.
Alkalating agents (example, cyclophosphamide)	As it affects all lymphocytes it affects humoral and cellular immunity. As neutropenia can be a side effect of this medication, neutrophil dysfunction can also be affected.	Age greater than 65 years significantly increases the risk of infection in patients on cyclophosphamide.
Immunophilin binding agents (example, cyclosporin A, tacrolimus, sirolimus)	T cell function	Cyclosporin and tacrolimus inhibit calcineurin. Sirolimus inhibits a different pathway affecting mRNA translation.
Nucleotide synthesis inhibitors (azathioprine, mycophenolate, methotrexate)			Azathioprine affects primarily actively dividing T cells.	Predominantly see viral infections like CMV, less commonly fungal or parasitic infections.
Mycophenolate selectively affects proliferating T cells and primary humoral responses. Does not affect memory T cells or secondary humoral responses.	CMV infections in particular are increased. Pneumocystis is less commonly seen as mycophenolate may have some anti-pneumocystis activity.
Methotrexate primarily affects T cell responses.	Side effects of myelosuppression, diarrhea, and hepatotoxicity can be reversed with folic or folinic acid.
Monoclonal Antibodies (example, rituximab, tumor necrosis factor-alpha inhibitors)		Rituximab (binds CD20) affects B cell function	Rituximab can have effect months after administration.
TNF inhibitors primarily affect T cell function dealing with intracellular infections.	Mycobacterial infections are most commonly described and testing for latent tuberculosis should be performed before starting these medications.

B. History Part 2: Prevalence:

As birds occupy abandoned buildings and bridges, outbreaks occur during building demolitions and during bridge cleaning. Also, moving soil and spelunking releases the organism into the air. The number of conidia (mold from the soil) inhaled determines the severity of the infection.

Individuals with compromised cell-mediated immunity are at increased risk for disseminated infection. At risk include: infants, AIDS (CD4 <150), systemic steroids, hematologic malignancies, and solid organ transplantation. Also, at increased risk are patients receiving anti- tumor necrosis factor (TNF) such as etanercept, infliximab, and adalimumab. Infliximab has the highest risk among the anti-TNF medications and histoplasmosis, when occurs, usually presents within 6 months of initiation of therapy.

C. History Part 3: Competing diagnoses that can mimic histoplasmosis.

Atypical pneumonia due to Legionella and mycoplasma infection

While the clinical presentation may be similar, histoplasmosis and other fungal infections are associated with hilar and mediastinal lymphadenopathy. Histoplasmosis needs to be considered in the setting of rapidly progressive pneumonia among immunosuppressed patients or immunocompetent patients exposed to a large inoculum (particularly in endemic areas).

Tuberculosis

The presence of calcified pulmonary granuloma has been characteristic of prior infection with histoplasmosis (particularly when the calcification is seen in other organs).

Sarcoidosis

The empiric treatment with steroids in patients with suspected sarcoidosis, when histoplasmosis is the culprit, may result in the rapid dissemination of histoplasmosis.

D. Physical Examination Findings.

Crackles (which are usually not prominent) and hepatosplenomegaly are seen during the acute infection.
Mouth ulcers are characteristic in disseminated infection in immunocompromised individuals.

E. What diagnostic tests should be performed?

H. capsulatum serum antibody at presentation and at convalescence
H. capsulatum urine antigen

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

H. capsulatum serum antibody (complement fixation – CF, immunodiffusion – ID) are more helpful in immunocompetent individuals (a 4-fold increase in titers is noted) and among patients with chronic cavitary and chronic disseminated histoplasmosis. The sensitivity is 80%. False positive tests can be seen in patients with: lymphoma, tuberculosis, sarcoidosis, blastomycosis, and coccidioidomycosis.

H. capsulatum urine antigen by enzyme immuno-assay (EIA). The sensitivity is 90% among patients with disseminated infection and AIDS and 75% for patients with acute pulmonary infection. False positives are seen in patients with other fungal infections (the endemic area of blastomycosis overlaps with the one for histoplasmosis). Cross-reactivity does not occur with aspergillosis, candidiasis, or cryptococcosis.

Histopathological exam and culture of fluids and tissues are reserved for critically ill patients or in cases of clinical uncertainty. The 2-4 micrometer oval budding yeasts seen in silver or periodic acid-Schiff staining are characteristic.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest radiograph (CR) shows patchy pneumonitis and hilar adenopathy during acute infection. After the acute infection, calcification of the necrotic tissue and lymph nodes is characteristic – especially if calcifications in other organs are noted (liver, spleen).
Computed tomography (CT) of the chest may be helpful if cavitary disease, granulomatous mediastinitis, or fibrosis mediastinitis are suspected.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Polymerase chain reaction (PCR) is not well standardized.

III. Default Management.

Itraconazole

Itraconazole can be used for mild to moderate infections in immunocompetent patients with symptoms more than 4 weeks. Most patients with acute pulmonary infection resolve spontaneously during this time frame, thus not requiring treatment.

Dosing: 200mg three times daily for 3 days, followed by 200mh once or twice daily for 6-12 weeks. The oral solution is given on an empty stomach and the capsule with food. Serum monitoring is recommended after 2 weeks of treatment (a level of 1 micro g/mL is desired).

Patients with chronic cavitary pneumonia can be treated with 200mg twice daily of itraconazole for at least 12 months.

Patients with granulomatous mediastinitis are usually treated with 200-400mg daily of itraconazole for 6-12 weeks. Patients with fibrosing mediastinitis do not usually respond to anti-fungals.

Fluconazole

Fluconazole is a second line (responses lower than itraconazole). Ketoconazole should not be used.

Amphotericin B

Amphotericin B, deoxycholate or lipid formulations (lipid complex or liposomal), is used for severe infections (usually in immunosupressed patients) or moderate to severe disseminated histoplasmosis. Liposomal formulation at 3mg/Kg/day is recommended. After a clinical improvement is noted, patients can complete the course with 200mg twice daily of itraconazole for at least 12 months.

Patients with meningeal invasion require a higher initial dose of liposomal amphotericin (5mg/Kg/day for 1-2months).

A. Immediate management.

None in particular.

B. Physical Examination Tips to Guide Management.

None in particular.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

H. capsulatum urine antigen is used to monitor clinical improvement and detect early relapse.

D. Long-term management.

Long-term management is warranted for patients with severe disease, disseminated infection, immunosuppressed patients, chronic cavitary pneumonia, granulomatous mediastinitis, fibrosing mediastinitis, and meningitis.

Itraconazole serum monitoring is recommended after 2 weeks of treatment (a level of 1 micro g/mL is desired).

E. Common Pitfalls and Side-Effects of Management

Renal dysfunction with the use of amphotericin B.