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Histoplasma Capsulatum (Histoplasmosis) Updated September, 2010
GENERAL DESCRIPTION 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. Microbiology Guided Medline Search 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. Baron EJ. Mold Hagan T. Discovery and Naming of Histoplasmosis: Samual Taylor Darling, 2010 Epidemiology Guided Medline Search Histoplasmosis, although worldwide in distribution, is more prevalent in certain parts of North and Latin America (1,2) (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 (3). Several outbreaks have resulted from exploration of caves inhabited by bats (4-6). Other animal species also may be infected with H. capsulatum var capsulatum, including sea mammals (3). Factors accounting for its geographic distribution are poorly understood but include high humidity, moderate climate, and acidic soil characteristics. Activities that disturb environments containing the 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. Hagan T. Histoplasmosis in the U.S., 2010 Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401. Clinical Manifestations Guided Medline Search Histoplasmosis usually is asymptomatic or non-progressive in healthy individuals (7). 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 (8). Acute Pulmonary Histoplasmosis: The common clinical findings of self-limited infection include acute pulmonary histoplasmosis, pericarditis (9), and rheumatologic syndromes (10). 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 (11). Patients also may experience symptoms caused by obstruction of mediastinal structures by enlarged lymph nodes (12). The severity of illness correlates with the intensity of exposure (13). Following heavy exposure, patients may present with diffuse pulmonary involvement (11,14,15). Symptoms of fever, chills, sweats, headache, myalgia, anorexia, cough, and chest pain characterize these illnesses (16), and respiratory failure and death may ensue (17). Chest radiograms show diffuse reticulonodular or miliary pulmonary infiltrates in 90% of cases, sometimes with mediastinal lymphadenopathy (5,14,15). Following the more typical, low-level exposure, the pulmonary illness is more commonly sub acute and mild, or even asymptomatic. Chest roentgenograms show enlarged hilar or mediastinal lymph nodes with patchy infiltrates (18), but may be normal (19). While rapid improvement in two to three weeks is characteristic (16), fatigue may linger (19). 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 (20-24). 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 (22,25,26). Chronic Pulmonary Histoplasmosis: Patients with emphysema develop chronic pulmonary histoplasmosis characterized by recurrent symptoms, progressive lung infiltrates, fibrosis and cavitation (7,34). Upper lobe infiltrates with cavities are present in most cases. While some patients recover spontaneously (34), 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 (7,34). 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. Rheumatologic Syndromes and Pericarditis: Pericarditis is a local inflammatory or immunologic reaction to the adjacent mediastinal histoplasmosis, occurring in about 5% of symptomatic cases (9). 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 (9). Patients usually respond to anti-inflammatory medications without antifungal therapy (9,10), while those with hemodynamic compromise may require corticosteroid therapy or drainage of the pericardial fluid. Outcome is excellent, with rare progression to constrictive pericarditis (9,27-29). Antifungal therapy is unnecessary (9,30) 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 (10,31,32). 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 (33). Disseminated Histoplasmosis: 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 (35). Progressive disseminated histoplasmosis is seen most often in patients who are immunosuppressed or at the extremes of age. 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 (36). 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 (37). 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. 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 (35,37,38). In older studies, although recognized clinically in only 4% of cases, CNS involvement was present at autopsy in one to two-thirds (15,36). About 5% of cases in recent series of disseminated histoplasmosis in patients with AIDS exhibited CNS involvement (Wheat, unpublished). Of 89 cases of CNS histoplasmosis reviewed with the author since 1991, 67% had meningitis, 27% brain lesions, and 7% cord involvement (Wheat, unpublished). 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 (39), stroke syndromes caused by vascular involvement or emboli, or encephalitis (38,40) . CNS infection may occur as manifestations of widely disseminated disease or as isolated sites of dissemination, with nearly equal frequency. Endocarditis is a rare complication of disseminated histoplasmosis and usually is manifested by systemic emboli in a person with other finding of disseminated disease, but may present as isolated culture-negative endocarditis (41,42). No such cases have been identified during the recurrent outbreaks in Indianapolis, although a single case of a left atrial myxoma infected with H. capsulatum was reported from our institution (43). Other 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. Broncholithiasis: Calcified mediastinal nodes and pulmonary granulomas may erode into adjacent bronchi (44). Patients may expectorate rock-like particles of tissue and experience hemoptysis, bronchial obstruction or tracheoesophageal fistula. Mediastinal Fibrosis: Mediastinal fibrosis is a rare manifestation of histoplasmosis which is felt to represent an abnormal host response to the infection (45) (12,46). Viable organisms cannot be found in these tissues, supporting the belief that fibrosing mediastinitis represents an exuberant fibrotic reaction to past infection rather than an active, progressive infection. 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 (12,46). 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 (12). Enlarging Pulmonary Histoplasmoma: Rarely patients may develop a slowly enlarging pulmonary nodule which has been called enlarging histoplasmoma (47). 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. Presumed Ocular Histoplasmosis: Choroiditis involving the macula and causing visual loss has been attributed to histoplasmosis (48), 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 (49). Identification of patients with similar findings outside the endemic area for histoplasmosis further weakens the association of histoplasmosis with this clinical syndrome (50). However, the eye may be involved in patients with disseminated histoplasmosis (51). Laboratory Diagnosis Guided Medline Search A battery of diagnostic procedures is needed for diagnosis of histoplasmosis (52). Serologic tests for antibodies forms 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. Serologic Tests: Antibodies to H. capsulatum measured by immunodiffusion or complement fixation develop in most patients. H precipitin bands can be demonstrated in less than 25% of patients and clear during the first 6 months following exposure (53,54). 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 active histoplasmosis while those 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 or radioimmunoassay methods are more difficult to interpret because of higher background positivity rates and have not been validated adequately to recommend their use in place of immunodiffusion and complement fixation (55). 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 (54). Positive results caused by cross reactions occur in patients with blastomycosis, coccidioidomycosis and paracoccidioidomycosis (56). High levels of antibodies, particularly M precipitin bands and low titers (1:8 or 1:16) of complement fixing antibodies, may require several years to clear after acute infection, occasionally causing confusion in patients with other diseases. Consequently, histoplasmosis may be diagnosed incorrectly in a patient with another illness who has high levels of antibodies to H. capsulatum persisting after an earlier episode of histoplasmosis. Culture: Cultures are most useful in patients with disseminated or chronic pulmonary histoplasmosis. The sensitivity is only l0 to 15% in patients with other forms of histoplasmosis (54). In disseminated histoplasmosis, the highest yield is from bone marrow or blood, positive in over 75% of cases (35,37). Organisms can be found in sputum or bronchoscopy specimens in 60 to 85% of cases of cavitary histoplasmosis (7).
Antigen Detection: 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 in severe cases
(54,57). Antigen is found in the blood, urine and bronchoalveolar lavage fluid
of most individuals with disseminated histoplasmosis and in the urine of 75%
of those with extensive pneumonitis following heavy acute exposure. Antigen
may be found in CSF of 25 to 50% of patients with meningitis caused by
histoplasmosis. Cross-reactions may be seen in patients with African
histoplasmosis, blastomycosis, paracoccidioidomycosis, and Penicilliosis
marneffii. Antigen levels decline during treatment and increase with relapse,
providing a tool for monitoring therapy (58). Antigen testing is available at MiraVista Diagnostics.
Fungal Stains: 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 (35). Candida glabrata, Cryptococcus neoformans, Blastomyces dermatitidis, Penicillium marneffei, Pneumocystis carinii, Toxoplasma gondii, Leishmania and staining artifacts may be misidentified as H. capsulatum. Histoplasmin Skin Test: Skin test reagents are no longer available, and should not be used diagnostically because of high rates of positivity (50-80%) in endemic areas and false-positive results in patients with other fungal diseases (59). Skin tests also may be falsely negative in patients with disseminated disease. Skin tests increase levels of antibody, causing confusion in the interpretation of serologic tests. In vitro methods for measurement of cellular immune response, including lymphoproliferative and induced interferon-γ production have been described (60). Pathogenesis Guided Medline Search Infection develops when conidia are inhaled and transform into yeasts in the lungs. may occur in non-immunosuppressed individuals (36,37). Cellular immunity is the primary host defense against H. capsulatum (62-64). CD4 lymphocytes activate macrophages to assume fungicidal properties (65,66), serving to control the infection in immunocompetent individuals. Progressive disseminated disease is seen in those with underlying immunosuppression (67) or at the extremes of age (36,67). 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 (66,68). Reactivation of quiescent infection is postulated to occur during immunosuppression (37,69,70). Such cases are suspected outside endemic areas in patients who previously lived in endemic regions. Identification of a Panamanian genotype in immigrants to New York City supports this hypothesis (71). The ability to reactivate old lesions may decline over time, however. Reinfection also may occur, as suggested by the occurrence of acute histoplasmosis in persons with radiographic, skin test or laboratory evidence of past infection (61,72-74). 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 because of residual immunity induced by the initial episode (61,72-74). Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401. Review Article: Gauthier G, et al. Insights into Fungal Morphogenesis and Immune Evasion. Microbe 2008;3(9):416-423.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Single Drug 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. Studies comparing the susceptibility of the yeast and the mold phase have not been performed, precluding a conclusion that the mold phase could be substituted for the yeast in susceptibility testing. 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 (75-78) and to determine the cause for treatment failure or relapse. Susceptibility testing on the yeast phase is available at MiraVista Diagnostics using a modified NCCLS procedure. We have reported on the potential usefulness of such information in clinical research. We have shown that resistance to fluconazole developed in 59% of AIDS patients with disseminated histoplasmosis who failed treatment, explaining why it was less effective than itraconazole. Susceptibility testing also has been used to evaluate several new antifungal agents. We have found that H. capsulatum is highly susceptible to posaconazole, and show an excellent response to that agent in experimental infection (75,79). Conversely, H. capsulatum was not susceptible to caspofungin, and caspofungin was ineffective in our murine model (77). Variable susceptibility was observed to nikkomycin, correlating with its effect in the mouse model (76). Others have shown voriconazole to be active against H. capsulatum (80), but animal studies have not been conducted. Combination Drugs We have explored the combination of itraconazole or fluconazole with amphotericin B in vitro and in our murine model. Although antagonism was not observed in vitro, fluconazole and amphotericin B were antagonistic in the pulmonary model of histoplasmosis (81). Recently we have extended these observations to a murine model Guided Medline Searchof Histoplasma meningitis, established through direct infection of the meninges, where, again, fluconazole antagonized the effect of amphotericin B (R. Haynes, in press, 2002).
ANTIMICROBIAL THERAPY Guided Medline Search Smart search Acute Pulmonary Histoplasmosis: Patients with extensive acute pulmonary histoplasmosis who are dyspneic and hypoxic respond to antifungal therapy (11,82). Left untreated, recovery may be slow (15) and the outcome may be fatal (17,83). Patients with acute histoplasmosis who have less extensive disease but who remain symptomatic for a month or more also may benefit from therapy.
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 measured by bioassay
should be effective for treatment of histoplasmosis, but higher concentrations
(4 to 10 µg/ml) are preferred. 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 (85). Dosage could be
reduced in patients with concentrations above 10 µg/ml. Itraconazole is better
tolerated than
ketoconazole and more active than Mediastinal Granulomas: Mediastinal granuloma may produce obstructive symptoms or fistula. Occasional patients with these complications improve following antifungal therapy (87). 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 helpful (88). Other patients have responded favorably to surgical resection of the granuloma (89). Antifungal treatment or resection of granuloma to prevent fibrosing mediastinitis is not indicated since progression of granulomatous mediastinitis to fibrosing mediastinitis has not been documented and must be rare (12). Rheumatologic Syndromes and Pericarditis: 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 (9,10). 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.
Chronic Pulmonary Histoplasmosis: Untreated chronic pulmonary histoplasmosis usually is slowly progressive (34,90). Treatment improves
survival, reduces symptoms, promotes radiographic healing and eradicates H. capsulatum from the sputum (91). Most patients with chronic pulmonary histoplasmosis respond well to treatment with Mediastinal Fibrosis: 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 (12,46), one report suggested benefit from ketoconazole therapy (93). 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 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 (12), requiring antibacterial therapy. Surgery is controversial in management of fibrosing mediastinitis. Fewer than 40% of patients benefited and 20% died as a complication of surgery in the largest review of the surgical treatment of fibrosing mediastinitis (12,94). Intravascular stents may be helpful in selected patients with superior vena cava, pulmonary vascular or pulmonary venous obstruction (95), and embolization may relieve pulmonary hemorrhage.
Disseminated Histoplasmosis: Disseminated histoplasmosis is usually fatal
if untreated (35,96).
Amphotericin B and
Treatment can be changed to itraconazole after patients become afebrile,
usually in 3 to 7 days. Longer courses of Central Nervous System: The outcome is unsatisfactory in patients with meningitis. Although most patients responded to treatment with amphotericin B, half relapsed during the next two years (38). 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 (98). 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 (R. Haynes, in press, 2002). Furthermore, fluconazole antagonized the activity of amphotericin B in the meninges 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. Itraconazole 200 mg twice or three times daily should be given for another year to prevent relapse. 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 (86). 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 (38), and one that is very rarely performed. Voriconazole is active against H. capsulatum and penetrates the CSF but has not been studied in histoplasmosis. Cerebritis or histoplasmomas in the brain or spinal cord usually do not require surgical excision (38). 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. Endocarditis: Treatment of Histoplasma endocarditis is unsatisfactory (41,42). Antifungal therapy combined with resection of the infected valve is recommended (42). In that report, 5 of 7 (71%) cases treated with antifungal therapy combined with surgery were cured compared to 4 of 9 (44%) who received antifungal therapy alone (42). These observations support a recommendation to administer amphotericin B, preferably the liposomal preparation, at maximal doses for two to three months, followed by itraconazole for another year. The valve also should be replaced, if possible. Chronic maintenance therapy may be appropriate in those who relapse or cannot undergo valve replacement. Presumed Ocular Histoplasmosis: 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 ( 48) . Corticosteroids and laser therapy have been used in these patients ( 103-105) . Maintenance Treatment: Relapse occurs in 10% to 20% of patients with disseminated histoplasmosis, and up to 80% of those with AIDS. In addition to AIDS, other immunosuppressive disorders (35,37), adrenal insufficiency (99), and inadequate therapy (7,35,36,96,100) increase the likelihood for relapse. Most experience with treatment to prevent relapse results from clinical trials in patients with AIDS. Until recently, maintenance therapy was recommended in all patients with AIDS who recovered following treatment for histoplasmosis. Ongoing studies suggest that it is safe to stop maintenance therapy in patients with AIDS who have responded well to antifungal therapy, as evidenced by reduction of Histoplasma antigen levels to <4 units, and to antiretroviral therapy, based upon restoration of CD4 counts to >150 cells/mm3. Several regimens have been used for maintenance therapy. Amphotericin B 50 mg weekly, although highly effective (81-97%), is inconvenient and not well tolerated in some patients (37,101). Itraconazole 200 mg given once or twice daily is over 90% effective and well tolerated (102), but may not be appropriate in some patients because of drug interaction, gastrointestinal intolerance, or inability to achieve therapeutic serum levels. A high relapse rate (31%) occurred using fluconazole 400 mg daily as maintenance therapy. These findings support use of itraconazole 200 mg daily. If fluconazole is used, doses of at least 400 mg daily are recommended, and patients should be monitored for relapse by clinical assessment and measurement of Histoplasma antigen in urine and serum. New Therapies: Both voriconazole (80) and posaconazole (75) show activity in vitro, and posaconazole was more effective than itraconazole in vivo in a murine model of histoplasmosis (75,79). Neither has been studied in man, however. Nikkomycin Z is also active against some strains of H. capsulatum (76), while the echinocandins appear not to be effective (77).
(Printable Version of Antimicrobial Therapy for Review Article: Singh, N., Perfect, J. Immune Reconstitution Syndrome Associated with Opportunistic Mycoses. The LANCET Infectious Diseases 2007; Vol.7, Issue 6, 395-401. ADJUNCTIVE THERAPY Guided Medline Search There are two situations in which adjunctive immunomodulatory therapy should be considered. The first is in the patient with severe or relapsing disseminated disease. Animal data support a potential role of granulocyte/monocyte colony stimulating factor (107), interferon-g (110), or IL-12 (111) in such cases, but there are no studies in man, or even anecdotal reports. Of note is that our laboratory has not confirmed the benefit of interferon-g and IL-12 in experimental histoplasmosis, and the benefit seen in other studies often was very modest. Furthermore, interferon-g and IL-12 are quite toxic. Thus, these treatments cannot be endorsed until some experience in man supports their efficacy and tolerability. The second situation is that of acute pulmonary or mediastinal histoplasmosis 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 (11,82,88), supporting adjunctive corticosteroids in selected patients: diffuse acute pulmonary histoplasmosis causing respiratory compromise and mediastinal 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.
ENDPOINTS IN MONITORING THERAPY Guided Medline Search Laboratory Monitoring There have been no studies defining endpoints for monitoring therapy, but clinical experience does support some guidelines in the absence of firm data. 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 (53). 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 does cause progressive decline in antigen levels in the urine and blood (108), and relapse has been associated with rising levels (58). Recent unpublished observations indicate that antigen levels should eventually become undetectable with successful antifungal therapy, and immune reconstitution (CD4 counts increase to above 150 cells/ml) in patients with AIDS. Thus, strong consideration should be given to continuation of antifungal therapy for disseminated histoplasmosis until antigen can no longer be detected in the blood or urine. Clinical Monitoring Guidelines have been provided for duration of therapy in the preceding section and in other reviews (109). 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 may persist, as may evidence of prominent interstitial markings; and these 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 has disappeared from the blood and urine. If antigen concentrations persist at greater than 2 units in the blood or urine, consideration should be given to the use of chronic maintenance therapy. Review Article: Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-825.
VACCINES Guided Medline Search A vaccine against histoplasmosis may be needed is some circumstances (106), and is under investigation (107). First a more complete understanding of the epitopes that are involved in the development of protective immunity to H. capsulatum is needed. Then we must determine 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.
PREVENTION OR INFECTION CONTROL Guided Medline Search Smart search 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 (112). 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 should be warned to avoid activities that place them at high risk for exposure to H. capsulatum. 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. They should avoid activities associated with disturbance of an accumulation of bird or bat droppings. Another concern is the risk for reactivation of histoplasmosis in persons with evidence of prior infection who are to undergo immunosuppression. 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. Our experience suggests that relapse is rare in such cases (113), 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. Itraconazole 200 mg daily reduced the case rate of histoplasmosis and cryptococcosis by 70% (114). Prophylaxis had no impact on survival, however, and may have promoted the development of resistance of C. albicans to itraconazole and fluconazole (115). 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 (112), so that decontamination or quarantine procedures can be considered.
Figure 1. Endemic Distribution of Histoplasmosis in the Americas. The Highest Incidence is in the Finely Stippled Area of North and Central America. Reprinted With Permission Of The Publisher (1).
REFERENCES 1. Rippon JW. Histoplasmosis Histoplasmosis capsulati.. In: Wonsiewicz M, editor. Medical mycology: the pathogenic fungi and the pathogenic actinomycetes. Philadelphia: W.B. Saunders Company, 1988: 381-423. [PubMed] 2. Wheat LJ. Histoplasmosis. Infect Dis Clin North Am 1988; 2:841-859. [PubMed] 3. Emmons CW, Klite PD, Baer GM, Hill WB Jr. Isolation of Histoplasma capsulatum from bats in the United States. Am J Epidemiol 1966; 84:103-109. [PubMed] 4. Hasenclever HF, Shacklette MH, Young RV, Gelderman GA. The natural occurrence of Histoplasma capsulatum in a cave. Am J Epidemiol 1967; 86:238-245. [PubMed] 5. Johnson J, Kabler JD, Gourley MF, D'Alessio DJ, Dodge RW, Golubjatnikov R et al. Cave-associated histoplasmosis: Costa Rica. MMWR 1988; 37:312-313. [PubMed] 6. Sacks JJ, Ajello L, Crockett LK. An outbreak and review of cave-associated histoplasmosis capsulati. J Med Vet Mycol 1986; 24:313-327. [PubMed] 7. Wheat LJ, Wass J, Norton J, Kohler RB, French ML. Cavitary histoplasmosis occurring during two large urban outbreaks: Analysis of clinical, epidemiologic, roentgenograghic, and laboratory features. Medicine Baltimore. 1984; 63:201-209. [PubMed] 8. Ward JI, Weeks M, Allen D, Hutcheson RH Jr., Anderson R, Fraser DW et al. Acute histoplasmosis: Clinical, epidemiologic and serologic findings of an outbreak associated with exposure to a fallen tree. Am J Med 1979; 66:587-595. [PubMed] 9. Wheat LJ, Stein L, Corya BC, Wass JL, Norton JA, Grider K et al. Pericarditis as a manifestation of histoplasmosis during two large urban outbreaks. Medicine Baltimore. 1983; 62:110-119. [PubMed] 10. Rosenthal J, Brandt KD, Wheat LJ, Slama TG. Rheumatologic manifestations of histoplasmosis in the recent Indianapolis epidemic. Arthr Rheum 1983; 26:1065-1070. [PubMed] 11. Kataria YP, Campbell PB, Burlingham BT. Acute pulmonary histoplasmosis presenting as adult respiratory distress syndrome: Effect of therapy on clinical and laboratory features. South Med J 1981; 74:534-537. [PubMed] 12. Loyd JE, Tillman BF, Atkinson JB, des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine Baltimore. 1988; 67:295-310. [PubMed] 13. Larrabee WF, Ajello L, Kaufman L. An epidemic of histoplasmosis on the isthmus of Panama. Am J Trop Med Hyg 1978; 27:281-285. [PubMed] 14. Loosli CG, Grayston JT, Lester W Jr., Tanzi F, Combs LW, Alexander ER. Some epidemiological and clinical aspects of pulmonary histoplasmosis in a farm family. Trans Assoc Am Physic 1952; LXV:159-167. [PubMed] 15. Rubin H, Furcolow ML, Yates JL, Brasher CA. The course and prognosis of histoplasmosis. Am J Med 1959; 27:278-288. [PubMed] 16. Brodsky AL, Gregg MB, Kaufman L, Mallison GF. Outbreak of histoplasmosis associated with the 1970 Earth Day activities. Am J Med 1973; 54:333-342. [PubMed] 17. Sollod N. Acute fulminating disseminated histoplasmosis. J S Carol Med Assoc 1971; 67:231-234. [PubMed] 18. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French MLV, Biesecker JL. A large urban outbreak of histoplasmosis: Clinical features. Yearbook of Medicine 1982;203-205. [PubMed] 19. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French MLV, Bieseckler JL. A large urban outbreak of histoplasmosis: Clinical features. Ann Intern Med 1981; 94:331-337. [PubMed] 20. Coss KC, Wheat LJ, Conces DJ Jr., Brashear RE, Hull MT. Esophageal fistula complicating mediastinal histoplasmosis: Response to amphotericin B. Am J Med 1987; 83:343-346. [PubMed] 21. Kunkel WM Jr., Clagett OT, McDonald JR. Mediastinal granulomas. J Thorac Surg 1954; 27:565-574. [PubMed] 22. Garrett HE Jr., Roper CL. Surgical intervention in histoplasmosis. Ann Thorac Surg 1986; 42:711-722. [PubMed] 23. Landay MJ, Rollins NK. Mediastinal histoplasmosis granuloma: Evaluation with CT. Rad 1989; 172:657-659. [PubMed] 24. Lerner MH, Deluca SA. Mediastinal granuloma secondary to histoplasmosis. AFPRH 1991; 43:1649-1651. [PubMed] 25. Schowengerdt CG, Suyemoto R, Beachley F. Granulomatous and fibrous mediastinitis. J Thorac Cardiovasc Surg 1969; 57:365-379. [PubMed] 26. Rabinowitz JG, Prater W, Silver J, Phillips JC, Wieder S. Mediastinal histoplasmosis. Mt Sinai J Med 1980; 47:356-363. [PubMed] 27. Bilgi C, Slesar S. Constrictive pericarditis and pericardial calcification with positive histoplasmin skin test. Can Med Assoc J 1976; 114:877-882. [PubMed] 28. Klieger HL, Fisher ER. Fibrocalcific constrictive pericarditis due to Histoplasma capsulatum. N Engl J Med 1962; 267:593-596. [PubMed] 29. Wooley CF, Hosier DM. Constrictive pericarditis due to Histoplasma capsulatum. N Engl J Med 1961; 264:1230-1232. [PubMed] 30. Picardi JL, Kauffman CA, Schwarz J, Holmes JC, Phair JP, Fowler NO. Pericarditis caused by Histoplasma capsulatum. Am J Cardiol 1976; 37:82-88. [PubMed] 31. Sellers TF Jr., Price WN Jr., Newberry WM Jr. An epidemic of erythema multiforme and erythema nodosum caused by histoplasmosis. Ann Intern Med 1965; 62:1244-1262. [PubMed] 32. Thornberry DK, Wheat LJ, Brandt KD, Rosenthal J. Histoplasmosis presenting with joint pain and hilar adenopathy: Pseudosarcoidosis. Arthr Rheum 1982; 25:1396-1402. [PubMed] 33. Medeiros AA, Marty SD, Tosh FE, Chin TD. Erythema nodosum and erythema multiforme as clinical manifestations of histoplasmosis in a community outbreak. N Engl J Med 1966; 274:415-420. [PubMed] 34. Goodwin RA, Jr., Owens FT, Snell JD, Hubbard WW, Buchanan RD, Terry RT et al. Chronic pulmonary histoplasmosis. Medicine Baltimore. 1976; 55:413-452. [PubMed] 35. Sathapatayavongs B, Batteiger BE, Wheat LJ, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine Baltimore. 1983; 62:263-270. [PubMed] 36. Goodwin RA Jr., Shapiro JL, Thurman GH, Thurman SS, des Prez RM. Disseminated histoplasmosis: Clinical and pathologic correlations. Medicine Baltimore. 1980; 59:1-33. [PubMed] 37. Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfman MF, Eads ME, Israel KS et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine Baltimore. 1990; 69:361-374. [PubMed] 38. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system: a clinical review. Medicine 1990; 69:244-260. [PubMed] 39. Bazan CI, New PZ. Intramedullary spinal histoplasmosis efficacy of gadolinium enhancement. N 1991; 33:190. [PubMed] 40. Anaissie E, Fainstein V, Samo T, Bodey GP, Sarosi GA. Central nervous system histoplasmosis: An unappreciated complication of the acquired immunodeficiency syndrome. Am J Med 1988; 84:215-217. [PubMed] 41. Gaynes RP, Gardner P, Causey W. Prosthetic value endocarditis caused by Histoplasma capsulatum. Arch Intern Med 1981; 141:1533-1537. [PubMed] 42. Kanawaty DS, Stalker MJ, Munt PW. Nonsurgical treatment of Histoplasma endocarditis involving a bioprosthetic valve. Chest 1991; 99:253-256. [PubMed] 43. Rogers EW, Weyman AE, Noble RJ, Bruins SC. Left artial myxoma infected with Histoplasma capsulatum. Am J Med 1978; 64:683-690. [PubMed] 44. Arrigoni MG, Bernatz PE, Donoghue FE. Broncholithiasis. J Thorac Cardiovasc Surg 1971; 62:231-237. [PubMed] 45. Davis A, Pierson D, Loyd JE. Mediastinal fibrosis. Sem Resp Infect 2001; 162.:119-130. [PubMed] 46. Goodwin RA, Nickell JA, des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and tuberculosis. Medicine Baltimore. 1972; 51:227-246. [PubMed] 47. Goodwin RA Jr., Snell JD Jr. The enlarging histoplasmoma: Concept of a tumor-like phenomenon encompassing the tuberculoma and coccidioidoma. Am Rev Respir Dis 1969; 100:1-12. [PubMed] 48. Ciulla T, Piper H, Xiao M, Wheat LJ. Presumed ocular histoplasmosis syndrome: update on epidemiology, pathogenesis, and photodynamic, antiangiogenic, and surgical therapies. Current Opinion in Ophthalmology 2001; 12:442-449. [PubMed] 49. Spaeth GL. Presumed Histoplasma uveitis: continuing doubts as to its actual cause. In: Ajello LP, Chick EM, Furcolow MMS, editors. Histoplasmosis. Springfield, IL: Charles C. Thomas, 1971: 221-230. [PubMed] 50. Suttorp-Schulten MS, Bollemeijer JG, Bos PJ, Rothova A. Presumed ocular histoplasmosis in the Netherlands - An area without histoplasmosis. Br J Ophthalmol 1997; 811.:7-11. [PubMed] 51. Specht CS, Mitchell KT, Bauman AE, Gupta M. Ocular histoplasmosis with retinitis in a patient with acquired immune deficiency syndrome. Oph 1991; 98:1356-1359. [PubMed] 52. Wheat LJ. Laboratory diagnosis of histoplasmosis: A review. Sem Resp Infect 2001; 16(2):131-140. [PubMed] 53. Wheat LJ, French ML, Kohler RB, Zimmerman SE, Smith WR, Norton JA et al. The diagnostic laboratory tests for histoplasmosis: Analysis of experience in a large urban outbreak. Ann Intern Med 1982; 97:680-685. [PubMed] 54. Williams B, Fojtasek M, Connolly-Stringfield P, Wheat J. Diagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind. Arch Pathol Lab Med 1994; 118:1205-1208. [PubMed] 55. Wheat LJ. The role of the serologic diagnostic laboratory and the diagnosis of fungal disease. In: Sarosi GA, Davies SF, editors. Fungal Diseases of the Lung. NewYork: RavenPress, 1993: 29-38. [PubMed] 56. Wheat LJ, French ML, Kamel S, Tewari RP. Evaluation of cross-reactions in Histoplasma capsulatum serologic tests. J Clin Microbiol 1986; 23:493-499. [PubMed] 57. Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med 1986; 314:83-88. [PubMed] 58. Wheat LJ, Connolly-Stringfield P, Blair R, Connolly K, Garringer T, Katz BP. Histoplasmosis relapse in patients with AIDS: detection using Histoplasma capsulatum variety capsulatum antigen levels. Ann Intern Med 1991; 115:936-941. [PubMed] 59. Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE. An atlas of sensitivity to tuberculin, PPD-B and histoplasmin in the United States. Am Rev Respir Dis 1969; 99:1-18. [PubMed] 60. Vail G, Goldberg JS, Durkin MM, Goldman M, Wheat J. In vitro determination of cell mediated immunity in histoplasmosis. abstract , 141. 1998. [PubMed] 61. Goodwin RA Jr., des Prez RM. Histoplasmosis. Am Rev Respir Dis 1978; 117:929-956. [PubMed] 62. Deepe GS Jr., Bullock WE. Histoplasmosis: A granulomatous inflammatory response. In: Gallin JI, Goldstein IM, Snyderman R, editors. Inflammation: Basic Principals and Clinical Correlates. New York: Raven, 1988: 733-749. [PubMed] 63. Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother 2001; 453.:922-926. [PubMed] 64. Newman SL. Cell-Mediated Immunity to Histoplasma capsulatum. Sem Resp Infect 2001; 162.:102-108. [PubMed] 65. Wu-Hsieh B, Howard DH. Histoplasmosis. In: Murphy JW, editor. Fungal Infections and Immune Responses. New York: Plenum Publishing, 1993: 213-250. [PubMed] 66. Allendoerfer R, Biovin GP, Deepe GS Jr. Modulation of immune responses in murine pulmonary histoplasmosis. J Infect Dis 1997; 1754.:905-914. [PubMed] 67. Wheat LJ, Slama TG, Norton JA, Kohler RB, Eitzen HE, French MLV et al. Risk factors for disseminated or fatal histoplasmosis. Ann Intern Med 1982; 96:159-163. [PubMed] 68. 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] 69. Salzman SH, Smith RL, Aranda CP. Histoplasmosis in patients at risk for the acquired immunodeficiency syndrome in a nonendemic setting. Chest 1988; 93:916-921. [PubMed] 70. Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically suppressed patients. Am J Med 1978; 64:94-100. [PubMed] 71. Keath EJ, Kobayashi GS, Medoff G. Typing of Histoplasma capsulatum by restriction fragment length polymorphisms in a nuclear gene. J Clin Microbiol 1992; 30:2104-2107. [PubMed] 72. Powell KE, Hammerman KJ, Dahl BA, Tosh FE. Acute reinfection pulmonary histoplasmosis. Am Rev Respir Dis 1973; 107:374-378. [PubMed] 73. Schwarz J, Baum GL. Reinfection in histoplasmosis. Arch Pathol 1963; 75:475-479. [PubMed] 74. Goodwin RA, Loyd JE, des Prez RM. Histoplasmosis in normal hosts. Medicine Baltimore. 1981; 60:231-266. [PubMed] 75. Connolly P, Wheat J, Schnizlein-Bick C, Durkin M, Kohler S, Smedema M et al. Comparison of a new triazole antifungal agent, Schering 56592, with itraconazole and amphotericin B for treatment of histoplasmosis in immunocompetent mice. Antimicrob Agents Chemother 1999; 432.:322-328. [PubMed] 76. Goldberg J, Connolly P, Schnizlein-Bick C, Durkin M, Kohler S, Smedema M et al. Comparison of nikkomycin Z with amphotericin B and itraconazole for treatment of histoplasmosis in a murine model. Antimicrob Agents Chemother 2000; 446.:1624-1629. [PubMed] 77. Kohler S, Wheat LJ, Connolly P, Schnizlein-Bick C, Durkin M, Smedema M et al. Comparison of the Echinocandin Caspofungin with Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in a Murine Model. Antimicrob Agents Chemother 2000; 447.:1850-1854. [PubMed] 78. LeMonte A, Washum K, Smedema M, Schnizlein-Bick C, Kohler R, Wheat LJ. Amphotericin B combined with itraconazole or fluconazole for treatment of histoplasmosis. J Infect Dis 2000;182.:545-550. [PubMed] 79. Sorensen KN, Sobel RA, Clemons KV, Pappagianis D, Stevens DA, Williams PL. Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis. Antimicrob Agents Chemother 2000; 446.:1512-1517. [PubMed] 80. Li RK, Ciblak MA, Nordoff N, Pasarell L, Warnock DW, McGinnis MR. In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum. Antimicrob Agents Chemother 2000; 44(6).:1734-1736. [PubMed] 81. Lo Y, Tintelnot K, Lippert U, Hoppe T. Disseminated Penicillium marneffei infection in an African AIDS patient. Trans R Soc Trop Med Hyg 2000; 94(2).:187. [PubMed] 82. Wynne JW, Olsen GN. Acute histoplasmosis presenting as the adult respiratory distress syndrome. Chest 1974; 66:158-161. [PubMed] 83. Prior JA, Saslaw S, Cole CR. Experiences with histoplasmosis. Ann Intern Med 1954; 40:221-244. [PubMed] 84. Dismukes WE, Bradsher RW Jr., Cloud GC, Kauffman CA, Chapman SW, George RB et al. Itraconazole therapy for blastomycosis and histoplasmosis. Am J Med 1992; 93:489-497. [PubMed] 85. Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Am J Med 1995; 98:336-342. [PubMed] 86. Wheat J, Marichal P, Vanden Bossche H, Le Monte A, Connolly P. Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum. Antimicrob Agents Chemother 1997; 41:410-414. [PubMed] 87. 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] 88. Greenwood MF, Holland P. Tracheal obstruction secondary to Histoplasma mediastinal granuloma. Chest 1972; 62:642-645. [PubMed] 89. Gilliland MD, Scott LD, Walker WE. Esophageal obstruction caused by mediastinal histoplasmosis: Beneficial results of operation. Sur 1984; 95:59-62. [PubMed] 90. Furcolow ML. Course and prognosis of untreated histoplasmosis. JAMA 1961; 177:292-296. [PubMed] 91. Sutliff WD, Andrews CE, Jones E, Terry RT. Histoplasmosis cooperative study: Veterans Administration-Armed Forces Cooperative Study on histoplasmosis. Am Rev Respir Dis 1964; 89:641-650. [PubMed] 92. Putnam LR, Sutliff WD, Larkin JC, Baum GL, Busey JF, Johns LE et al. Histoplasmosis cooperative study: Chronic pulmonary histoplasmosis treated with amphotericin B alone and with amphotericin B and triple sulfonamide. Am Rev Respir Dis 1968; 97:96-102. [PubMed] 93. Urschel HC Jr., Razzuk MA, Netto GJ, Disiere J, Chung SY. Sclerosing mediastinitis: Improved management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 1990; 50:215-221. [PubMed] 94. Mathisen DJ, Grillo HC. Clinical manifestations of mediastinal fibrosis and histoplasmosis. Ann Thoracic Surgery 1992; 54:1053-1058. [PubMed] 95. McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Am J Hum Genet 2001; 693.:641-NIL7. [PubMed] 96. Furcolow ML. Comparison of treated and untreated severe histoplasmosis. JAMA 1963; 183:121-127. [PubMed] 97. Johnson P, Wheat LJ, Cloud G, Thomas C, Dismukes W, Goldman M et al. A Multicenter Randomized Trial Comparing Amphotericin B AmB. and Liposomal Amphotericin B AmBisome, LAmB. as Induction Therapy of Disseminated Histoplasmosis DH. in AIDS Patients. Ann Intern Med 2002; in press. [PubMed] 98. Groll AH, Giri N, Petraitis V, Petraitiene R, Candelario M, Bacher JS et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis 2000; 1821.:274-282. [PubMed] 99. Paya CV, Hermans PE, van Scoy RE, Ritts RE Jr., Homburger HA. Repeatedly relapsing disseminated histoplasmosis: Clinical observations during long-term follow-up. J Infect Dis 1987; 156:308-312. [PubMed] 100. Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: Results of long-term follow-up. Ann Intern Med 1971; 75:511-516. [PubMed] 101. McKinsey DS, Gupta MR, Riddler SA, Driks MR, Smith DL, Kurtin PJ. Long-term amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immune deficiency syndrome. Ann Intern Med 1989; 111:655-659. [PubMed] 102. Wheat J, Hafner R, Wulfson M, Spencer P, Squires K, Powderly W et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1993; 118:610-616. [PubMed] 103. Schwarz J. Histoplasmosis of the eye. Histoplasmosis. New York, NY: Praeger, 1981: 317-350. [PubMed] 104. Fine SL, Wood WJ, Isernhagen RD, Singerman LJ, Bressler NM, Folk JC et al. Laser treatment for subfoveal neovascular membranes in ocular histoplasmosis syndrome: Results of a pilot randomized clinical trial. Arch Ophthalmol 1993; 111:19-20. [PubMed] 105. Macular Photocoagulation Study Grp. Laser photocoagulation for neovascular lesions nasal to the fovea: Results from clinical trials for lesions secondary to ocular histoplasmosis or idiopathic causes. Arch Ophthalmol 1995; 113:56-61. [PubMed] 106. Deepe GS Jr. Prospects for the Development of Fungal Vaccines. Clin Microbiol Rev 1997; 10(4).:585-596. [PubMed] 107. Deepe GS Jr., Gibbons R. Recombinant Murine Granulocyte-Macrophage Colony-Stimulating Factor Modulates the Course of Pulmonary Histoplasmosis in Immunocompetent and Immunodeficient Mice. Antimicrob Agents Chemother 2000; 44(12).:3328-3336. [PubMed] 108. Wheat LJ, Cloud G, Johnson PC, Connolly PA, Goldman M, Le Monte A et al. Clearance of Fungal Burden during Treatment of Disseminated Histoplasmosis with Liposomal Amphotericin B versus Itraconazole. Antimicrob Agents Chemother 2001; 458.:2354-2357. [PubMed] 109. Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 2000; 304.:688-695. [PubMed] 110. Clemons KV, Lutz JE, Stevens DA. Efficacy of interferon-gamma and amphotericin B for the treatment of systemic murine histoplasmosis. Microbe Infect 2001; 31.:3-10. [PubMed] 111. Zhou P, Sieve MC, Tewari RP, Seder RA. Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum. Infect Immun 1997; 653.:936-942. [PubMed] 112. Lenhart S. Recommendations for Protecting Workers from Histoplasma capsulatum Exposure During Bat Guano Removal from a Church's Attic. Appl Occup Environ Hyg 1994; 94.:230-236. [PubMed] 113. Vail G, Young R, Filo RS, Cornetta K, Wheat J, Goldman M. Incidence of histoplasmosis following allogeneic bone marrow transplant aBMT. or solid organ transplant SOT. in a hyperendemic area. Program and Abstracts of the 36th Infectious Diseases Society of America Meeting in Denver, CO, November 11-14, 1998. 141. 1998. [PubMed] 114. McKinsey DS, Wheat LJ, Cloud GA, Pierce M, Black JR, Bamberger DM et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: Randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999; 285:1049-1056. [PubMed] 115. Goldman M, Cloud GA, Smedema M, LeMonte A, Connolly P, McKinsey DS et al. Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection? Antimicrob Agents Chemother 2000; 446:1585-1587. [PubMed]
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