OVERVIEW: What every clinician needs to know
Pathogen name and classification
Histoplasmosis is the most common endemic mycosis in the United States, usually presenting as a community acquired respiratory infection. Pulmonary histoplasmosis also may present as mediastinal lymphadenopathy or lung nodules, often mistaken as malignancy. Progressive disseminated histoplasmosis commonly presents as fever of unknown etiology, and occurs most often in an immunocompromised host. Once suspected, diagnosis can be established within a week or two using a battery of mycological or immunological tests.
Treatment is indicated in all patients with progressive disseminated or chronic pulmonary histoplasmosis and in patients with acute pulmonary histoplasmosis who have not substantially improved by the time the diagnosis is established. The role of antifungal treatment for other manifestations of histoplasmosis is uncertain. Lipid formulation of amphotericin B, preferably liposomal amphotericin B, is recommended in patients with moderately severe or severe disease in which hospitalization is necessary, and itraconazole in mild cases and following response to amphotericin B.
Histoplasma capsulatum is a dimophic fungus in the class Ascomycetes. Three varieties have been described: capsulatum, duboisii, and farciminosum. Variety capsulatum is the most common cause for disease in humans and animals and is distributed worldwide. The variety duboisii is found primarily in certain regions of Africa and also causes disease in humans and animals. The variety farciminosum is found in a wide geographic distribution and causes disease in horses.
What is the best treatment?
A lipid formulation of amphotericin B, preferably liposomal amphotericin B, is recommended for moderately severe and severe cases, and itraconazole is recommended for mild cases and after patients have improved in response to amphotericin B.
Liposomal amphotericin is administered at a dose of 3 mg/kg daily for 7-14 days.
Some patients may experience a systemic histamine type response following the administration of liposomal amphotericin B, which can be minimized by pre-treatment with antihistamines.
Liposomal amphotericin B was more effective than the deoxycholate formulation in patients with AIDS and disseminated histoplasmosis. Overall response rate and mortality were significantly better and adverse effects were fewer in patients receiving the liposomal formulation.
Amphotericin B lipid complex may also be used but has not been studied in histoplasmosis to assess its relative effectiveness and safety as compared to the deoxycholate or liposomal formulations.
Itraconazole is the azole of choice in histoplasmosis and is administered 200 mg three times daily for 3 days, then 200 mg twice daily in adults and 5-10 mg/kg not to exceed 400 mg daily in children. Although itraconazole has not been compared directly to fluconazole, several studies have reported higher response rates and lower relapse rates in patients treated with fluconazole.
In patients with AIDS, response was 85% in those treated with itraconazole and 74% in those treated with fluconazole. However, 31% of those treated with fluconazole relapsed when the dosage was reduced from 800 mg per day during the first 12 weeks to 400 mg per day, prompting closure of the study. Approximately 5% of patients treated with itraconazole relapsed when the dosage was reduced from 400 mg daily to 200 mg daily.
Lower response rates and higher relapse rates were also demonstrated in patients with chronic pulmonary and disseminated histoplasmosis that did not have AIDS.
Itraconazole inhibits cytochrome P450 and, thus, causes potentially serious drug interactions with medications cleared by that enzyme. The potential for drug interactions should be reviewed before beginning itraconazole in patients who are receiving other medications.
Fluconazole, voriconazole, and posaconazole are alternatives to itraconazole. Fluconazole is less effective than itraconazole. The roles of voriconazole and posaconazole have not been established for the treatment of histoplasmosis. The echinocandins are not active in vitro or in murine models of histoplasmosis. Too few patients have been treated with the echinocandins to establish their role for treatment, but the available evidence does not support their use in histoplasmosis.
Resistance testing of Histoplasma capsulatum is rarely performed in clinical practice.
Development of resistance was reported in a single study using fluconazole for treatment of histoplasmosis in patients with AIDS. In that study, among patients who relapsed, 70% of the isolates demonstrated development of resistance to fluconazole by comparison of the susceptibility in the initial isolates with the failure or relapse isolate. Isolates obtained before and after treatment failure were tested for susceptibility to fluconazole, voriconazole, and itraconazole. A four-fold or more reduction in susceptibility developed to fluconazole in 70% of isolates and to voriconazole in 41%, but none developed resistance to itraconazole or posaconazole.
Use of higher doses of fluconazole has been recommended, but whether that reduces the development of resistance is unknown. Resistance has not been reported with amphotericin B or its lipid formulations, itraconazole or posaconazole.
Resistant strains demonstrated reduced susceptibility of the alpha demethylase and 3-ketosteroid reductase to fluconazole. A single amino acid substitution at tyrosine 156 was found in the active site of the CYP 51 protein of resistant strains.
Antifungal susceptibility testing is performed using NCCLS method M27A developed for yeasts, as modified for H. capsulatum. The yeast phase should be used for susceptibility testing. The yeast phase is resistant to echinocandins, which were not effective in the murine model of histoplasmosis. The mechanism for resistance to echinocandins has not been determined. In vitro resistance among yeast phase isolates also correlated with in vivo failure in mice treated with nikkomycin Z.
The mechanisms for resistance to nikkomycin Z or the echinocandins have not been investigated.
Resistance has not been demonstrated to amphotericin B, itraconazole, or posaconazole.
Rationale for use of liposomal amphotericin B
Liposomal amphotericin B was more effective and less toxic than deoxycholate amphotericin B in a randomized double-blind study in patients with AIDS complicated by disseminated histoplasmosis. Mortality and time to clinical improvement were significantly less in patients receiving liposomal amphotericin B, and renal toxicity was lower. Mortality was 2% in patients treated with what liposomal amphotericin B and 13% with amphotericin B deoxycholate. Overall response was 88% with liposomal amphotericin B and 64% with amphotericin B deoxycholate.
Other lipid formulations of amphotericin B have not been specifically studied for treatment of histoplasmosis. Liposomal amphotericin B achieves higher concentrations in brain tissue, making it the preferred formulation for treatment of histoplasmosis involving the central nervous system. None of the amphotericin B formulations achieve detectable levels in cerebrospinal fluid, however.
Who should be treated?
Treatment is indicated in all patients with progressive disseminated histoplasmosis or chronic pulmonary histoplasmosis. Although some patients with these manifestations recover without therapy, the majority experience progressive disease and the mortality is high. Eighty percent of patients with progressive disseminated disease die without treatment, as well about one-third of patients with chronic progressive pulmonary histoplasmosis.
Although placebo-controlled treatment studies have not been conducted, mortality rates below10% have been achieved following treatment with amphotericin B or itraconazole. Underlying immunosuppressive conditions should also be considered in decisions about treatment. Immunosuppressed patients are likely to have progressive disseminated disease and should be treated as such, even in the absence of proof for dissemination. At least 1 year of therapy is recommended for treatment of progressive disseminated or chronic pulmonary histoplasmosis.
Symptomatic patients with acute pulmonary histoplasmosis manifested by diffuse pulmonary infiltrates who present within a few weeks of exposure should be treated, unless they are substantially improved by the time in the diagnosis is established, in which case the inconvenience, adverse effects, and cost of itraconazole may outweigh any potential benefit. These patients have usually experienced a large inoculum exposure, and, although they may recover without treatment, recovery may be slow and the morbidity may be significant, interfering with school, work, or daily activities. Additionally, up to 10% of patients with acute pulmonary histoplasmosis following heavy exposure may die without therapy, usually as a result of progressive disseminated disease. Others may require hospitalization for the management of respiratory failure.
Although treatment studies of acute pulmonary histoplasmosis have not been conducted, case reports and experience suggest that treatment reduces the duration of illness in such cases. Additionally, in those with respiratory failure, a short course of corticosteroids may hasten recovery, suggesting that inflammatory response may play a role in the physiological impairment associated with acute pulmonary histoplasmosis. For these reasons, there should be a low threshold for antifungal treatment in patients with diffuse pulmonary infiltrates following heavy exposure. At least 12 weeks of therapy is recommended for treatment of acute pulmonary histoplasmosis in cases following heavy exposure or with diffuse pulmonary infiltrates, although the duration of therapy has not been established for such cases. A longer course may be necessary in some cases based on residual symptoms or evidence for disseminated disease. A shorted cause may be adequate in patients with side effects of itraconazole that are moderately severe.
Antifungal treatment is not indicated in patients with other manifestations of pulmonary histoplasmosis. Most common among these are patients with localized pulmonary infiltrates and/or mediastinal lymphadenopathy following unrecognized, presumably low-inoculum exposure. Illnesses are usually subacute and mild, causing little functional impairment or interruption of normal activities. In some cases, symptoms may persist for several months and may interfere with work or school. Accordingly, treatment is recommended if patients are not already showing improvement after 1 month of symptoms. However, whether antifungal treatment hastens recovery is unknown. A 6- to 12-wekk course of treatment had been recommended.
Some patients with acute or subacute pulmonary histoplasmosis exhibit pericarditis or rheumatologic findings of arthritis or arthralgia usually accompanied by erythema nodosum. These represent inflammatory processes, rather than progressive infection, in response to mediastinal lymphadenitis in the case of pericarditis and a systemic inflammatory response in patients with the rheumatologic manifestations. These findings usually respond to treatment with nonsteroidal anti-inflammatory agents alone. Antifungal treatment is only indicated in patients felt to require treatment with corticosteroids. Many patients will experience exacerbation of symptoms when the anti-inflammatory agents are stopped, necessitating resumption of anti-inflammatory treatment. Treatment may be required for several months in some cases.
The role of therapy in patients with mediastinal complications of histoplasmosis is also uncertain. Some patients with pulmonary histoplasmosis experience encroachment of mediastinal structures caused by enlarged mediastinal nodes. These manifestations are classified into three groups: mediastinal lymphadenitis, mediastinal granuloma, and mediastinal fibrosis.
Mediastina lymphadenitis is usually recognized in children as an early manifestation of the initial infection. Combined antifungal and anti-inflammatory therapy appears effective at reducing the size of the lymph nodes and associated symptoms. Accordingly treatment may be appropriate if the patients are not already improving by the time the diagnosis is established.
Mediastina granulomas caused by a persistent inflammation and necrosis of mediastinal nodes are usually manifested as chest pain and compression of mediastinal structures. Although antifungal treatment is recommended in patients who are not improving without therapy, its effectiveness is unknown. Anti-inflammatory treatment may also be tried, but its effectiveness is uncertain. Surgery to remove the enlarged nodes should be considered in patients who continue to have unacceptable symptoms despite antifungal and anti-inflammatory therapy. The mediastinal granuloma can usually be removed without damaging adjacent structures. However, surgery is very rarely performed in such cases, as consultation with in expert on management of mediastinal histoplasmosis is recommended to differentiate mediastinal granuloma from fibrosis and decide if surgery is warranted.
Mediastinal fibrosis is differentiated from mediastinal granuloma by dense fibrosis invading adjacent structures. Antifungal and anti-inflammatory therapy is usually ineffective but may be tried if the differentiation from mediastinal granuloma is uncertain. In many cases characterized by encroachment of vascular structures, improvement may result from vascular stenting. Surgical resection of the fibrotic masses should be avoided because of the high risk for injury of vascular structures or airways. Most patients with mediastinal fibrosis have non-disabling symptoms that are not progressive, and, in such cases, the risk of injury or death from surgery may be greater than the potential benefit. Consultation with an expert on management of mediastinal histoplasmosis is recommended to differentiate mediastinal granuloma from fibrosis and decide if surgery is warranted. Only surgeons experienced with surgery for mediastinal fibrosis caused by a histoplasmosis should undertake surgery for mediastinal fibrosis, and, even then, surgical mortality may be greater than 20%.
How do patients contract this infection, and how do I prevent spread to other patients?
Histoplasmosis is acquired by inhaling micro-conidia aerosolized by disturbing environmental sites containing the organism. As few as ten organisms are sufficient to cause experimental infection. Such low-level exposure may occur at distances of several miles from the disturbed site. Much heavier exposure may occur in individuals doing the activity that disturbs the site. There is no evidence of a person-to-person respiratory transmission in histoplasmosis, but transmission by inoculation from infected mucosal sites and by accidental inoculation in the laboratory has been reported.
There is no relationship of exposure with weather patterns or wind direction. Several outbreaks have occurred during the winter when the ground was frozen. Infection occurs when soil or accumulations of bird or bad guano containing the organism are disturbed, during any season of the year.
Endemic areas are characterized by high humidity during the summer and moderate temperatures. Soil characteristics have not been carefully studied, but the presence of heavy accumulations for bird or bat droppings can be found in sites associated with exposure to histoplasmosis.
Histoplasmosis occurs in North, Central, and South America and parts of Asia and Africa. Rates of histoplasmin skin test reactivity in persons living in endemic areas of the United States range from 5 to nearly 100%. Reasons for this geographic distribution are unknown. The mold form is present in so-called “microfoci” within the endemic area and may be aerosolized when the soil is disturbed. Histoplasma may be found in the microfoci but not in adjacent areas only a few yards away. Skin test reactivity to histoplasmin may be high in persons residing near the microfocus, dropping off to background levels 1 mile away.
Infection occurs by 20 years of age in most individuals. To achieve 100% skin test reactivity by 20 years of age, assuming infection occurs at a constant rate over those 20 years, the infection rate per year would be 5%. Accordingly, infection rates would range from 0.25% per year in areas with a skin test positivity rate of 5% to 5% per year in areas with a skin test positivity rate of 100%.
There is no evidence to indicate the incidence of histoplasmosis is declining in the United States as a result of urbanization. However, few data are available. In a study of Navy recruits from Indianapolis, Indiana, conducted in the 1950s, 55% exhibited positive histoplasmin skin test. In a study of postgraduate students conducted in 1982, 50% were skin test positive, and, in a study evaluating cytokine response as a marker for past infection with H. capsulatum in 2000, 45% of hospital employees were skin test positive. The skin test reagent is no longer commercially available, however. Interferon release assays showing that interferon gamma or interleukin 12 production correlates with skin test reactivity have been reported to have not been developed into FDA cleared tests.
Infection control issues
As person-to-person transmission does not occur, infection control measures are unnecessary in management of patients with histoplasmosis, either in the hospital, home, or community.
Laboratory personnel who work with histoplasma mold are at risk for exposure and should follow guidelines for handling of airborne pathogens. These include working with the organism in a biosafety cabinet and use of gloves and gowns. Individuals involved in the clean-up of a laboratory spill must be trained in the safe handling of the organism and use certified respirators, as well as gowns, gloves, and foot covers. Exposure can also occur by inoculation of the organism by needles or other sharp objects.
Workers involved in clean-up of an environmental site thought to contain the organism should follow guidelines to reduce aerosol exposure, including use of respirators and other personal protective equipment and wetting the soil or material to be removed. Formalin application has been tried but does not kill the mold more than a few inches from the surface and is harmful to the environment and workers exposed to the fumes. In situations in which the site cannot be safely decontaminated, it should be quarantined.
There is no vaccine against histoplasmosis for use in humans. Vaccination has been shown to reduce the rate of infection and severity following experimental infection; however, the optimal antigen has not determined, and studies in humans or animals, except for experimental studies in mice, have not been conducted.
Itraconazole prophylaxis is recommended for individuals with unprotected laboratory or environmental airborne exposure or percutaneous inoculation to Histoplasma yeast or mold. Studies have not been performed to determine efficacy or optimal duration of prophylaxis following exposure, but a 1-3 month course is reasonable. Prophylaxis was demonstrated to reduce the risk of infection in patients with AIDS from cities in which the incidence of histoplasmosis exceeded 10%, supporting the role of prophylaxis following laboratory or environmental exposure.
What host factors protect against this infection?
Cellular immunity provides the key host defense in histoplasmosis. Immunity develops within 1 month following initial infection, killing the yeast and preventing progression of the illness. Tumor necrosis factor alpha, interferon gamma, and interleukin 12 (IL-12) are key mediators of protective immunity. Cases have been described by investigators at the National Institutes of Health in patients with defects in interferon gamma and IL-12 pathways. In the absence of immunosuppressive conditions or defects in these immune pathways, immunity is life-long in most individuals, and reinfection usually does not cause recurrent illness in the absence of heavy exposure. Therapy that impairs cellular immunity causes progressive illnesses usually associated with extra-pulmonary dissemination. Antibodies are not required for immunity in histoplasmosis.
There are no health conditions that affect the risk for contracting histoplasmosis. However, several factors affect the course of the infection following exposure. Healthy individuals are susceptible to histoplasmosis, and the extent of the pulmonary illness correlates with the magnitude of exposure: light exposure may cause no symptoms, and heavy exposure often causes moderate or severe illness. Underlying chronic lung disease caused by cigarette smoking is associated with chronic pulmonary histoplasmosis. Immunocompromising conditions, defects in cellular immunity, infancy, being 54 years of age or older, and perhaps pregnancy predispose to progressive disseminated disease. Whether age or other underlying chronic disease explains the risk of persons older than 54 years of age for disseminated disease is unknown. Other host factors may play a role in some of the complications of histoplasmosis, such as fibrosing mediastinitis, a theory for which there is no evidence.
Granuloma formation is characteristic in the pathology in histoplasmosis. T lymphocytes and macrophages are the cells involved in host defense against H. capsulatum and are the major components of granuloma. Fibrosis and calcification develop in response to the infection, perhaps limiting spread of the organism outside the granuloma and further interaction of the yeast with the immune system. Calcification, as demonstrated radiologically, requires 1 year or more to develop in adults, less in children. Whether calcification might be detected earlier by CT scan or histopathology is unknown, however. The yeast persists in calcified and non-calcified granuloma but appear to not be viable: there is no evidence for truly latent infection as in tuberculosis. Yeast may remain viable in individuals with reduced cellular immunity, however.
What are the clinical manifestations of infection with this organism?
Histoplasmosis is commonly overlooked in the evaluation of patients with community acquired pneumonia (CAP). In patients who reside in or have recently visited endemic areas, histoplasmosis should be considered and tested for in patients with CAP. Clinical clues would include failure to respond to antibiotics appropriate for therapy of CAP, diffuse reticular, nodular, or military infiltrates, mediastinal or hilar lymphadenopathy, or cavitary lung disease unresponsive to antibiotics in patients with negative tests for tuberculosis.
Manifestations depend on the magnitude of exposure and underlying condition of the person infected. No symptoms may occur in a healthy subject following a low inoculum exposure. Heavier exposure may produce mild flu-like symptoms associated with mediastinal lymphadenopathy and/or focal pulmonary infiltrates. Exposure is usually unrecognized in these situations, and the presentation is usually subacute with pulmonary symptoms, including cough and chest pain lasting several weeks to a few months.
Large inoculum exposure as occurs in point-source outbreaks or work at a contaminated environmental site causes acute pulmonary symptoms within 1-2 weeks of exposure and diffuse or miliary infiltrates. Symptoms are often moderately severe, and recovery is slow. More severe cases may develop respiratory failure or progressive disseminated disease, both of which may be fatal if not treated. Self-limited disseminated infection may be demonstrated in the pre-immune phase of acute pulmonary histoplasmosis following heavy exposure, and usually resolves without therapy. However, a few cases of fatal progressive dissemination have been reported following large inculum, acute histoplasmosis.
Reinfection in a healthy subject is expected to be less severe and shorter in duration.
Infection in a patient with chronic obstructive pulmonary disease (COPD) causes progressive pulmonary histoplasmosis resembling tuberculosis. Pulmonary defenses appear unable to eradicate the infection in such cases. Illness is chronic and characterized by respiratory symptoms, weight loss, and cavitary infiltrates, which represent inflammation superimposed on underlying bullous lung disease. Without treatment, progressive lung destruction occurs and progressive disseminated disease may develop, which may be fatal in about 10% if cases.
Histoplasmosis should be suspected in patients with fever of unknown origin who reside in or have visited endemic areas, as a manifestation of progressive disseminated disease. Other manifestations may include bone marrow suppression, hapatosplenomegaly, chronic meningitis or brain lesions, adrenal mass or insufficiency, culture-negative endocarditis, enteritis, or mucocutaneous lesions.
What common complications are associated with infection with this pathogen?
Complications are uncommon in otherwise healthy subjects. These are usually caused by the mass effect of the enlarged mediastinal nodes, the localized inflammatory reaction in the mediastinum, or the systemic immunological response.
A rheumatologic syndrome characterized by arthralgia or arthritis, usually associated with erythema nodosum or erythema multiform, occurs in 5-10% of patients. This manifestation appears to be caused by a systemic immunological reaction, rather than actual infection of the joins or cutaneous tissues, and this manifestation is responsive to anti-inflammatory treatment without antifungal therapy.
Pericarditis may also follow acute infection, presumably as an inflammatory reaction to the adjacent mediastinal lymphadenitis, rather than an infective pericarditis. The pericarditis is usually responsive to anti-inflammatory therapy and rarely causes chronic restrictive pericarditis. Pericarditis may be a complication of progressive disseminated histoplasmosis.
Acute mediastinal lymphadenitis, characterized by enlargement and inflammation of mediastinal lymph nodes, may cause obstruction of vascular structures, airways, or the esophagus in young children. This manifestation is usually responsive to anti-inflammatory treatment administered in conjunction with antifungal therapy.
Granulomatous mediastinitis uncommonly follows the initial pulmonary infection. Enlargement of the lymph node with chronic inflammation, necrosis, and surrounding fibrosis are characteristic of granulomatous mediastinitis, and fistula may develop between the necrotic lymph node and adjacent structures, including airways, the esophagus, or subcutaneous tissue.
Fibrosing mediastinitis differs from granulomatous mediastinitis in the degree of surrounding fibrosis, which is more intense. The fibrosis invades the adjacent mediastinal structures, most commonly causing superior vena cava obstruction. Other structures commonly involved are pulmonary arteries and veins and large airways.
Chronic progressive pulmonary infection is characterized by necrosis, cavitation, and fibrosis, occurring mostly in individuals with chronic obstructive pulmonary disease caused by long-term cigarette use.
Progressive disseminated infection usually occurs in patients with underlying immunocompromising disorders or treatment with medications that impair cellular immunity. Up to a quarter of cases, however, may not have a recognizable immune defect. Among such cases may be individuals with unrecognized defects, as noted in patients with IL-12 and interferon-gamma pathway abnormalities. Testing for such immune defects may be available at a few specialized laboratories. Adrenal insufficiency, endocarditis, chronic meningitis, and hydrocephalus may be isolated complications of disseminated histoplasmosis.
How should I identify the organism?
The mold grows in the soil and shows branching septate hyphae with microconidia (2-4 micrometers) and tuberculate macroconidia (9-15 micrometers). Following inhalation of microconidia and hyphal fragments, conversion to the yeast (2-5 micrometers) form occurs in the alveoli and terminal airways, followed by lymphangitic spread to regional lymph nodes. Prior to the development of cellular immunity, yeast disseminate hematogenously to the reticuloendothelial tissues, most commonly the liver, spleen, or extrapulmonary lymph nodes.
The development of cellular immunity during the first few months following infection halts the progression in the lungs and extra-pulmonary tissues. The presence of conditions that suppress cellular immunity permits progressive infection. Viable yeast release polysaccharide antigens into the alveolar spaces and infected tissues, and these enter the blood and other bodily fluids and are subsequently excreted in the urine.
How should I diagnose the disease?
The most accurate approach to diagnosis involves use of battery mycological and serological tests. Although culture remains the gold standard for diagnosis, cultures are negative in milder cases and in patients with the inflammatory complications of the infection. Also, the recognition of positive cultures may be slow, limiting the role of culture for rapid diagnosis. Visualization of yeast in the tissues and respiratory secretions of patients with histoplasmosis may provide a rapid diagnosis; however, direct examination may be negative in one-quarter to one-half of patients with disseminated or chronic pulmonary histoplasmosis and in most patients with other manifestations of histoplasmosis.
Direct examination is not 100% specific, as staining artifacts may be misinterpreted as yeast, and, in some cases, other fungi may be mistaken as Histoplasma. Direct examination often requires an invasive procedure to obtain tissue, representing another limitation of that approach. Detection of antigen in bodily fluids is most useful for diagnosis of disseminated and acute pulmonary histoplasmosis. Serologic test for antibodies is most useful for diagnosing milder forms of histoplasmosis in which test for antigens, direct examination, and culture are negative
Detection of antigen in blood, and urine provides the highest diagnostic yield in patients with acute pulmonary and progressive disseminated histoplasmosis. This antigen cross reacts with antigens produced in blastomycosis (95%), paracoccidioidomycosis and penicilliosis marneffei (80%), and less commonly with coccidioidomycosis (20%). Cross reactions have also been noted in aspergillosis (10%) and sporotrichosis (one case). Antigen concentration correlates with the severity of infection, with concentrations greater than 19 ng/mL seen more commonly in patients requiring hospitalization and/or critical care unit admission. Antigen detection is most useful for diagnosis of progressive disseminated or acute pulmonary histoplasmosis, positive in over 90% and over 80% of cases, respectively. The highest sensitivity is achieved by testing urine and serum in all cases, bronchoalvelolar lavage fluid or bronchial washings in those undergoing bronchoscopy, and cerebrospinal fluid if lumbar puncture is performed to exclude meningitis or encephalitis.
Visualization of yeast microscopically by histopathology or cytology in respiratory secretions, lung tissues, bone marrow, liver, and lymph nodes is less sensitive but more specific than antigen detection.
Histoplasma yeast are oval in shape, 2-5 mm in diameter, and characteristically demonstrate narrow necked budding. Yeasts may be seen by Wright staining of peripheral blood in patients with severe disseminated histoplasmosis. Gomori’s methenamine silver stain is the most sensitive method for visualization of the yeast by histopathology. Yeast may also be seen by Dif-quick staining of tissues or bodily fluids, Papanicolaou staining of cytology specimens, and Giemsa staining in tissues, bronchoalveolar lavage specimens and peripheral blood smears.
Distinction from other organisms may be difficult in some cases, and staining may be falsely negative if only a few organisms are present. The accuracy of diagnosis by microscopic examination depends on the experience of the pathologist in recognition and differentiation of fungal pathogens.
Cultures should use fungal media and should be incubated at room temperature for a least 1 month, as the organism grows slowly.
A variety of media have been used for isolation of Histoplasma capsulatum. These include brain heart infusion and Sabouraud dextrose agar.
Mold colonies are white or buff-brown and cottony in consistency. Yeast colonies are smooth, white, and pasty in consistency.
Specific identification may be obtained by detection of exoantigens in extracts of the organism by agar gel immunodiffusion or by detection of DNA by molecular methods.
Histoplasma multiplies slowly, usually requiring at least 1 week and up to 4 weeks before growth can be detected.
The sensitivity of culture is highest in respiratory specimens from patients with chronic pulmonary histoplasmosis or progressive disseminated histoplasmosis, positive in about 75% of cases. Cultures of the blood, bone marrow, or other extra-pulmonary tissues are positive in about two-thirds of cases of disseminated histoplasmosis. Cultures of cerebrospinal fluid (CSF) in patients with meningitis are positive in only about one-quarter of cases. Cultures are usually negative in patients with acute and subacute pulmonary histoplasmosis and in those with granulomatous or fibrosing mediastinitis.
Although several publications suggest PCR is useful for diagnosis of histoplasmosis and assays are commercially available, their roles are uncertain. Sensitivity was only 33% in bronchoalveolar lavage specimens but 100% in other respiratory specimens in one report. In another study of antigen positive specimens, PCR was positive in 8% of urine specimens, 22% of bronchoalveolar lavage specimens, but none of the serum or cerebrospinal fluid specimens.
Immunohistochemical staining has not been evaluated for diagnosis of histoplasmosis, and commercial reagents for use in immunohistochemical staining are not available.
Serologic testing for antibodies is useful for diagnosis of histoplasmosis. Antibodies develop 1-3 months following primary infection and, thus, may be falsely negative early in the course of the infection. Antibodies clear slowly over several years and, thus, may not distinguish active from past infection. Antibody production is reduced in immunocompromised patients and may be falsely negative in patients with proven histoplasmosis. Also, cross reactions may be seen in patients with other fungal infections, most notably blastomycosis and coccidioidomycosis. Acknowledging these limitations, antibody testing complements other diagnostic methods and may be the sole basis for diagnosis in some patients, most often those with subacute pulmonary histoplasmosis or its complications, and in chronic pulmonary histoplasmosis. Many physicians assume that background positivity limits the usefulness of antibody testing in endemic areas, a myth for which there is no basis. In fact antibody positivity in endemic areas with histoplasmin skin test positivity rates above 50% is only 4% by complement fixation and 0.5% by immunodiffusion. The titers in these cases were 1:8 or 1:16.
The two methods most useful are immunodiffusion and complement fixation. H and/or M precipitin bans may be observed by immunodiffusion. H precipitins may be detected in about one-quarter of cases, and clear within 6 months following initial infection. M precipitins occur in about three-quarters of patients and may persist for several years following primary infection. The complement fixation test uses yeast (Y phase) and mold antigens (M phase), and results are expressed as titers. Positive results are reported as titers of 1:8 or higher to either the yeast or the mold antigen and may persist for several years. Complement fixation titers of 1:32 or higher are more suggestive of active disease, but titers of 1:8 or1:16 should not be dismissed.
How does this organism cause disease?
Several factors have been associated with in virulence in H. capsulatum. The Down’s strain, a member of class 1, is less temperature tolerant at mammalian temperatures and less virulent than the more common class 2 strains of H. capsulatum, perhaps related to altered expression of fatty-acid desaturase. Other factors thought to be related to virulence include heat shock protein 60, catalase B and beta-glucosidases, yeast phase specific protein 3, calcium binding protein and alpha-(1,3)-glucan synthase.
Importantly, these observations are based mostly on in vitro studies. There are few in vivo correlations in experimental models of histoplasmosis but no data in humans to suggest that virulence factors influence clinical manifestations in patients and no data to suggest clinical manifestations differ in patients infected with the different genetic classes of H. capsulatum variety capsulatum, overwhelmingly the most common cause for histoplasmosis in humans throughout the world.
WHAT’S THE EVIDENCE for specific management and treatment recommendations?
The evidence on which management and treatment guidelines were developed has been reviewed. Liposomal amphotericin B was more effective than the deoxycholate formulation for treatment of disseminated histoplasmosis in patients with AIDS, providing a higher response rate, lower mortality, and reduced toxicity. Itraconazole appears more effective than fluconazole for management of cases with milder manifestations of histopl in a osmosis, by comparison of results in patients with AIDS and disseminated histoplasmosis in two separate clinical trials. Posaconazole and voriconazole have not been adequately studied. Evidence to date is favorable but is based on anecdotal reports describing treatment in small numbers of cases, usually following some treatment with amphotericin B and/oritraconazole, complicating assessment of the role of the newer azoles.
Hage, CA, Bowyer, S, Tarvin, SE, Helper, D, Kleiman, MB, Joseph, WL. “Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy”. Clin Infect Dis. vol. 50. 2010 Jan 1. pp. 85-92. (Review of histoplasmosis in patients receiving to as blockers, including a discussion of pathogenesis in immunocompromised patients and approach to prevention.)
Hage, CA, Davis, TE, Fuller, D. “Diagnosis of Histoplasmosis by Antigen Detection in BAL Fluid”. Chest. vol. 137. 2010 Mar. pp. 623-8. (Review of diagnosis based on an analysis of bronchoalveolar lavage in specimens.)
Hage, CA, Kirsch, EJ, Stump, TE. “Histoplasma antigen clearance during treatment of histoplasmosis in patients with AIDS determined by a quantitative antigen enzyme immunoassay”. Clin Vaccine Immunol. vol. 18. 2011 Apr. pp. 661-6. (Analysis of antigen clearance for use in monitoring treatment for histoplasmosis.)
Hage, CA, Knox, KS, Wheat, LJ. “Endemic mycoses: overlooked causes of community acquired pneumonia”. Respir Med. vol. 106. 2012 Jun. pp. 769-76. (Up-to-date review of laboratory approach to diagnosis of community acquired pneumonia considering histoplasmosis as a cause.)
Hage, CA, Ribes, JA, Wengenack, NL. “A multicenter evaluation of tests for diagnosis of histoplasmosis”. Clin Infect Dis. vol. 53. 2011 Sep. pp. 448-54. (Review of diagnostic approach in histoplasmosis.)
Kauffman, CA. “Histoplasmosis: a clinical and laboratory update”. Clin Microbiol Rev. vol. 20. 2007 Jan. pp. 115-32. (Up-to-date comprehensive review.)
Swartzentruber, S, Rhodes, L, Kurkjian, K. “Diagnosis of acute pulmonary histoplasmosis by antigen detection”. Clin Infect Dis. vol. 49. 2009 Dec 15. pp. 1878-82. (Review of method for diagnosis of acute pulmonary histoplasmosis, including recent findings in a large number of cases.)
Vinh, DC. “Insights into human antifungal immunity from primary immunodeficiencies”. Lancet Infect Dis. vol. 11. 2011 Oct. pp. 780-92. (Review of rare immunological disorders predisposing to fungal diseases.)
Wheat, LJ, Conces, DJ, Allen, S, Blue-Hnidy, D, Loyd, J. “Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management”. Sem Resp Crit Care Med. vol. 25. 2004. pp. 129-44. (Review of pulmonary histoplasmosis, including complications.)
Wheat, LJ, Freifeld, AG, Kleiman, MB. “Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 45. 2007 Oct 1. pp. 807-25. (Latest IDSA guideline for treatment of histoplasmosis in adults and children.)
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- OVERVIEW: What every clinician needs to know
- Pathogen name and classification
- What is the best treatment?
- Rationale for use of liposomal amphotericin B
- Who should be treated?
- How do patients contract this infection, and how do I prevent spread to other patients?
- What host factors protect against this infection?
- What are the clinical manifestations of infection with this organism?
- What common complications are associated with infection with this pathogen?
- How should I identify the organism?
- How should I diagnose the disease?
- How does this organism cause disease?
- WHAT’S THE EVIDENCE for specific management and treatment recommendations?