2.1. Mycology and Pathogenesis
H. capsulatum is a dimorphic fungus that is a mold in the environment and when grown in the laboratory at 25–30 °C [
5]. Two different types of conidia, the infectious elements, are produced. The larger conidia (tuberculate conidia) are 8–15 µm in diameter, have a thick wall, and distinctive projections on the surface. These structures provide a strong hint to the identity of the fungus. The smaller conidia, 2–4 µm, are the infectious form because their size allows them to be inhaled into the alveoli. At body temperature and at 35–37 °C in the laboratory, the organism is a tiny, 2–4 µm, oval budding yeast.
After the small conidia are aerosolized into the lungs, they are phagocytized by alveolar macrophages. Within macrophages, the conidia transform to the yeast phase, and then, in the cells, disseminate widely through the lymphatics and the bloodstream. Although dissemination occurs in most infections, it is rarely symptomatic. When T lymphocytes become sensitized to the antigens of
H. capsulatum and produce cytokines that arm the macrophage to kill the intracellular organism, the infection can be contained [
8]. However, in immunosuppressed hosts, cell-mediated immunity may not develop, the organism remains viable within macrophages, and disseminated infection ensues.
2.2. Epidemiology
H. capsulatum is found in the soil in the Mississippi and Ohio River valleys, but is also found in microfoci along the eastern coast [
9]. Additionally, it is commonly found throughout Central America, and periodically is reported from focal areas in Africa and Southeastern Asia. The organism grows best in soil that has a high nitrogen content, which is frequently found under trees used by birds for roosting or in caves that provide nesting places for bats [
5]. Point-source outbreaks associated with activities, such as demolition of old structures and large landscaping projects, have led to infection in many people, but most cases in transplant patients appear to be sporadic and not directly related to specific high-risk behaviors leading to exposure.
The five-year transplant-associated surveillance network (TRANSNET) study that collected data from 15 transplant centers in the U.S. between 2001 and 2006 established a 12-month cumulative incidence rate for histoplasmosis among solid organ transplant recipients of 0.1% [
3]. They reported on a total of 48 cases of histoplasmosis, noting that the occurrence was bimodal, with 40% of cases occurring within the first six months, but others occurring as long as 18–20 years after transplantation. Kidney transplant recipients accounted for half the cases of histoplasmosis, and liver transplant recipients for a quarter.
In the small number of cases in which
H. capsulatum was transmitted with a donor organ, the illness was severe and usually occurred early after transplantation during the time of maximal immunosuppression [
3,
7,
10,
11,
12,
13,
14]. In several patients,
H. capsulatum was found in the donor organ at the time of or immediately after transplantation, and the recipients were treated pre-emptively and successfully with antifungal agents before they developed symptoms of histoplasmosis [
3,
11].
2.3. Clinical Manifestations
In a normal host, histoplasmosis is primarily a pulmonary infection. However, in the transplant population, depending on the extent of immunosuppression, it is more likely to be a disseminated infection [
10,
15,
16]. In a patient who is not markedly immunosuppressed, focal pneumonia can occur, presenting with fever, myalgias, dry cough, and dyspnea. More often, diffuse pneumonia with more severe dyspnea and hypoxemia is the presenting manifestation of pulmonary histoplasmosis in transplant recipients [
11,
15]. Acute respiratory distress syndrome (ARDS) can occur in severe cases. Mediastinal and hilar lymphadenopathy, commonly seen in acute pulmonary histoplasmosis in healthy hosts, is not seen often in transplant recipients.
Disseminated histoplasmosis involves primarily the reticuloendothelial system; liver, spleen, bone marrow, and lymph nodes are commonly affected [
17]. Additionally, skin, gastrointestinal tract, adrenals, and the central nervous system (CNS) can be involved. The manifestations vary depending on the organs most affected. Fever, chills, night sweats, malaise, and weight loss are common. When the infection is severe, the patient can present in septic shock, can have symptoms and signs of adrenal insufficiency, and can develop disseminated intravascular coagulation.
Physical findings pointing toward disseminated histoplasmosis include hepatosplenomegaly, painful oropharyngeal ulcers or mass lesions, and skin lesions that may be papular, pustular plaque-like, or ulcerated. Patients with gastrointestinal tract involvement frequently have diarrhea, weight loss, and abdominal pain; endoscopy often shows diffuse involvement throughout the gut. Those patients who have CNS involvement usually have symptoms suggesting a subacute meningitis. Multiple small enhancing lesions can be seen on magnetic resonance imaging, but may be relatively asymptomatic.
2.4. Diagnosis
Routine laboratory studies that should prompt one to think about disseminated histoplasmosis include abnormal liver enzymes, primarily an elevated alkaline phosphatase, and pancytopenia, reflecting infiltration of the bone marrow. High serum potassium and low serum sodium occur with adrenal insufficiency, and inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, ferritin) are almost always elevated.
The definitive diagnosis of histoplasmosis is made by growing
H. capsulatum in the laboratory [
5]. Appropriate specimens for culture include blood, sterile body fluids, tissue biopsies, sputum, and bronchoalveolar lavage (BAL) fluid.
H. capsulatum grows slowly, taking as long as 4–6 weeks to grow. Even using the isolator lysis-centrifugation system for blood cultures, which is a more sensitive method for growing organisms such as
H. capsulatum, the delay is often weeks. Because of the delay in establishing the definitive diagnosis, other methods must be relied upon to quickly make a presumptive diagnosis, especially in an immunosuppressed patient who is quite ill.
Histopathological identification of the typical 2–4 μm budding yeasts in tissue biopsies is a rapid means to identify a patient who has histoplasmosis. Staining the tissue with methenamine silver stain or periodic acid-Schiff (PAS) stain is necessary to visualize the small yeast structures. Occasionally, in disseminated infection, the organisms can be seen within neutrophils or monocytes on a peripheral blood smear.
Tests for circulating
Histoplasma antigen, performed on urine and serum, increasingly are used for rapid diagnosis in immunosuppressed patients. The test detects and quantitates circulating galactomannan of the cell wall of
H. capsulatum [
18]. Sensitivity has increased with several modifications of the test, and both serum and urine should be tested [
19,
20]. Antigen testing of BAL fluid can be helpful in patients who have possible pulmonary infection [
21]. False positive test results occur with other endemic mycoses, most notably blastomycosis [
18]. Interestingly, patients who have disseminated histoplasmosis and who have a high burden of organisms can have a false positive
Aspergillus galactomannan result because of similarity of the cell wall polysaccharides of the two organisms [
22]. However, patients who have invasive aspergillosis have not been reported to have a false positive
Histoplasma antigen test.
In immunosuppressed hosts, who often cannot mount a good antibody response, antibody tests for H. capsulatum—complement fixation and immunodiffusion—are not very sensitive. In our opinion, these tests should be ordered, and if positive, may be helpful, but cannot be relied upon for diagnosis.
2.5. Treatment
Most transplant recipients should be treated initially with amphotericin B. Moderate to severe disseminated or pulmonary histoplasmosis in all patients should be treated with amphotericin B [
23]. In transplant recipients, even for those who have less severe disease, consideration should be given to beginning therapy with amphotericin B. Within a short time (1–2 weeks) step-down therapy to an azole almost always can be accomplished. For the uncommon presentation of mild localized acute pulmonary histoplasmosis in a transplant recipient, an azole can be given as primary therapy.
Lipid formulations of amphotericin B have supplanted amphotericin B deoxycholate in many medical centers because the lipid formulations are less nephrotoxic. For histoplasmosis, liposomal amphotericin B (AmBisome) is preferred because of data in AIDS patients with disseminated histoplasmosis that showed, not only less toxicity, but also increased efficacy [
24]. The dose is 3–5 mg/kg given intravenously (IV) IV daily.
H.
capsulatum remains very susceptible to amphotericin B, and improvement often occurs within the first 7–10 days. After the patient is clinically improved, therapy can be changed to an azole to continue the course of therapy.
If the patient has CNS involvement, the dose of liposomal amphotericin B should be 5 mg/kg daily. This agent should be continued for 4–6 weeks before changing to an azole.
The azole of choice for the treatment of histoplasmosis is itraconazole [
23]. This agent is used for step-down therapy after initial amphotericin B treatment and for initial therapy in transplant recipients with mild localized acute pulmonary infection. The loading dose is 200 mg three times daily for three days, followed by 200 mg twice daily. The total length of therapy should be 12 months, but some patients may require suppressive therapy, as discussed below.
Fluconazole is a second-line agent for histoplasmosis; the dose should be 800 mg daily [
23]. There is increasing experience with successful treatment of histoplasmosis with voriconazole and posaconazole, and these are preferred over fluconazole for step-down therapy when itraconazole cannot be used [
25,
26,
27]. The dosage of oral voriconazole is 400 mg twice daily for the first day, then 200 mg twice daily. The posaconazole extended-release tablet should be used and not the oral suspension, in order to ensure better absorption. The dose is 300 mg twice daily for the first day, then 300 mg daily. For itraconazole, voriconazole and posaconazole, serum concentrations should always be measured to ensure appropriate levels (see Section on azole treatment of endemic mycoses).
Echinocandins are not active against H. capsulatum and should not be used for the treatment of histoplasmosis.
Because histoplasmosis has been reported to relapse in the face of ongoing immunosuppression in transplant recipients, it is prudent to continue therapy with an azole as long as the patient is markedly immunosuppressed. However, there are no firm criteria for deciding what is marked immunosuppression. Studies to guide the length of suppressive therapy for histoplasmosis have been reported in AIDS patients. In that population, suppression is recommended to continue until the patient has been treated for at least one year and their CD4 count is >150/μL for at least six months [
23]. No similar criteria have been established for transplant recipients. Thus, physicians have to judge whether an individual patient is at risk for relapse of infection and whether they should remain on long-term azole therapy. The preferred antifungal agent is itraconazole, 200 mg once or twice daily.