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Previous Article | Next Article 
Clinical Microbiology Reviews, January 2007, p. 115-132, Vol. 20, No. 1
0893-8512/07/$08.00+0 doi:10.1128/CMR.00027-06
Infectious Diseases Division, Department of Internal Medicine, Ann Arbor Veterans Affairs Healthcare System, University of Michigan Medical School, Ann Arbor, Michigan
SUMMARY INTRODUCTION CLINICAL MANIFESTATIONS Pulmonary Histoplasmosis Acute pulmonary histoplasmosis. Chronic cavitary pulmonary histoplasmosis. Granulomatous mediastinitis. Mediastinal fibrosis. Other manifestations of pulmonary histoplasmosis. Disseminated Histoplasmosis Patient groups at risk for disseminated histoplasmosis. Symptoms, signs, and laboratory findings with disseminated disease. Endocarditis and vascular infection. Central nervous system infection. DIAGNOSIS Culture Histopathology Antigen Detection PCR Assays Antibody Tests Skin Tests TREATMENT Treatment Options Acute Pulmonary Histoplasmosis Chronic Cavitary Pulmonary Histoplasmosis Complications of Pulmonary Histoplasmosis Disseminated Histoplasmosis Endocarditis Central Nervous System Histoplasmosis REFERENCES
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There are two varieties of H. capsulatum that are pathogenic to humans, H. capsulatum var. capsulatum and H. capsulatum var. duboisii, and a third variety that is an equine pathogen, H. capsulatum var. farciminosum (63). H. capsulatum var. duboisii exists in Africa, and cases have been reported in both Africa and Europe, when patients from Africa seek care there. This review will focus solely on disease manifestations of H. capsulatum var. capsulatum, hereafter referred to as H. capsulatum.
H. capsulatum exists as a mold in the environment and forms a white to tan colony on Sabouraud dextrose agar at 25 to 30°C. Two types of conidia are formed. The macroconidia or tuberculate conidia are 8 to 15 µm in diameter and have a thick wall with distinctive projections on the surface; the microconidia are tiny, smooth structures that are 2 to 4 µm in diameter and are the infectious form. At 37°C in vitro and in tissues, the organism converts into the yeast phase that is composed of tiny 2- to 4-µm oval budding yeasts that are found both inside and outside macrophages. The organism is not encapsulated, although in tissues, it appears to be surrounded by a clear zone that was misinterpreted as being a capsule by Darling (19).
H. capsulatum occurs most commonly in North America and Central America, but the organism exists in many diverse areas around the world (63). In the United States, H. capsulatum is endemic in the Mississippi and Ohio River valleys and also exists in localized foci in many mideastern states. Soil containing large amounts of bird or bat guano, especially that found under blackbird roosts or next to chicken coops, supports luxuriant growth of the mold (11). Once contaminated, soil yields H. capsulatum for many years after birds no longer roost in the area. Caves can be highly contaminated by H. capsulatum that thrives on the bat guano (77).
Infection with H. capsulatum occurs during day-to-day activities in areas where H. capsulatum is highly endemic or in the course of occupational and recreational activities that disrupt the soil or accumulated dirt and guano in old buildings, on bridges, and in caves where bats have roosted (11, 59). Outbreaks that involve anywhere from a handful to tens of thousands of individuals have been described (8, 131, 136).
Every year, hundreds of thousands of individuals in the United States and Central America are infected with H. capsulatum. Most do not realize that they have had a fungal infection. The true extent of infection with H. capsulatum in the Ohio and Mississippi River valleys was defined only after the development of a skin test antigen that could be used in epidemiological studies (12). The seminal studies by Christie and Peterson and Palmer established the relationship of histoplasmin skin test positivity to pulmonary calcifications in tuberculin-negative persons (12, 95). Subsequent large-scale population studies by the Public Health Service defined the area where H. capsulatum is endemic (32) and demonstrated that over 80% of young adults from the states bordering the Ohio and Mississippi Rivers had been previously infected with H. capsulatum.
This review will focus on the clinical, diagnostic, and therapeutic aspects of infection with this dimorphic fungus.
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Acute self-limited pulmonary histoplasmosis is accompanied by rheumatologic and/or dermatologic manifestations in approximately 5% of patients. Erythema nodosum and erythema multiforme are the most common skin manifestations; they occur most frequently in young women and are thought to be associated with a hypersensitivity response to the antigens of H. capsulatum (88, 94, 115). Myalgias and arthralgias are common symptoms during acute infection; however, a minority of patients may develop self-limited, polyarticular, symmetrical arthritis (108). Joint symptoms usually resolve over several weeks and respond to nonsteroidal anti-inflammatory agents. Patients who have hilar lymphadenopathy, arthralgias, and erythema nodosum can be mistakenly given the diagnosis of sarcoidosis (125, 144).
Included in the differential diagnosis of acute pulmonary histoplasmosis is acute pulmonary blastomycosis and atypical community-acquired pneumonias, such as those due to Mycoplasma, Legionella, and Chlamydia (see Table 1). Hilar or mediastinal lymphadenopathy is common with histoplasmosis and can be seen with blastomycosis but would be extremely uncommon with the above-listed agents that cause community-acquired pneumonia.
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The above-described picture changes when either the host is immunosuppressed or the inoculum of H. capsulatum conidia is massive. In the host who has deficient cell-mediated immunity, the pulmonary infection will frequently progress to involve multiple lobes. The patient is acutely ill with fever, chills, cough, and marked dyspnea. Rales can often be heard throughout the lung fields. Chest radiographs show bilateral diffuse reticulonodular infiltrates, and adult respiratory distress syndrome can ensue.
Acute severe pulmonary infection also occurs when a person is exposed to a large inoculum of H. capsulatum (49, 154). The onset of illness is abrupt, and the patient presents with fever, chills, malaise, dyspnea, cough, and chest pain. Rales may be heard throughout the lungs. Chest radiographs show diffuse pulmonary infiltrates that usually are described as reticulonodular; coalescence of nodules sometimes occurs in discrete areas of the lung (Fig. 1). Acute respiratory distress syndrome can occur within a few days (62, 164). Pleural involvement is rare. Mediastinal and hilar lymphadenopathy may or may not be present. Many patients will recover without treatment, but severe disease should always be treated, because respiratory compromise can occur and recovery without an antifungal agent is slow. As the pneumonia resolves, the remaining nodules often calcify, leaving the appearance of "buckshot" throughout the lung fields (49, 51).
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Wheat et al. reported that a small proportion of persons involved in the large outbreak of histoplasmosis in Indianapolis, Indiana, in the late 1970s developed cavitary pulmonary disease (140). Not all the patients had a history of chronic obstructive pulmonary disease, and 11% appeared to resolve the cavitary lesions and all symptoms without antifungal therapy. One patient had subsequent development of disseminated histoplasmosis, a rare event in this form of histoplasmosis. The difference between the observations of this outbreak and those cases described by Goodwin et al. probably relate to the time course of infection and presentation for medical care. It is likely that the patients described by Goodwin et al., who were seen in a chest disease hospital and a Veterans Affairs medical center beginning in 1955, had more extensive disease before the diagnosis was made, and the patients described by Wheat et al., who were seen acutely in the midst of or soon after a large outbreak in the late 1970s, sought medical care and had the diagnosis of histoplasmosis made much more quickly.
The systemic manifestations of chronic cavitary pulmonary histoplasmosis include fatigue, fever, night sweats, anorexia, and weight loss. Specific pulmonary symptoms include cough, sputum production, hemoptysis, and dyspnea, which are similar to the symptoms of chronic obstructive pulmonary disease experienced by those patients. Hemoptysis is generally mild; if massive, it suggests the development of an aspergilloma in a cavity lesion (47, 60). The differential diagnosis of chronic cavitary pulmonary histoplasmosis includes, first and foremost, tuberculosis (Table 1). Nontuberculous mycobacterial infections, especially Mycobacterium avium complex and Mycobacterium kansasii; other endemic fungal infections, including blastomycosis, sporotrichosis, and coccidioidomycosis; and sarcoidosis are also possible differential diagnoses. The natural history of untreated chronic pulmonary histoplasmosis is one of progressive pulmonary insufficiency leading to death (39, 47, 96). The patients do not appear to die of overwhelming infection but rather of the consequences of the infection in lungs that are already damaged.
Granulomatous mediastinitis. Granulomatous mediastinitis, or mediastinal granuloma, is a complication of the almost uniform infection of mediastinal lymph nodes that occurs with pulmonary infection. However, instead of enlargement of a few nodes that eventually recede and ultimately calcify as the host handles the infection, granulomatous mediastinitis is characterized by the massive enlargement of multiple nodes that are often matted together and undergo caseation necrosis. This mass of nodes remains enlarged for months to even years. The center of the mass can contain putty-like necrotic material or liquefied material. Yeast forms typical of H. capsulatum can sometimes be seen in the midst of necrotic material that is obtained by needle aspiration or tissue biopsy.
Many patients are asymptomatic, and the nodes are discovered on a chest radiograph. However, others experience symptoms related to the encroachment of this mass of nodes around mediastinal structures. These nodes can impinge on the superior vena cava, the bronchi, or the esophagus, with symptoms varying according to the structures involved. The nodes also can spontaneously drain into adjacent soft tissues of the neck, into the airways, or even into the pericardium. Although it was initially thought that granulomatous mediastinitis progressed to fibrosing mediastinitis, current thinking is that these are two separate complications of pulmonary histoplasmosis (22).
Radiographs show enlarged hilar, subcarinal, or paratracheal lymph nodes. Computed tomography (CT) scans of the chest best define the extent of nodal enlargement, the presence of necrosis, and encroachment on adjacent structures (Fig. 3). Bronchoscopy and esophagoscopy document extrinsic compression, traction diverticulae, and fistulae that are rare complications of granulomatous mediastinitis. Most patients will have resolution of this process and ultimately calcify the involved nodes.
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The disease progresses slowly over years, gradually encroaching upon the superior vena cava, the pulmonary arteries and veins, or the bronchi. Less often, the thoracic duct, recurrent laryngeal nerve, and right atrium are involved. Symptoms include increasing dyspnea, cough, hemoptysis, and chest pain. Signs of superior vena cava syndrome or right heart failure may be prominent (82), but many patients have no abnormalities upon physical examination. Systemic signs of infection, such as fever, chills, and night sweats, are usually absent.
Chest radiographs show subcarinal or superior mediastinal widening. CT scans reveal the extent of invasion into mediastinal structures (22, 117). Angiography also helps define the constriction of the large vessels, and ventilation-perfusion lung scans reveal perfusion abnormalities caused by the constriction of pulmonary arteries. Mediastinal fibrosis that involves structures supplying both lungs is almost uniformly fatal. If only one lung is involved, patients may survive for decades with stable disease (22); however, regression of the fibrosis does not occur.
Other manifestations of pulmonary histoplasmosis. A small proportion of patients with acute pulmonary histoplasmosis develop pericarditis as a complication of the infection. In the large outbreak of histoplasmosis in Indianapolis, pericarditis was identified in 6% of patients (137). This complication occurs predominantly in younger patients. The disease is self-limited in almost all patients, but the course can be protracted, and recurrences are common. The presentation is typical of that of acute pericarditis, with substernal chest pain and dyspnea as the prominent symptoms. Most patients have a pleural effusion, and many have mediastinal lymphadenopathy as well as pneumonia (101, 137) (Fig. 4). The pericardial and pleural fluids are exudative and frequently hemorrhagic, but tamponade is uncommon. The organism is rarely found in the fluid (167). It is thought that this manifestation occurs as a result of the host immune response to the fungus, and treatment with nonsteroidal anti-inflammatory agents relieves the symptoms. In some patients, corticosteroids may be required to dampen the immune response. Calcification of portions of the pericardium has been documented years later, but constrictive pericarditis rarely follows (101).
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Broncholithiasis occurs when a calcified node adjacent to a bronchus erodes into the bronchus, causing obstruction, inflammation, and subsequent bronchial scarring. Lithoptysis, the spitting of stones, which is more often the spitting of tiny pieces of gravel-like material, can result (49, 51, 114). Cough, with or without hemoptysis, and localized wheezing can occur. The broncholith can be identified on a chest CT scan, which will also document postobstructive atelectasis and pneumonitis (51). When the calcified mass is coughed up or removed through the bronchoscope, the symptoms resolve.
Patient groups at risk for disseminated histoplasmosis. The development of disease associated with the initial dissemination of H. capsulatum is dependent on the host. Patients who are immunosuppressed and are unable to develop effective cell-mediated immunity against the organism are likely to manifest symptomatic disease during the period of acute dissemination (Table 2). This includes patients with AIDS, transplant recipients, those with hematologic malignancies, and those on corticosteroids (37, 57, 64, 139, 146). Infants, presumably because of the immaturity of their cell-mediated immune system, are a special group that develops severe life-threatening infection when exposed to H. capsulatum (35, 50, 92). A person who develops an immunosuppressive condition years after leaving the area of endemicity may reactivate a focus of infection and, through that mechanism, develop severe disseminated histoplasmosis (64, 80).
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Recently, other immunosuppressive conditions have highlighted the importance of cell-mediated immunity in the defense against disseminated histoplasmosis. The most dramatic are cases of severe histoplasmosis in patients receiving tumor necrosis factor antagonists such as etanerecept (Enbrel) and imfliximab (Remicade) (18, 162, 165). Deficiency of the gamma interferon receptor has been described as a risk factor for refractory and recurrent disseminated histoplasmosis (168), and hyperimmunoglobulin M syndrome, which has T-cell defects in addition to immunoglobulin deficiencies, has also been associated with disseminated histoplasmosis (54).
Chronic progressive disseminated histoplasmosis is a term used to describe the slowly progressive and generally fatal infection due to H. capsulatum that occurs mostly in older adults who are not overtly immunosuppressed (50, 104, 119). The majority of the cases described by Parsons and Zarafonetis in 1945 in their classic description of disseminated histoplasmosis fall into this category (97). These patients have no obvious immunosuppression, but their macrophages clearly cannot effectively kill H. capsulatum. It is thought that there is a specific defect in the cellular immune response to this specific organism (50). The time course of the infection in these patients is measured in months, and the disease is uniformly fatal if not treated. This is in contrast to the rapidly fatal acute form of dissemination that occurs in infants and immunosuppressed patients (57, 92).
Symptoms, signs, and laboratory findings with disseminated disease. The symptoms of disseminated histoplasmosis include fever, malaise, anorexia, and weight loss. Physical examination will often show hepatosplenomegaly, lymphadenopathy, pallor and petechiae if pancytopenia is present, and, in some patients, mucous membrane ulcerations as well as skin ulcers, nodules, or molluscum-like papules (50, 104, 119). Laboratory studies reveal elevated alkaline phosphatase levels, pancytopenia, an increased Westergren sedimentation rate, elevated C-reactive protein levels, high lactate dehydrogenase levels, and increased ferritin expression, none of which are specific for disseminated histoplasmosis but all of which are highly suggestive of this diagnosis in the appropriate patient (16, 50, 68). Hypercalcemia occurs uncommonly and is similar to that described for a number of other granulomatous diseases (90). Chest radiographs may be normal or show a diffuse reticulonodular infiltrate. Many of the manifestations are similar to those of sarcoidosis; the latter diagnosis should not be considered established unless histoplasmosis is definitely excluded (144, 166).
Severe disease can present as sepsis syndrome with hypotension, disseminated intravascular coagulation, renal failure, and acute respiratory distress. This has been described mostly for infants and patients with AIDS (17, 50, 146, 154). Reactive hemophagocytic syndrome in AIDS patients with severe disseminated histoplasmosis has been described (72). Rarely, transmission across the placenta to the fetus has been described (158).
Gastrointestinal tract involvement is common during disseminated infection as determined by autopsy studies but remains asymptomatic or with only vague abdominal symptoms in many patients (50). Symptomatic infection appears to be more common in AIDS patients and can mimic other AIDS-associated opportunistic infections that cause diarrhea. Intermittent abdominal pain and tenderness are common, and severe diarrhea can lead to malabsorption (74, 93). The diagnosis of histoplasmosis is often not made until a tissue biopsy obtained by laparotomy or colonoscopy shows typical yeast forms of H. capsulatum (122). The colon is most commonly involved, followed by the small bowel; ulcerations, polypoid lesions, strictures, and perforations have been noted.
Several unique manifestations occur more frequently with histoplasmosis than with other disseminated fungal infections. This includes Addison's disease, which occurs when there is extensive destruction of both adrenal glands by the infection. The patient exhibits fever, malaise, orthostatic hypotension, nausea, and vomiting (110, 119). Hyperkalemia, hyponatremia, and eosinophilia are usually present. CT scan shows markedly enlarged adrenals, often with necrosis in the central area (160). Adrenal insufficiency was a frequent cause of death in earlier years (110). Mucous membrane lesions are also more frequently seen in disseminated histoplasmosis than in other endemic mycoses, with the exception of paracoccidioidomycosis (50, 104, 119). The tongue, gingival and buccal mucosa, lips, pharynx, and larynx can be involved. Superficial ulcerations, deeper ulcerations with heaped-up borders, nodular masses, and verrucous lesions have been noted. Although localized oral lesions in patients with no other symptoms of disseminated infection have been described (89), this is very uncommon, and mucocutaneous lesions should always be considered a manifestation of disseminated disease.
Histoplasmosis can involve every organ system during the course of dissemination, but symptomatic disease is rare at some sites. In some instances, patients have obvious systemic infection with widespread dissemination, and in other instances, focal disease in a single organ is the only manifestation of dissemination. For example, genitourinary tract involvement, although frequently documented at autopsy in patients with disseminated infection (64, 97), is rarely symptomatic. Testicular abscess, prostatic abscess, epididymitis, penile lesions, and bladder ulcerations have been reported for a few patients each (38, 65, 84, 112). The patients are often thought to have a tumor of the prostate, testes, or epididymis until a biopsy specimen reveals the typical yeast-like forms of H. capsulatum. In a few cases, immune complex glomerulonephritis with H. capsulatum antigen demonstrated in the mesangium has been described (9, 10).
Osteoarticular infection with H. capsulatum is another uncommon manifestation of histoplasmosis. Involvement can primarily involve tendons, presenting as carpal tunnel syndrome (121), or be manifest by septic arthritis of either native or prosthetic joints (20, 36) and, rarely, osteomyelitis (58). The diagnosis is generally not entertained until culture of surgical material or synovial fluid yields H. capsulatum. Sites such as gall bladder, breast, thymus, and thyroid gland are rarely infected and usually discovered only at autopsy (42, 113).
Endocarditis and vascular infection. Histoplasma endocarditis is a rare manifestation of disseminated histoplasmosis. Infection can occur on native valves, prosthetic valves, and even atrial myxomas (3, 6, 41, 107). The patient has symptoms typical of chronic disseminated histoplasmosis and also has cardiac findings and embolic phenomena. The diagnosis is often delayed, and the patient is usually labeled as having culture-negative endocarditis. The outcome is dismal unless the diagnosis is made in a timely fashion so that effective antifungal therapy can be given (3). Infection of vascular grafts has also been described in a few cases (83).
Central nervous system infection. Patients can have involvement of the central nervous system (CNS) either as one manifestation of a disseminated infection or as an isolated focal infection (145, 157). CNS involvement occurs as a result of hematogenous dissemination to the meninges or brain. Chronic meningitis is the most common manifestation and is characterized by basilar meningeal involvement that can lead to communicating hydrocephalus. With the increased use of magnetic resonance imaging (MRI) scans, it has become clear that small ring-enhancing lesions can frequently be found throughout the brain and spinal cord (Fig. 5). These occur with meningitis or exist as isolated lesions without meningeal involvement. Larger, more typical brain abscesses can also be found (70).
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For patients who have disseminated infection, samples can be taken from blood, bone marrow, liver, skin lesions, or any other site of infection. The lysis-centrifugation (Isolator tube) system has been shown to be more sensitive than automated systems for growing H. capsulatum from blood (98, 99, 161). When sputum or bronchoalveolar lavage fluid is sent for culture, a selective medium that adds ammonium hydroxide to the surface of the agar to increase the pH is very helpful; it decreases the growth of commensal fungi, thus allowing the slowly growing H. capsulatum to appear (118).
The greatest yield of culture positivity occurs in those patients who have disseminated infection, chronic cavitary pulmonary histoplasmosis, and acute pulmonary histoplasmosis following exposure to a large inoculum of the organism. For other forms of histoplasmosis, including mild to moderate acute pulmonary infection, granulomatous mediastinitis, mediastinal fibrosis, and chronic meningitis, cultures usually remain negative. Cultures usually yield no growth from cerebrospinal fluid, and the diagnosis must be made in a different manner.
Routine hematoxylin and eosin stains generally will not allow the visualization of the tiny yeasts, although when a large number of organisms are present, one gets the impression that the macrophages are filled with something; however, the exact nature of the substance cannot be evaluated (113). Tissue should be stained with methenamine silver or periodic acid-Schiff stains to best visualize H. capsulatum. Yeasts are typically found within macrophages but can also be seen free in tissues (Fig. 6).
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In addition to patients with disseminated histoplasmosis, the antigen assay is most useful for those patients who have acute pulmonary histoplasmosis following exposure to a large number of conidia. In this group, antigenuria is detected in approximately 75% of patients within the first few weeks of illness (151). However, only 10 to 20% of patients who have less severe acute pulmonary histoplasmosis or chronic cavitary pulmonary histoplasmosis will have antigen detected in urine (151). Patients with granulomatous mediastinitis and mediastinal fibrosis generally do not have Histoplasma antigen detected in serum or urine.
There are few data on the usefulness of the Histoplasma antigen assay for bronchoalveolar lavage fluid obtained from patients with diffuse pulmonary infiltrates due to histoplasmosis (149). The 27 patients studied were all AIDS patients, and antigen was detected in 19 (70%) of those patients, a sensitivity less than that of urine, which was 93%. There have been no reported data on the usefulness of this assay on bronchoalveolar lavage fluid from non-AIDS patients. Antigen was shown to be present in cerebrospinal fluid of patients with Histoplasma meningitis by using the original radioimmunoassay (143). The sensitivity of the EIA has been reported to be from 40 to 66%, with the higher rates noted in immunosuppressed patients who presumably had a higher burden of organisms in the central nervous system (151).
False-positive reactions for Histoplasma antigen in urine are common among patients who have other endemic mycoses (Table 3). In one study, 8 of 9 patients with paracoccidioidomycosis, 12 of 19 with blastomycosis, and 17 of 18 with penicilliosis had urine antigen tests that were positive for Histoplasma antigen (133). There do not appear to be false-positive tests in patients with coccidioidomycosis. In North America, there is little concern about this lack of specificity, except for those patients who have blastomycosis, because only the areas of endemicity of histoplasmosis and blastomycosis overlap (40). Diagnosis should not be based on a urine antigen test alone; almost always, other serologic and culture data are available to confirm the diagnosis of histoplasmosis.
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The amount of Histoplasma antigen detected in urine can be used to monitor a patient's response to therapy (147, 148, 150, 152). Most of the reported studies were done with AIDS patients. Antigenuria should be expected to fall to below the level of detection with successful therapy (148, 150, 152). A subsequent rise in antigen levels with recrudescent infection has been noted (147). Follow-up antigen studies of non-AIDS patients have not been reported but presumably should be useful.
An inhibition EIA for the detection of Histoplasma antigens that uses a murine monoclonal antibody, rather than a polyclonal antibody, has been developed and appears to be more sensitive in serum than in urine (44, 45). However, this assay is not currently commercially available.
1:32 is suggestive but not diagnostic. CF antibodies persist for years after infection; thus, the presence of a single low CF titer means little other than that the patient was exposed to H. capsulatum at some time. The CF test appears to be less specific than the ID assay; cross-reactions occur with other fungal infections and other granulomatous processes, including tuberculosis and sarcoidosis (102, 141). The ID assay tests for the presence of M and H precipitin bands. An M band develops with acute infection, is often present in chronic forms of histoplasmosis, and persists for months to years after the infection has resolved. An H band is much less common, is rarely, if ever, found without an M band, and is indicative of chronic or severe acute forms of histoplasmosis (2, 102). The ID assay is approximately 80% sensitive but is more specific than the CF assay. Several investigators have shown that the detection of H and M precipitating antibodies by counterimmunoelectrophoresis is more sensitive than that by immunodiffusion (69, 102, 124). However, this technique has not been commercialized, and the standard immunodiffusion assay is the only assay available. A radioimmunoassay has been described, but false-positive reactions appear to be higher than those noted with the CF assay, and standardization has not been established (138). This assay is currently not available.
Tests for antibody are most useful in patients who have chronic forms of histoplasmosis that have allowed enough time for antibody to develop and in patients who have acute pulmonary histoplasmosis, in whom documentation of a fourfold rise in antibody titer to H. capsulatum can be diagnostic. Because 2 to 6 weeks may be required for the appearance of antibodies, these assays are less useful for patients who have severe acute infection and in immunosuppressed patients, who mount a poor response (64). For those patients who have mediastinal lymphadenopathy, antibody assays may or may not be positive and cannot be relied upon to make a definitive diagnosis. Tissue biopsy is always required in these instances. False-positive CF tests occur in patients with lymphoma, tuberculosis, sarcoidosis, and other fungal infections, all of which may present as a mediastinal mass.
One unique circumstance in which the presence of antibodies may be the only assay leading to a diagnosis of histoplasmosis is in a patient who has chronic meningitis due to H. capsulatum. In this case, the presence of either CF or ID antibodies against H. capsulatum in the cerebrospinal fluid allows one to make the diagnosis of Histoplasma meningitis even when the culture shows no growth (128, 145).
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Those studies also established an effective total dose of amphotericin B to be used for these forms of histoplasmosis. For the next 30 years, patients generally received a total dosage of 25 to 35 mg/kg amphotericin B over several months, often with resultant serious toxicity (39, 96, 104). By the time that the first Mycoses Study Group/Infectious Diseases Society of America (IDSA) guidelines for the management of histoplasmosis were published in 2000, treatment with amphotericin B for the entire course of therapy was unusual. Amphotericin B was listed as the preferred regimen only for severe disease and then only for initial therapy, with a step down to an azole agent when the patient had begun to show improvement (135).
With the introduction of ketoconazole, the hopes of treating histoplasmosis in the outpatient setting with an oral medication were finally realized. This azole was found to be effective for both disseminated and pulmonary forms of histoplasmosis; the overall success rate was 85% if the drug was taken for at least 6 months (27). Although less toxic than amphotericin B, side effects were significant, occurring in 60% of patients. At the higher dosage of 800 mg daily, interference with steroid metabolism was common, leading to gynecomastia, decreased libido, menstrual irregularities, and even hypoadrenalism (27). Ketoconazole is now rarely used for the treatment of histoplasmosis.
In the late 1980s and early 1990s, the NIAID Mycoses Study Group carried out open-label clinical trials of itraconazole for the treatment of pulmonary and disseminated histoplasmosis. The drug proved to be more effective than ketoconazole and with many fewer side effects (28). In AIDS patients who had mild to moderate disseminated histoplasmosis, itraconazole also proved to be effective therapy (130). Itraconazole has remained the drug of choice for the treatment of mild to moderate histoplasmosis for more than a decade (135).
Fluconazole is less effective than itraconazole in both patients with AIDS and those without AIDS (85, 132). Success rates of 63% for patients without AIDS (85) and 50% for those with AIDS (132) were noted. Fluconazole remains a second-line agent for the treatment of histoplasmosis.
Clinical data on the new azoles, voriconazole and posaconazole, for the treatment of histoplasmosis are limited. Both agents have activity in vitro against H. capsulatum (34, 46, 76, 127). Posaconazole has been shown to be more effective than itraconazole in both immunocompetent and immunocompromised mice infected with H. capsulatum (14, 15); voriconazole has not been tested in animal models of histoplasmosis.
Voriconazole, which is similar to fluconazole in structure, has resulted in success in the treatment of a few patients (37, 100). In one series of six transplant recipients with histoplasmosis, three were treated with voriconazole after initial therapy with other agents, and all three appeared to be cured of their infection (37). Posaconazole, which is similar to itraconazole in structure, was reported to be effective in six of seven patients, four of whom had disseminated infection and all of whom had failed or were intolerant of other therapy (104a). One of these seven patients, who had meningitis, was also later reported as having been successfully treated with posaconazole (103). One other patient who had disseminated histoplasmosis was also successfully treated with posaconazole (13). The echinocandins do not have in vitro activity against H. capsulatum and are ineffective in animal models of infection (73); they should not be used for treating histoplasmosis. Treatment options for each form of histoplasmosis are discussed below and generally reflect IDSA guidelines, which are currently undergoing revision and will be published in 2007 (135).
Patients who have acute severe pulmonary histoplasmosis with diffuse reticulonodular infiltrates and hypoxemia should definitely receive antifungal therapy. When amphotericin B was the only treatment option available, these patients generally were not treated. Most patients recovered but only after many months, and some died. Current recommendations are to treat patients with severe acute pulmonary infection (135). Initial treatment should be amphotericin B, 0.7 to 1 mg/kg daily, or a lipid formulation of amphotericin B, 3 to 5 mg/kg daily, until the patient begins to show improvement; therapy can then be switched to itraconazole, 200 mg orally twice daily, for a total of approximately 3 months, depending on the clinical and radiographic response. Some patients may require therapy for as long as 6 months. Corticosteroids, given as intravenous methylprednisolone for several days or 60 mg prednisone orally daily for a week with tapering over the next 1 to 2 weeks, appear to be beneficial, but there are no controlled studies that verify this practice.
Mediastinal fibrosis does not respond to antifungal therapy. Oral itraconazole is given out of a desire to do something, but there is no evidence that it has any positive effect. Corticosteroids and nonsteroidal anti-inflammatory agents also are not effective. Surgery has been advocated in the past, but current recommendations are to avoid surgery because the operative mortality rates are high and there has been no evidence of benefit (78, 82, 135). The most effective intervention appears to be the placement of intravascular stents in vessels that are shown to be impinged upon by the fibrosis (22, 29). This should be performed after careful review of angiograms and CT scans by an interventional radiologist who is experienced in the treatment of this disease. For vessels identified as the source of hemoptysis, angiographic embolization can be attempted.
Pericarditis associated with acute pulmonary histoplasmosis responds to treatment with nonsteroidal anti-inflammatory agents; rarely, corticosteroids may have to be used (137). Antifungal agents should not be used, because the pericarditis reflects an inflammatory reaction to H. capsulatum rather than an active infection of the pericardium. In the exceptional case associated with tamponade, pericardiocentesis and the creation of a pericardial window are important therapeutic measures (101).
Patients with severe disseminated infection should be treated initially with amphotericin B at a dosage of 0.7 to 1 mg/kg daily or a lipid formulation of amphotericin B at a dosage of 3 to 5 mg/kg daily. Current practice is to use lipid formulations of amphotericin B in most patients because of their reduced toxicity. A randomized, blinded, comparative trial in AIDS patients with severe disseminated histoplasmosis showed that not only was liposomal amphotericin B less toxic than standard amphotericin B deoxycholate, it also led to a more prompt resolution of fever and improved survival (56). Continuing amphotericin B throughout the entire course of therapy is no longer the standard of care. For almost all patients, as their condition improves, generally within a few weeks, their therapy is switched to oral itraconazole at a dosage of 200 mg twice daily (135).
It is not clear whether patients have better outcomes if they receive an initial few weeks of therapy with an amphotericin B formulation before itraconazole is prescribed. A retrospective analysis of the length of time that AIDS patients remained fungemic and had persistent antigenuria when treated with either itraconazole or liposomal amphotericin B showed that those patients who received liposomal amphotericin B had more rapid clearance of both fungemia and antigenuria than those who received itraconazole (150). It must be emphasized that this was not a controlled prospective analysis of these two treatment regimens; however, if anything, the results would likely be biased in favor of itraconazole because those patients were less ill.
The length of therapy depends on the severity of the infection and the immune status of the host. IDSA guidelines recommend 6 to 18 months total. This wide range emphasizes the fact that it is the immune response of the host that determines when and if azole therapy is stopped. The minimum period of treatment should be 6 months for the relatively healthy host; most patients will be treated for 12 months. Patients with chronic progressive dissemination often respond slowly, and treatment may have to continue for a total of 18 to 24 months.
Because of the high rate of relapse, it has been standard practice for AIDS patients who have histoplasmosis to be placed on maintenance azole therapy for life after their initial response to antifungal therapy (129). However, this has changed with the use of highly active antiretroviral therapy that restores CD4 cell numbers to normal or at least higher levels. Studies have shown a very low risk of relapse when CD4 counts have remained at >200 cells/µl for a year (43). The current practice is to discontinue antifungal therapy for patients achieving this level of CD4 reconstitution. For those who do not achieve immune reconstitution, maintenance therapy with 200 mg itraconazole daily should continue for life. It has also been established that prophylaxis with 200 mg itraconazole daily is effective at preventing histoplasmosis in patients with AIDS who have CD4 counts below 150 cells/µl (86). However, with the use of effective antiretroviral therapy, rates of histoplasmosis have fallen in the AIDS population, and prophylaxis is no longer recommended.
The azole of choice is not clear; fluconazole and itraconazole were both recommended as possible agents by IDSA guidelines (135). Itraconazole does not achieve adequate cerebrospinal fluid levels but has been used successfully for the treatment of cryptococcal and coccidioidal meningitis. Fluconazole achieves higher cerebrospinal fluid concentrations but is less active against H. capsulatum than itraconazole. The failure of fluconazole in a murine model of CNS histoplasmosis has been noted (53, 75). Both azoles have been used successfully for secondary treatment following induction therapy with amphotericin B (1, 70, 126). The dosage suggested for itraconazole is 200 mg twice or thrice daily, and that for fluconazole is 800 mg daily. Primary azole therapy of CNS histoplasmosis should be discouraged. Although success has been reported in a few cases, failures rates are high (71, 106, 116, 130).
Enhancing lesions in the brain or spinal cord should be treated in the same manner as meningitis. Surgical excision is not necessary. MRI scans are the appropriate test to be followed to ensure resolution. Antifungal therapy should continue for several months after all the lesions have resolved on an MRI scan (157).
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