Histoplasma capsulatum (Histoplasmosis)

Histoplasmosis is the most common endemic mycosis and a major cause of morbidity in patients who live in endemic areas. It has emerged as an important opportunistic infection in immunocompromised patients including those with AIDS or who are taking medications that impair cellular immunity. Exposure to bird or bat guano are important epidemiological clues to the diagnosis. Unique clinical manifestations may alert the clinician to consider the diagnosis of histoplasmosis. Serologic tests measuring the antibody response and tests for antigen complement cultural methods for diagnosis. Newer treatment options have improved the outcome of therapy and offered effective and well-tolerated alternatives to amphotericin B.

The mold form of Histoplasma capsulatum grows in soil containing rotted bird or bat guano. Microconidia are the infectious particles of the mold, while the macroconidia are characteristic of the organism and provide a clue to its identification. H. capsulatum grows as a yeast above 35°C. The yeast is the pathogenic form of the organism found in the tissues of infected individuals. Complete identification requires conversion of the mold to the yeast, identification of specific antigens by immunologic tests, or genetic verification using nucleic acid probes.

Histoplasmosis, although worldwide in distribution, is more prevalent in certain parts of North and Latin America (5, 36 87, 118), (Figure 1). Bird and bat excrement enhance the growth of the organism in soil by accelerating sporulation. Birds, because of their higher body temperature, are not susceptible to histoplasmosis and do not acquire the infection; while bats, however, may be infected with H. capsulatum, and spread the organisms to different locations in the environment (24).  Several outbreaks have resulted from exploration of caves inhabited by bats (6, 49, 52, 91).  Other animal species also may be infected with H. capsulatum var. capsulatum, including sea mammals (66).  Factors accounting for its geographic distribution are poorly understood but include high humidity, moderate climate, and acidic soil characteristics. Activities that disturb environments containing H. capsulatum cause airborne spread of the microconidia, infecting those who are exposed during the disturbance. These environmental sites typically are visibly contaminated by heavy accumulations of bat or bird droppings, but patients often are unaware of any such exposure.

Histoplasmosis usually is asymptomatic or non-progressive in healthy individuals (119). The clinical and radiographic manifestations may be similar to those in community-acquired pneumonia (23), sarcoidosis (38, 52, 55), tuberculosis (52), and malignancy (15, 17, 33).  Consequently cases may be misdiagnosed with these conditions without testing to exclude histoplasmosis.  With low-level exposure, asymptomatic infection is most common. Such cases are detected by skin test surveys or identification of pulmonary nodules, mediastinal lymphadenopathy, or splenic calcifications on CT scan or abdominal radiogram. In endemic areas, half to more than 80% of young adults are infected with H. capsulatum, based upon skin test surveys. While fewer than 5% of individuals develop symptomatic disease after low level exposure, attack rates exceeding 75% follow heavy exposure, as might occur during work or recreation at a contaminated site (116).

The common clinical findings of self-limited infection include acute pulmonary histoplasmosis, pericarditis (120), and rheumatologic syndromes (90). Patients present with fever, cough and chest pain; and chest radiograms show mediastinal lymphadenopathy with infiltrates. Heavy exposure causes more extensive pulmonary involvement, sometimes accompanied by respiratory insufficiency (55). Patients also may experience symptoms caused by obstruction of mediastinal structures by enlarged lymph nodes (70).

The severity of illness correlates with the intensity of exposure (63). Following heavy exposure, patients may present with diffuse pulmonary involvement (55, 69, 89). Symptoms of fever, chills, sweats, headache, myalgia, anorexia, cough, and chest pain characterize these illnesses (10), and respiratory failure and death may ensue (103). Chest radiograms show diffuse reticulonodular or miliary pulmonary infiltrates in 90% of cases, sometimes with mediastinal lymphadenopathy (55, 69, 89). Following the more typical, low-level exposure, the pulmonary illness is more commonly subacute and mild, or even asymptomatic. Chest roentgenograms show enlarged hilar or mediastinal lymph nodes with patchy infiltrates (121), but may be normal (121). While rapid improvement in two to three weeks is characteristic (10), fatigue may linger (121).

Enlarged mediastinal lymph nodes may impinge upon the airways, pulmonary vessels or vena cava, or the esophagus, occurring in <10% of patients with acute pulmonary histoplasmosis (15, 31, 61, 62, 66). These findings may first present years after the initial infection, as a result of smoldering inflammation and necrosis in the involved node. Symptoms include chest pain, cough, hemoptysis, dyspnea and dysphagia (31, 85, 96).

Symptoms of more than six weeks duration was proposed as the definition for chronic pulmonary histoplasmosis  (58). In outbreaks in Indianapolis, most of the patients with self-limited pulmonary histoplasmosis had symptoms for more than six weeks and would have met this definition (121). The definition for chronic pulmonary histoplasmosis used in other reviews (43, 51) required the presence of cavities, and while not included in the definition, most patients had underlying chronic obstructive pulmonary disease and were symptomatic for more than three months at diagnosis. Chronic pulmonary histoplasmosis is characterized by recurrent pulmonary symptoms, progressive lung infiltrates, fibrosis and cavitation (37, 119). Upper lobe infiltrates with cavities are present in most cases. While some patients recover spontaneously (37), the majority demonstrate progression with cavity enlargement, formation of new cavities, and spread to new areas of the lungs. Rarely bronchopleural fistula may develop. Care must be taken to exclude cancer in patients with nodular lesions not responding to treatment, as cigarette use is a shared risk factor for both conditions. Tuberculosis also may coexist and must be excluded (37, 119). Bacterial infection, common in patients with underlying emphysema or other chronic lung diseases, may be the cause of recurrent symptoms, rather than relapse or progression of histoplasmosis. Aspergilloma, chronic invasive aspergillosis, and atypical mycobacterial infections also may complicate chronic pulmonary histoplasmosis.

Pericarditis is a local inflammatory or immunologic reaction to the adjacent mediastinal histoplasmosis, occurring in about 5% of symptomatic cases (120). Perhaps necrotic mediastinal nodes erode into the pericardium, releasing antigenic or inflammatory substances in some cases. Pericarditis rarely may be a complication of disseminated histoplasmosis. Hemodynamic compromise occurs in 40% of these patients (120). Patients usually respond to anti-inflammatory medications without antifungal therapy (90, 120), while those with hemodynamic compromise may require corticosteroid therapy or drainage of the pericardial fluid. Outcome is excellent, with rare progression to constrictive pericarditis (9, 59, 120, 141). Antifungal therapy is unnecessary (81, 120) unless the patient receives corticosteroids or has disseminated disease.

Rheumatologic syndromes also occur in about 5% of patients with recent histoplasmosis, and appear to represent a systemic immunologic reaction to the pulmonary infection (90, 100, 112). Arthralgia or arthritis, usually polyarticular and symmetrical, may be the sole finding, or may be associated with pulmonary complaints. Half of patients exhibit erythema nodosum. Joint radiograms are normal, while chest radiograms may show pulmonary histoplasmosis. The joint symptoms usually resolve in response to anti-inflammatory therapy (76).

Hematogenous spread outside the lungs occurs in a high proportion of individuals during the acute infection but rarely is recognized clinically. These patients recover with the development of cellular immunity to H. capsulatum. Disseminated infection is progressive in about one in 2000 acute infections, however (94). Progressive disseminated histoplasmosis is seen most often in patients who are immunosuppressed or at the extremes of age. Histoplasmosis is a major opportunistic infection among patients with HIV/AIDS  (37, 40) or who have undergone solid organ transplantation (3, 16) or treatment with tumor necrosis factor inhibitors (11, 19, 28).  Deficiency in the interferon-γ/interleukin-12 pathway has been described as a rare cause for PDH  (58, 144).  Severity varies with the degree of immune deficiency. An acute, rapidly-fatal course with diffuse reticuloendothelial involvement characterizes the infection in infants and others who are severely immunosuppressed, while a chronic course with a more focal organ distribution is more typical in non-immunocompromised children and adults (38).

Clinical findings of progressive disseminated histoplasmosis are non-specific. Fever, weight loss and respiratory symptoms are the most common clinical findings. Examination often reveals hepatomegaly, splenomegaly or lymphadenopathy; and laboratory tests may show findings of bone marrow suppression and hepatitis. Shock and multi-organ failure may complicate severe cases (122). Other frequent sites of dissemination include the oral mucosa, gastrointestinal tract, skin, kidneys and adrenal glands. Skin lesions include papules, pustules, folliculitis, ulcers, subcutaneous nodules, and roseacea-like eruptions. Gastrointestinal involvement also is common, presenting as mass lesions or ulcerations, causing pain, bleeding, perforation or malabsorption. Hemophagocytic lymphohistiocytosis (HLH) manifested by pancytopenia and hemophagocytosis may be seen in disseminated histoplasmosis (34, 43).  A macrophage activation syndrome (MAS) characterized by hepatic dysfunction, encephalopathy, pancytopenia and disseminated intravascular coagulation has also been described (25).  Both are life-threatening conditions associated with a high mortality rate if the cause is not established promptly and antifungal treatment is delayed.  Chest roentgenograms usually show diffuse infiltrates but may be normal in one third of cases.  Chest roentgenograms usually show diffuse infitrates but may be normal in one third of cases.

Brain, spinal cord or meningeal involvement occurs in about 5% to 10% of cases (94, 122, 123). In older studies, although recognized clinically in only 4% of cases, CNS involvement was present at autopsy in one to two-thirds (38, 89). About 5% of cases in recent series of disseminated histoplasmosis in patients with AIDS exhibited CNS involvement (40). Of 89 cases of CNS histoplasmosis reviewed with the author since 1991, 67% had meningitis, 27% brain lesions, and 7% cord involvement (40). Among those with meningitis, 17% had hydrocephalus, most of which had CSF shunts in place at the time of diagnosis of meningitis. In many cases, the diagnosis was overlooked for months to years before testing for histoplasmosis was performed. Clinical syndromes include sub acute or chronic meningitis, focal brain or spinal cord lesions (6), stroke syndromes caused by vascular involvement or emboli, or encephalitis (2,123). CNS infection may occur as manifestations of widely disseminated disease or as isolated sites of dissemination, with nearly equal frequency (136).

Endocarditis is a rare complication of disseminated histoplasmosis and usually is manifested by systemic emboli, found in 29% of cases (46) to 40% of cases (7), in a person with other finding of disseminated disease in 29% (46) to 75% of cases (7). Prosthetic valves (31) were involved in 20%  (7) to 71% of cases (46). Use of fungal serology and antigen detection may facilitate earlier diagnosis and is recommended in the evaluation of patients with “culture-negative” endocarditis (7, 31, 46).

Other less common sites of dissemination include the kidneys, ureters, bone and joints, sinuses, eye, ears, gallbladder, cystic duct, common bile duct, prostate, breast, epididymis, urinary bladder, penis or vagina, testis or ovary, heart, pleura, and aorta. Thymus involvement is common in fatal cases in children. Cases presenting with necrotizing cellulitis, psoas abscess, myositis, and renal mass also have been seen in disseminated histoplasmosis.

Calcified mediastinal nodes and pulmonary granulomas may erode into adjacent bronchi (4). Patients may expectorate rock-like particles of tissue and experience hemoptysis, bronchial obstruction or tracheoesophageal fistula.

Mediastinal fibrosis is a rare manifestation of histoplasmosis which is felt to represent an abnormal host response to the infection (17, 39, 45, 70). Viable organisms cannot be found in these tissues.  Histologic examination and immunostaining reveals fibrinoinflammatory infiltrates containing CD20-positive B lymphocytes (45). The superior vena cava, airways, pulmonary arteries or veins, or esophagus are most commonly involved but any mediastinal structure can be trapped in these fibrotic masses (39, 70). Chest radiograms may be normal or show only mediastinal widening, but CT scans reveal restriction and invasion of mediastinal structures. Calcification often is present. Recurrent hemoptysis is a common symptom and respiratory failure often ensues. Commonly-reported symptoms include cough, dyspnea, chest pain, hemoptysis, pleurisy caused by vascular obstruction, dyspnea or recurrent pneumonia caused by airway narrowing; facial or upper extremity swelling or congestion, varicose veins on the head, neck, arms or abdomen, dizziness, headache, and rarely syncope caused by superior vena cava obstruction (70).

Single or multiple pulmonary nodules are common radiographic or CT scan findings in histoplasmosis.  Histoplasmosis is the most common cause of resected non-malignant pulmonary granulomatous nodules and masses from patient who reside in the endemic area (39). The clinical and radiographic presentations often mimic those of primary or metastatic lung cancers (7, 15).  The radionuclide uptake using PET-CT is high in lung nodules caused by histoplasmosis, which lead clinicians to confuse them with malignant nodules (10).  Newer imaging strategies based on intensity and timing of the radionuclide uptake have been developed to differential granulomatous from malignant nodule (27).  Pulmonary nodules are nearly always asymptomatic, and require no antifungal therapy.  A management strategy based upon the diameter of the nodules has been evaluated in patients from an endemic area who were at least 50 years of age, had at least a 20 pack year smoking history, and denied symptoms of cancer or evidence of cancer in the prior 5 years (48).  Yearly CT was performed for nodules less than 5 mm, twice yearly CT for nodules of 5-7 mm, and review by a multidisciplinary tumor board for nodules 8 mm or more in diameter, reserving biopsy for nodules greater than 12 mm in diameter.  Using this approach, cancer was diagnosed in 5% of study patients, no cancers were missed, and no biopsies were performed for benign lesions.

Rarely patients may develop a slowly enlarging pulmonary nodule which has been called "enlarging histoplasmoma." (40). Histoplasmomas usually are asymptomatic but often cause concern about malignancy. They range in diameter from 8 mm to 35 mm and enlarge an average of 2 mm per year, presumably through inflammation and fibrosis in response to antigenic materials released from the central core into the surrounding tissue. Calcification occurs in the core and the periphery of the lesion. Histologically they are characterized by a necrotic center surrounded by a fibrous-like capsule. Organisms may be seen in the necrotic center but usually cannot be isolated in cultures.

Choroiditis involving the macula and causing visual loss has been attributed to histoplasmosis (11), but there is no scientific basis establishing H. capsulatum as its cause. The association has been based on high rates of skin test reactivity rather than demonstration of the fungus in the tissues (105). Identification of patients with similar findings outside the endemic area for histoplasmosis further weakens the association of histoplasmosis with this clinical syndrome (108). However, the eye may be involved in patients with disseminated histoplasmosis (106).

A battery of diagnostic procedures is needed for diagnosis of histoplasmosis (124). Serologic tests for antibodies form the basis for diagnosis in most patients with mild infections, while cultures, stains, and tests for antigens are more useful in those with more severe disease.  Biopsy of the involved organ for histopathology and culture may be required in some patients in whom test for antibodies in serum and CSF, test for antigens in urine, serum and other body fluids, and cytological analysis are negative or in severely ill patients in whom an immediate diagnosis is judged to be necessary to begin antifungal therapy before antigen results can be obtained.

Antibodies to H. capsulatum measured by immunodiffusion or complement fixation develop in most patients (2). H. precipitin bands can be demonstrated in less than 25% of patients and clear during the first 6 months following exposure (125, 140).  M bands occur in over three-quarters of cases and persist for years in some patients. Complement fixation titers of 1:8 or more are found in most patients with histoplasmosis while titers of 1:32 or higher are more suggestive of active infection. Both the immunodiffusion and complement fixation test should be performed to obtain the highest sensitivity for diagnosis. Tests for antibodies using enzyme immunoassay may be used for screening, reserving immunodiffusion and complement fixation for specimens that are positive by enzyme immunoassay.  However, specimens that are positive by complement fixation or immunodiffusion may be negative by enzyme immunoassay, detracting from reliance upon negative enzyme immunoassay results as evidence that histoplasmosis has been excluded.

Antibodies require 4 to 8 weeks to develop following acute infection and may be negative when the patient is first seen. Furthermore, serologic tests may be falsely-negative in up to one-third of immunocompromised patients (140). Interestingly, serology was positive in nearly 90% of cases in patients receiving TNF inhibitors, usually with other immunosuppressive agents (46) but only one third % of those following organ transplantation (3,16). Positive results caused by cross reactions occur in patients with blastomycosis, coccidioidomycosis and paracoccidioidomycosis (127).

High levels of antibodies, particularly if complement fixation titers of 1:8 or 1:16, may persist for several years following acute infection, causing confusion in patients with other diseases, resulting in a mistaken diagnosis of histoplasmosis. Despite limitations noted above, antibody testing by immunodiffusion and complement fixation is recommended in the work up of suspected histoplasmosis, including cases in immunocompromised patients (56).

Cultures are most useful in patients with disseminated or chronic pulmonary histoplasmosis. Culture is a particularly reliable diagnostic method for patients with disseminated histoplasmosis and HIV/AIDS (2).  The sensitivity is only l0 to 15% in patients with other forms of histoplasmosis (140). In disseminated histoplasmosis, the highest yield is from bone marrow or blood, positive in over 75% of cases (94, 122).  Organisms can be found in sputum or bronchoscopy specimens in 60 to 85% of cases of cavitary histoplasmosis (119).  Due to their time consuming nature, fungal cultures cannot be relied up for a rapid diagnosis of histoplasmosis especially in patients with severe disease where timely initiation of antifungal therapy might be lifesaving. 

Sensitive methods for rapid diagnosis of histoplasmosis in patients with severe manifestations are essential to allow prompt initiation of therapy. Fungal stain is rapid but insensitive. Detection of antigen offers a valuable approach to the rapid diagnosis, especially in patients with the “epidemic” form of acute pulmonary, which follows within a week or two of a heavy exposure and is characterized by diffuse infiltrates (109) and for disseminated histoplasmosis (14, 128, 140). The high sensitivity can be achieved by testing both here and serum specimens (109, 110). Antigen is also found in bronchoalveolar lavage fluid of most individuals with pulmonary histoplasmosis (21). Antigen may be found in CSF of about 88% of patients with meningitis caused by histoplasmosis. Cross-reactions may be seen in most patients with African histoplasmosis, blastomycosis, paracoccidioidomycosis, and Penicilliosis marneffii, 10% with coccidioidomycosis (12, 13) and rarely with aspergillosis  (51). Antigen levels decline during treatment (22) and increase with relapse (40), providing a tool for monitoring therapy (129). These findings represent results of testing at MiraVista Diagnostics and should not be applied to testing using other assays (49, 59).

Silver stain of tissue sections or Wright stain of peripheral blood smears permits rapid diagnosis but with a lower sensitivity than culture or antigen detection. Fungal stains of tissues are positive in about half of cases of disseminated histoplasmosis (24). Candida glabrata, Cryptococcus neoformans, Blastomyces dermatitidis, Penicillium marneffei, Pneumocystis carinii, Toxoplasma gondii, Leishmania and staining artifacts may be misidentified as H. capsulatum.

The published studies have not demonstrated superiority of PCR over other rapid methods, such as cytology, histopathology, or antigen detection. PCR was falsely-negative in 31% of tissues in which yeast resembling H. capsulatum were seen by histopathology (8).  Tang evaluated PCR on urine specimens from patients with histoplasmosis, noting positive results in only 8% of specimens with elevated Histoplasma antigen results (111).  Others, using a nested PCR, reported a sensitivity of 100% in respiratory specimens or tissues from patients with “suspected” histoplasmosis and specificity of 95% in controls, among which false positive results occurred in four of 29 BAL specimens from which no “related” microorganisms were isolated (77).  More recently PCR exhibited high sensitivity and specificity in BAL and tissue specimens, positive in 73 % of specimens from which Histoplasma was isolated (4).  A multiplex real-time PCR platform has been developed to simultaneously detect three of the most frequent causative agents of fungal opportunistic pneumonia in AIDS patients including Histoplasma capsulatum, using clinical respiratory specimen (14).  PCR is offered for clinical use by a number of reference laboratories, but its role for diagnosis of histoplasmosis remains to be established (56).

Infection develops when conidia are inhaled and transform into yeasts in the lungs (38, 122).

Cellular immunity is the primary host defense against H. capsulatum (3, 19, 78). CD4 lymphocytes activate macrophages to assume fungicidal properties (1, 142), serving to control the infection in immunocompetent individuals. Progressive disseminated disease is seen in those with underlying immunosuppression (130) or at the extremes of age (38, 130). Interferon-γ and IL-12 play important roles in the development of an effective Th1 immune response to H. capsulatum. Depletion of these factors prevents the development of effective immunity in experimental histoplasmosis (1, 145).

Reactivation of quiescent infection is postulated to occur during immunosuppression (18, 92, 122), but appears to be rare (19). Identification of a Panamanian genotype in immigrants to New York City was postulated to support this hypothesis, but epidemiological information was not available to establish when the exposure occurred or the presence of latent infection (57). Latency and reactivation, as occurs in tuberculosis, have never been established in histoplasmosis. In fact, while organisms can be seen in most pulmonary or mediastinal granuloma, they are not viable (79, 117).  The duration required for sterilization of the tissues following acute infection has not been established.  Small numbers of viable organisms present in the tissues following acute infection may expand and cause disease when immunosuppression is induced, representing exacerbation of "smoldering" infection rather than reactivation of latent infection.  Evidence for this includes the increased risk for histoplasmosis during the first 2 years following solid organ transplantation (3).

Reinfection does occur, as suggested by the occurrence of acute histoplasmosis in persons with radiographic, skin test or laboratory evidence of past infection (41, 42, 82, 97).  Certainly persons living in endemic areas, especially those with jobs or hobbies that are likely to expose them to soil containing H. capsulatum spores, are at risk for reinfection. Reinfection histoplasmosis is postulated to be less severe than primary infection in healthy subjects because of residual immunity induced by the initial episode (41, 42, 82, 97).  However, immunity may be reduced in immunocompromised persons, and reinfection may be progressive, and ultimately fatal if not identified and treated.

Susceptibility testing shows H. capsulatum to be susceptible to a variety of drugs. Since the yeast phase is the pathogenic form of the organism found in the tissues of infected patients, testing is recommended using it rather than the mold phase of the organism.  While the mold phase of H.  capsulatum was highly susceptible to micafungin, the yeast phase was resistant, and micafungin was ineffective in an experimental model of histoplasmosis (20).  Since the mold phase is the form isolated by culture in the mycology laboratory, it must be converted to the yeast phase before susceptibility testing can be performed; and conversion may require several weeks. This delay reduces the usefulness of susceptibility testing in clinical practice; its main role is in research to identify agents to study in animal models (14, 34, 60, 64) and to determine the cause for treatment failure or relapse.

Resistance to fluconazole developed in 59% of AIDS patients with disseminated histoplasmosis who failed treatment, explaining why it was less effective than itraconazole (53). These strains also showed reduced susceptibility to voriconazole, but not to posaconazole or itraconazole (139). Susceptibility testing also has been used to evaluate several new antifungal agents. H. capsulatum is highly susceptible to posaconazole, and show an excellent response to that agent in experimental infection (13, 104).  Conversely, H. capsulatum was not susceptible to caspofungin, or micafungin, and both echinocandins were ineffective in a murine model of histoplasmosis (20, 60). Variable susceptibility was observed to nikkomycin, correlating with its effect in the mouse model (34). Others have shown voriconazole to be active against H. capsulatum (67), but animal studies have not been conducted.

Combination of fluconazole with amphotericin B exhibited antagonism in murine models of pulmonary and meningeal histoplasmosis while itraconazole did not (50, 68). In vitro antagonism was not observed, however (68).

While the IDSA treatment guidelines for histoplasmosis have not been updated since 2007 (54) the more recent literature related to treatment have been reviewed (30).  Patients with diffuse acute pulmonary histoplasmosis occurring In vitro antagonism was not observed, however within a few weeks of an identifiable exposure event appear to respond to antifungal therapy (55, 138, 143). Left untreated, recovery may be slow (89) and the outcome may be fatal (83, 103). Patients with a more subacute course who have localized disease but who remain symptomatic for a month or more also may benefit from therapy.

Lipid formulations of Amphotericin B 3-5mg/kg/d, given for one to two weeks, followed by itraconazole 200 mg three times daily for three days then twice daily for 3 months induces a rapid response and should be used in patients sufficiently ill to require hospitalization. Methylprednisolone (0.5-1.0 mg/kg/d intravenously) is also recommended for those with hypoxemia or respiratory distress Itraconazole 200 mg twice daily for 2 weeks followed by once or twice daily for 3 months is recommended in patients with milder illnesses, and has proven to be effective in controlled trials in patients with disseminated and chronic pulmonary infection (22, 131).

Itraconazole is highly active against H. capsulatum, with MICs of <0.019 µg/ml in most cases. Drug levels of at least 1 µg/ml of itraconazole measured by HPLC or 3µg/ml by bile assay are recommended for treatment of histoplasmosis. Dosages of 200 mg daily achieve peak blood concentrations 2 to 4 hours after an oral dose of about 3 µg/ml while doses of 200 mg twice daily yield concentrations of about 6 µg/ml (131).  Dosage should be reduced in patients with concentrations above 10 µg/ml, which are associated with toxicity (32). Itraconazole is better tolerated than ketoconazole  and more active than fluconazole  or voriconazole against H. capsulatum (132, 139).  Posaconazole also is highly active against H. capsulatum and has been used in a few cases (86) but has not been evaluated in a prospective clinical trial.

Mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis, and may lead to symptoms caused by obstruction of the airways, especially in children (48, 137). Itraconazole 200 mg three times daily for three days and then 200 mg once or twice daily for six to 12 weeks is recommended in patients with continued symptoms for more than one month, accompanied by prednisone (0.5-1.0 mg/kg/d) in more severe cases.

Inflammation and necrosis in mediastinal lymph nodes may continue for months to years in some patients (48, 137). Mediastinal granuloma may produce obstructive symptoms or fistula. Occasional patients with these complications improve following antifungal therapy (95). Itraconazole 200 mg once or twice daily given for 3 to 6 months is recommended. In severe cases or those that show no response to antifungal therapy, addition of corticosteroid therapy may be tried but evidence is lacking establishing the effectiveness (44). Other patients have responded favorably to surgical resection of the granuloma (33). Antifungal treatment or resection of granuloma to prevent fibrosing mediastinitis to fibrosing mediastinitis has not been documented and must be rare (70).

Patients with these inflammatory manifestations usually respond to aspirin or non-steroidal anti-inflammatory agents. Coriticosteroids may be required in patients with more severe manifestations or those who do not respond to less aggressive therapy (90, 120). Organisms are not found in the pericardium or joints and antifungal therapy would not be expected to alter the course in patients with these manifestations of acute histoplasmosis. Nevertheless, itraconazole 200 mg once or twice daily may be appropriate in patients who receive corticosteroids for treatment of pericardial tamponade. Rarely joints or pericardium are sites of disseminated infection, in which case treatment would be necessary.

Untreated chronic pulmonary histoplasmosis usually is slowly progressive (29, 37). Treatment improves survival, reduces symptoms, promotes radiographic healing and eradicates H. capsulatum from the sputum (107). Most patients with chronic pulmonary histoplasmosis respond well to treatment with itraconazole (22). Lipid Amphotericin B 3-5 mg/kg daily may be needed for the first few weeks of therapy in patients with more severe respiratory insufficiency to achieve a more rapid response to therapy. Itraconazole 200 mg once or twice daily should be continued for at least 18 months and until maximal clinical and radiographic benefit has been achieved. Successful treatment eliminates H. capsulatum from the sputum and causes regression of the pulmonary infiltrates in at least two-thirds of cases (84). Anti-Histoplasma antibody titers fall (84) but the significance of persistent seropositivity is unknown. Relapse is common (~ 25% of cases) after discontinuation of treatment, emphasizing the need for prolonged follow-up.

The course in slowly progressive in some patients, and may be fatal, supporting the urgent need for effective therapy. While most authorities believe that neither antifungal nor anti-inflammatory treatment ameliorates the outcome of this complication of histoplasmosis (39, 45, 70), one report suggested benefit from ketoconazole therapy (113). However, based upon the pathologic finding of extensive fibrosis, without inflammation or active infection, treatment would not seem likely to be beneficial.

A three-month trial of itraconazole 200 mg once or twice daily should be considered, particularly if complement fixation titers and the sedimentation rate are elevated. If follow-up CT scans and clinical evaluation show objective evidence for response, treatment should be continued for one year. Use of corticosteroids or other anti-inflammatory agents is not recommended. These patients may experience bacterial superinfections (70), requiring antibacterial therapy.

Surgery is controversial in management of fibrosing mediastinitis. In some reports fewer than 40% of patients benefited and 20% died as a complication of surgery (70, 72).  Others have reported improved outcome with surgical therapy, noting a fatality rate attributable to fibrosing mediastinitis of 12% and requirement for surgical resection to control hemorrhage in 29% of cases (45). Intravascular stents may be helpful in selected patients with central vascular obstruction (75), producing symptomatic improvement in nearly 90% of cases (1), and embolization may relieve pulmonary hemorrhage.

Disseminated histoplasmosis is usually fatal if untreated (30, 94). Interestingly, in two reviews, about 15% of cases were not treated, of which 20% died before the diagnosis was made and the remainder did well without therapy (5, 94), but long-term follow-up was not available to exclude subsequent progression. Amphotericin B and itraconazole are highly effective therapy, inducing a remission in 85 to 90% of patients, including those who are immunosuppressed (22, 94, 122, 131). Liposomal amphotericin B (AmBisome) was more effective than the deoxycholate formulation in a study in patients with AIDS (53). Resolution of fever and improvement of symptoms occurred in a higher proportion of patients treated with the liposomal formulation at a dose of 3 mg/kg/d than with the standard deoxycholate preparation at a dose of 0.7 mg/kg/d (53). Survival also was better with the lipid preparation. Thus, liposomal amphotericin B, 3 mg/kg/d is preferred in patients with severe or moderately severe disseminated histoplasmosis. Amphotericin B lipid complex 5 mg/kg/d is an alternative, and deoxycholate amphotericin B 1 mg/kg/d for 4-6 weeks remains the recommended therapy for children.

Treatment can be changed to itraconazole after patients become afebrile, usually in 3 to 7 days. Longer courses of amphotericin B may be required in patients who are severely ill as indicated by the presence of shock or respiratory failure. Itraconazole 200 mg twice daily should be administered for 12 months in most patients and indefinitely in some patients, for example those with irreversible immunosuppressive states or who relapse despite at least 12 months of recommended therapy with documented therapeutic itraconazole blood levels. Improvement can be expected within one week in most patients (94, 131), but relapse may occur in patients who are persistently immunosuppressed (94, 122). Poor adherence to antifungal and antiretroviral therapies is associated with increased risk for relapse and mortality in HIV infected patient with disseminated histoplasmosis (8, 9).  Levels of Histoplasma antigen decline with therapy and increase with relapse, providing a useful tool for monitoring the response to therapy (see below, monitoring therapy) (26, 56, 129). Treatment should be continued until antigen levels in the urine and serum have declined to 2 ng/ml or less (30, 54). 

In patients with underlying conditions requiring treatment with immunosuppressive medications, dosages of those medications should be reduced. Discontinuation of TNF inhibitors has been suggested in patients receiving them for inflammatory disorders (102). Abrupt discontinuation, however, may lead to clinical deterioration caused by the immune reconstitution inflammatory syndrome (46). Of note, before the availability of effective antiretroviral therapy, patients with AIDS and histoplasmosis often received treatment with corticosteroids for proven or presumed Pneumocystis pneumonia, which was well tolerated when amphotericin B was given concurrently. Thus, continuation of reduced doses of immunosuppressive medications would appear to be safe if when combined with amphotericin B or itraconazole.

The optimal therapy in patients with meningitis remains uncertain. Although most patients responded to treatment with amphotericin B, half relapsed during the next two years (123). The explanation for the poor outcome is unknown but may include the poor brain and CSF penetration of amphotericin B. The liposomal form of amphotericin B achieves higher concentrations in brain tissue, but also fails to penetrate the CSF (45). Fluconazole penetrates the CSF well, but is not highly active against H. capsulatum, and was less active than amphotericin B in an animal model of Histoplasma meningitis (50). Furthermore, fluconazole antagonized the activity of amphotericin B when administered concurrently. Liposomal amphotericin B is recommended at a dose of 3 to 5 mg/kg/d for a total dose of 100 to 150 mg/kg, over two to three months, and until CSF cultures are negative. While the earlier treatment guideline favored fluconazole 800 mg daily for 9-12 months after a 35 mg/kg course of amphotericin B deoxycholate, the 2007 guideline recommended itraconazole 200 mg twice or three times daily should be given for another year to prevent relapse (138). Unfortunately evidence on the effectiveness of either approach is insufficient to know which approach is best. Furthermore, whether penetration into the CSF is needed for treatment of meningitis is unknown: perhaps penetration into the tissues is more important than penetration into CSF.

Careful follow-up with monitoring of CSF culture (10 ml of CSF) and antigen concentration is advised as resistance to fluconazole can develop during therapy (132). Life-long maintenance therapy may be needed in patients who relapse after appropriate therapy. Patients who fail chronic maintenance therapy may require direct injection of amphotericin B into the ventricles, an approach commonly complicated by arachnoiditis or radiculopathy (123), and one that is very rarely performed. Voriconazole is active against H. capsulatum and penetrates the CSF but has not been studied adequately in meningitis caused by histoplasmosis. Voriconazole was successful in one (28) but not in another case (86).

Cerebritis or histoplasmomas in the brain or spinal cord usually do not require surgical excision (123). They resolve during antifungal therapy in most cases. Liposomal amphotericin B 3 mg/kg/d for two to three months, followed by itraconazole 200 mg twice daily to complete a year of therapy is recommended. Follow-up head CT or MRI is recommended to assure that the lesions have cleared before stopping therapy (136).

Liposomal preparation, 3 mg/kg/d for two to three months, followed by itraconazole for another year is recommended. The role of surgery to replace the involved valve is controversy all. While recommended in one report (54), the more recent review questions the need for valve replacement in all cases (7). Chronic maintenance therapy may be appropriate in those who relapse.

Presumed ocular histoplasmosis, if indeed caused by H. capsulatum, does not represent an active infection and would not be expected to respond to antifungal therapy (11). Corticosteroids and laser therapy have been used in these patients (25, 71, 98).

Studies in patients with AIDS showed that chronic suppressive therapy was unnecessary in patients who received itraconaconazole for at least one year, who achieved CD4 counts of least 150 cells/mLin response to antiretroviral therapy, and had negative or low levels of Histoplasma antigenemica and antigenuria (36). Additional considerations for discontinuing therapy in patients with AIDS included adherence to antifungal and antiretroviral therapy, control of HIV viremia, and presence of central nervous system involvement (40).

More recently, suppressive antifungal therapy was found to be unnecessary in some cases complicating TNF inhibitor therapy despite resumption of the TNF inhibitor (44, 46). and in patients who have undergone organ transplantation (3, 16, 27). However, relapse has occurred in a few patients who received less than 1 year of antifungal therapy (3, 44).  Careful monitoring for relapse, including clinical assessment and urine and serum testing for antigen is recommended to assist in the diagnosis of relapse permitting the resumption of antifungal therapy before the illness becomes severe.

Both voriconazole (67) and posaconazole (13) show activity in vitro, and posaconazole was more effective than itraconazole in vivo in a murine model of histoplasmosis (13, 104). Except for single case reports and small retrospective case series (86, 28) neither has been studied in man, however. Two presumed voriconazole treatment failure have been reported in which Histoplasma antigenuria failed to clear prompting substitution with itraconazole, with subsequent reduction in antigenuria (5, 27). While posaconazole is more active than voriconazole in histoplasmosis, therapeutic concentrations have been difficult to achieve using the suspension formulation.  Intravenous and tablet formulations of posaconazole have overcome this limitation (29, 35).  Nikkomycin Z is also active against some strains of H. capsulatum (34) but is not available for use in patients with histoplasmosis, while the echinocandins are not effective and not recommended for treatment (60).

There are two situations in which adjunctive immunomodulatory therapy should be considered. The first is in the patient with severe or relapsing disseminated disease who has a defect in interferon γ function  (144). The second situation is that where the immune or inflammatory response is thought to contribute to the illness. Examples include patients with diffuse pulmonary involvement presenting with respiratory compromise following high inoculum exposure, and those with enlarged mediastinal nodes that obstruct the airways or major pulmonary vessels. There are reports of improvement with combined antifungal and corticosteroid therapy in such cases  (44, 55, 142), supporting adjunctive corticosteroids in selected patients: diffuse acute pulmonary histoplasmosis causing respiratory compromise and mediastinal lymphadenitis or granuloma causing obstructive syndromes. The risk of promoting dissemination seems to be low if the patients receive concurrent antifungal therapy, and have no underlying immunosuppressive disorder. Corticosteroids also may be indicated in patients who appear to have immune reconstitution inflammatory syndrome following reduction in dosage of immunosuppressive medications during treatment for pulmonary or disseminated histoplasmosis  (46) or initiation of antiretroviral therapy in patients with AIDS (99).

There have been no studies defining endpoints for monitoring therapy, but clinical experience does support some guidelines in the absence of firm data (3,40). Whether monitoring titers of complement fixing antibodies to H. capsulatum would be useful is unknown. In untreated cases, antibody titers may remain elevated for several years (125). While treatment may accelerate the decline in antibody titers, studies showing the effect of treatment on antibody titers, and the correlation of antibody titer reduction with response to therapy have not been reported. Without such data, treatment decisions based upon antibody titer clearance cannot be recommended.

The effect of treatment on Histoplasma antigen levels has been investigated more fully. Treatment causes reduction in antigen levels in the urine and blood (134), occurring first in serum (22), and relapse has been associated with rising levels (40, 129). Antigen concentration declines first in the blood, followed by the urine (22).  In some cases, treatment has been stopped before antigenemia and/or antigenuria became undetectable, but became undetectable during subsequent follow-up. This suggests that antigen may be released from non-viable organisms persisting in the tissues or that host immunity improved sufficiently to eradicate remaining viable organisms. Treatment should be continued until antigenemia has resolved in antigenuria has declined to less than 2ng/mL (26).

Guidelines have been provided for duration of therapy in the preceding section and in other reviews (135). Unfortunately, clinical studies defining the optimal duration of therapy have not been conducted. Good clinical judgment must be used in recognition of these limitations. In patients with acute pulmonary histoplasmosis requiring therapy, treatment should be continued until the clinical findings have resolved, and the radiogram has shown resolution of the infiltrates. However, mediastinal adenopathy and prominent interstitial markings may persist and are not reasons to prolong therapy. With progressive, or cavitary pulmonary infection, treatment should be continued until the chest radiogram is stable and consistent with residual scarring rather than active inflammation. Most of these patients have underlying chronic obstructive lung disease, the clinical manifestations of which will persist after the infection has resolved. Treatment for disseminated infection should not be stopped until the clinical findings have resolved, the minimal duration of therapy has been reached, and antigen in the blood and urine decline to 2 ng/ml or below. If antigen concentrations persist at greater than 2 ng/mL, consideration should be given to continuing therapy until they decline to less than 2 ng/mL, and patients should be followed closely for relapse or increase in antigen concentration (26, 56).

A vaccine against histoplasmosis may be needed is some circumstances (20), and is under investigation (21).  An attenuated Blastomyces yeast vaccine, containing a mutation in the WI 1, gene induced immunity against blastomycosis, histoplasmosis and coccidioidomycosis, in mice(56).  Immunity required Th 17 lymphocyte(57), and was maintained by CD8 memory T lymphocytes, in the absence of CD4 lymphocytes(42).  Translation into clinical medicine will require a more complete understanding of the epitopes in protection and an understanding of who should be vaccinated: the entire population, just those living in an endemic area, only those at increased risk for exposure because of occupation or avocation, or those with diseases that predispose to complications of histoplasmosis.

Cavers and tour organizers should be aware of the high risk for histoplasmosis associated with exposure to bat guano in caves and familiar with the approaches to reduce that risk (65). Cavers should be advised to seek medical attention at the first sign of illness following potential exposure and should be aware of the potential benefit of antifungal treatment.

Immunosuppressed individuals with occupations or hobbies that expose them to dirt or to accumulations of composted bird or bat droppings may be at an increased risk for histoplasmosis.  Patients should be warned to avoid activities that place them at high risk for exposure to H. capsulatum, and physicians should be vigilant to the possibility of histoplasmosis as a cause for unexplained fever or other clinical syndromes associated with histoplasmosis (3, 19, 47) .They should avoid activities associated with disturbance of an accumulation of bird or bat droppings.  Screening for histoplasmosis, using test for antibodies and/or antigens, before initiation of immunosuppressive therapy is not thought to be useful because of the rarity (0.1% to 0.5%) of histoplasmosis in these populations (3, 19, 28, 47, 50).

Another concern is the risk for reactivation of histoplasmosis in persons with evidence of prior infection that undergo immunosuppression (46). Situations raising this concern include persons with a history of prior histoplasmosis, those with calcifications on chest radiograph, or persons with positive serologic tests done as part of pre-immunosuppression screening. Relapse is rare in such cases (115), and that prophylaxis or avoidance of immunosuppression (or transplantation) is unnecessary. However, if the clinical finding suggested that the episode of histoplasmosis was relatively recent (last 2 years) consideration should be given to prophylaxis with itraconazole.

Prophylaxis in persons with AIDS with CD4 counts < 150 cells/mm3 is appropriate if the case rate exceeds 10/100 patient years (41). Itraconazole 200 mg daily reduced the case rate of histoplasmosis and cryptococcosis by 70% (74). Prophylaxis had no impact on survival, however, and may have promoted the development of resistance of C. albicans to itraconazole and fluconazole (35).

Sites known or suspected to harbor H. capsulatum, particularly if cases have been diagnosed following exposure to those sites, should be posted as posing a danger of histoplasmosis. Such sites should be reported to public health authorities or the National Institute for Occupational Safety and Health (65), so that decontamination or quarantine procedures can be considered.

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95. Savides TJ, Gress FG, Wheat LJ, Ikenberry S, Hawes RH. Dysphagia due to mediastinal granulomas: Diagnosis with endoscopic ultrasonography. Gastroenterology 1995; 109:366-373. [PubMed]

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145. Zhou P, Sieve MC, Bennett J, Kwon-Chung KJ, Tewari RP, Gazzinelli RT et al. IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma. J Immunol 1995; 155:785-795. [PubMed]

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Swartzentruber S, Rhodes L, et al. Diagnosis of Acute Pulmonary Histoplasmosis by Antigen Detection. Clin Infect Dis. 2009 Dec 15;49:1878-82.

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