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Endemic mycoses: Overlooked causes of community acquired pneumonia

Open ArchivePublished:March 05, 2012DOI:https://doi.org/10.1016/j.rmed.2012.02.004

      Summary

      The endemic mycoses are important but often overlooked causes for community acquired pneumonia. Delays in recognition, diagnosis and proper treatment often lead to disastrous outcomes. This topic is not usually discussed in reviews and guidelines addressing the subject of community acquired pneumonia. In this review we discuss the three major endemic mycoses in North America that present as community acquired pneumonias; Coccidioidomycosis, Histoplasmosis and Blastomycosis. We discuss their epidemiology, clinical presentations, methods of diagnosis and current treatment strategies.

      Keywords

      Introduction

      The endemic mycoses are important but often overlooked causes for community acquired pneumonia (CAP). Of note is that they often occur outside of the traditional endemic area. For example, in a review of endemic mycoses among the elderly, one quarter of cases of coccidioidomycosis occurred outside the southwest United States.
      • Baddley J.W.
      • Winthrop K.L.
      • Patkar N.M.
      • et al.
      Geographic distribution of endemic fungal infections among older persons, United States.
      Not only are the endemic mycoses common causes for hospitalizations, they are often severe, fatal in nearly 10% of cases.
      • Chu J.H.
      • Feudtner C.
      • Heydon K.
      • et al.
      Hospitalizations for endemic mycoses: a population-based national study.
      Surprisingly, deaths occurred overwhelmingly (87%) in nonimmunocompromised subjects. The failure to consider and delay in testing for the endemic mycoses contributes to the poor outcome.

      Coccidioidomycosis

      Epidemiology

      Coccidioidomycosis is a common fungal cause of community acquired pneumonia in the southwest endemic areas,
      • Chang D.C.
      • Anderson S.
      • Wannemuehler K.
      • et al.
      Testing for coccidioidomycosis among patients with community-acquired pneumonia.
      • Kim M.M.
      • Blair J.E.
      • Carey E.J.
      • et al.
      Coccidioidal pneumonia.
      • Valdivia L.
      • Nix D.
      • Wright M.
      • et al.
      Coccidioidomycosis as a common cause of community-acquired pneumonia.
      Table 1. Most infections are acquired through soil disruption and subsequent inhalation of airborne arthroconidia. As such, “haboob” sand storms near Phoenix, Arizona as well as military training exercises in California are frequent culprits of outbreaks.
      Table 1Epidemiologic, clinical and radiographic characteristics.
      ParameterCoccidioidomycosisBlastomycosisHistoplasmosis
      Exposure historySand storms, construction, military exercises, often dry period following rainy seasonsOutdoor activity near waterwaysExposure to soil containing bat or bird droppings, usually unrecognized
      Clinical findingsRespiratory symptoms, fever, fatigue, eosinophiliaRespiratory symptoms, skin or bone lesionsRespiratory symptoms, fever, arthralgia
      Chest radiographs/CTFocal and diffuse infiltrates, cavities, pleural effusion, adenopathy, micronodular infiltratesLobar consolidation, diffuse infiltrates, nodular infiltratesFocal, diffuse or cavitary infiltrates, hilar or mediastinal lymphadenopathy

      Clinical

      Coccidioidomycosis mimics bacterial causes of CAP in healthy individuals and immunocompromised patients. About 60% of people infected are asymptomatic, and of symptomatic cases 95% experience a self-limited infection that resolves after several weeks. Approximately 1% of patients will have disseminated infection with the most common extra thoracic sites being skin, soft tissue, bone, and meninges.
      • Ampel N.M.
      The diagnosis of coccidioidomycosis.
      Symptoms of acute infection resemble bronchitis or pneumonia and are indistinguishable from other causes of community acquired pneumonia,
      • Chang D.C.
      • Anderson S.
      • Wannemuehler K.
      • et al.
      Testing for coccidioidomycosis among patients with community-acquired pneumonia.
      • Kim M.M.
      • Blair J.E.
      • Carey E.J.
      • et al.
      Coccidioidal pneumonia.
      • Galgiani J.N.
      Coccidioidomycosis: a regional disease of national importance. Rethinking approaches for control.
      Table 1. In retrospective studies, patients with coccidioidomycosis were less likely to have cough and sputum production but more likely to have eosinophilia, pleurisy, myalgia, rash, and fatigue than patients without coccidioidomycosis.
      • Kim M.M.
      • Blair J.E.
      • Carey E.J.
      • et al.
      Coccidioidal pneumonia.
      • Valdivia L.
      • Nix D.
      • Wright M.
      • et al.
      Coccidioidomycosis as a common cause of community-acquired pneumonia.
      Eosinophilia occurs in a quarter of cases and may suggest coccidioidal pneumonia or prompt further testing. Although resolution is the norm, chronic progressive, often apical cavitary pneumonia resembling tuberculosis may occur, and peripheral cavities can rupture causing pneumothorax or pyopneumothorax. Pleural manifestations are more prominent in coccidioidomycosis than other endemic fungal diseases.

      Radiographic

      The radiologic findings of acute coccidioidomycosis are diverse and nonspecific. Pulmonary infiltrates are identified in the majority of patients, and pleural effusions and adenopathy are common,
      • Wallace J.M.
      • Catanzaro A.
      • Moser K.M.
      • et al.
      Flexible fiberoptic bronchoscopy for diagnosing pulmonary coccidioidomycosis.
      Table 1. Pulmonary nodules and cavities are identified in less than 5% of cases. Immunosuppressed patients may manifest a diffuse “miliary” pattern.
      • Feldman B.S.
      • Snyder L.S.
      Primary pulmonary coccidioidomycosis.
      CT scans are more sensitive, identifying effusions, hilar lymph nodes, micronodular infiltrates, and multifocal ground glass infiltrates more readily. Mediastinal and hilar adenopathy is common, but not to the degree that is seen in some patients with acute histoplasmosis. Lymph nodes and nodules exhibit varying degrees of uptake on PET scans.
      Small non-calcified nodules are common residua of acute Coccidioides that can be confused with malignancy. Nodules may evolve into thin walled cavities by shelling out the nodule contents. These cavities usually resolve but may be sanctuary for secondary infection or mycetoma, or may cause pneumothorax or hemoptysis.

      Diagnosis

      In a large proportion of community acquired pneumonia patients in the endemic area, diagnostic testing for coccidioidomycosis is not performed.
      • Chang D.C.
      • Anderson S.
      • Wannemuehler K.
      • et al.
      Testing for coccidioidomycosis among patients with community-acquired pneumonia.
      In a large retrospective cohort, patients more likely to be tested for coccidioidomycosis were adults and immunosuppressed patients. Patients who experienced symptoms for >14 days, manifest a rash, or had chest pain were also more likely to be tested.
      • Chang D.C.
      • Anderson S.
      • Wannemuehler K.
      • et al.
      Testing for coccidioidomycosis among patients with community-acquired pneumonia.
      Rapid diagnosis can be achieved by cytopathologic examination of respiratory specimens in patients with lung infiltrates or cavitary disease, positive in one quarter
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      to two-thirds of cases,
      • Wallace J.M.
      • Catanzaro A.
      • Moser K.M.
      • et al.
      Flexible fiberoptic bronchoscopy for diagnosing pulmonary coccidioidomycosis.
      • DiTomasso J.P.
      • Ampel N.M.
      • Sobonya R.E.
      • et al.
      Bronchoscopic diagnosis of pulmonary coccidioidomycosis. Comparison of cytology, culture, and transbronchial biopsy.
      Table 2. Simultaneous transbronchial biopsy may increase the diagnostic yield.
      • DiTomasso J.P.
      • Ampel N.M.
      • Sobonya R.E.
      • et al.
      Bronchoscopic diagnosis of pulmonary coccidioidomycosis. Comparison of cytology, culture, and transbronchial biopsy.
      Nodules may be biopsied to exclude malignancy.
      • Jaroszewski D.E.
      • Halabi W.J.
      • Blair J.E.
      • et al.
      Surgery for pulmonary coccidioidomycosis: a 10-year experience.
      In many patients with negative cytopathology, culture is positive.
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      In patients with milder illnesses, however, cytopathology and culture are performed in only 40–60% of cases, respectively.
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      Despite the availability of more rapid diagnostic methods, culture remains an important part of the diagnostic workup, providing the only basis for diagnosis in some cases.
      Table 2Diagnostic tests in blastomycosis and coccidioidomycosis.
      ParameterCoccidioidomycosisBlastomycosis
      Cytopathology25–50
      • Wallace J.M.
      • Catanzaro A.
      • Moser K.M.
      • et al.
      Flexible fiberoptic bronchoscopy for diagnosing pulmonary coccidioidomycosis.
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      • DiTomasso J.P.
      • Ampel N.M.
      • Sobonya R.E.
      • et al.
      Bronchoscopic diagnosis of pulmonary coccidioidomycosis. Comparison of cytology, culture, and transbronchial biopsy.
      • Sarosi G.A.
      • Lawrence J.P.
      • Smith D.K.
      • et al.
      Rapid diagnostic evaluation of bronchial washings in patients with suspected coccidioidomycosis.
      • Durkin M.
      • Estok L.
      • Hospenthal D.
      • et al.
      Detection of Coccidioides antigenemia following dissociation of immune complexes.
      ,
      Sensitivity in percent (references).
      81
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Culture40–100
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      • DiTomasso J.P.
      • Ampel N.M.
      • Sobonya R.E.
      • et al.
      Bronchoscopic diagnosis of pulmonary coccidioidomycosis. Comparison of cytology, culture, and transbronchial biopsy.
      • Sarosi G.A.
      • Lawrence J.P.
      • Smith D.K.
      • et al.
      Rapid diagnostic evaluation of bronchial washings in patients with suspected coccidioidomycosis.
      • Vucicevic D.
      • Blair J.E.
      • Binnicker M.J.
      • et al.
      The utility of Coccidioides polymerase chain reaction testing in the clinical setting.
      86
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Antibody50–100
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      • DiTomasso J.P.
      • Ampel N.M.
      • Sobonya R.E.
      • et al.
      Bronchoscopic diagnosis of pulmonary coccidioidomycosis. Comparison of cytology, culture, and transbronchial biopsy.
      • Blair J.E.
      • Coakley B.
      • Santelli A.C.
      • et al.
      Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts.
      • Sarosi G.A.
      • Lawrence J.P.
      • Smith D.K.
      • et al.
      Rapid diagnostic evaluation of bronchial washings in patients with suspected coccidioidomycosis.
      • Vucicevic D.
      • Blair J.E.
      • Binnicker M.J.
      • et al.
      The utility of Coccidioides polymerase chain reaction testing in the clinical setting.
      32
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Antigenuria50–71
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      • Durkin M.
      • Estok L.
      • Hospenthal D.
      • et al.
      Detection of Coccidioides antigenemia following dissociation of immune complexes.
      55–93
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Bariola J.R.
      • Hage C.A.
      • Durkin M.
      • et al.
      Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis.
      • Keane C.
      • Chapman R.
      Evaluating nurses’ knowledge and skills in the detection of child abuse in the emergency department.
      Antigenemia70
      • Durkin M.
      • Estok L.
      • Hospenthal D.
      • et al.
      Detection of Coccidioides antigenemia following dissociation of immune complexes.
      80
      • Bariola J.R.
      • Hage C.A.
      • Durkin M.
      • et al.
      Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis.
      Antigen BALSingle case
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      80
      • Hage C.A.
      • Davis T.E.
      • Fuller D.
      • et al.
      Diagnosis of histoplasmosis by antigen detection in BAL fluid.
      PCR56–100
      • Vucicevic D.
      • Blair J.E.
      • Binnicker M.J.
      • et al.
      The utility of Coccidioides polymerase chain reaction testing in the clinical setting.
      • Binnicker M.J.
      • Buckwalter S.P.
      • Eisberner J.J.
      • et al.
      Detection of Coccidioides species in clinical specimens by real-time PCR.
      86
      • Babady N.E.
      • Buckwalter S.P.
      • Hall L.
      • et al.
      Detection of Blastomyces dermatitidis and Histoplasma capsulatum from culture isolates and clinical specimens by use of real-time PCR.
      a Sensitivity in percent (references).
      Serologic tests for antibodies are the most widely used method of diagnosis and are perhaps more useful in diagnosing coccidioidal infection than the other endemic mycoses. IgM specific for the tube precipitin antigen and IgG specific for the complement fixation antigen can be assayed locally by commercially available immunodiffusion kits or enzyme-linked immunoassay (EIA).
      • Ampel N.M.
      The diagnosis of coccidioidomycosis.
      IgG antibody to the complement fixation antigen, when positive, can be quantified at reference laboratories and reported as a titer. Any positive titer is considered significant and indicative of recent infection. Titers are often followed in symptomatic patients or patients with chronic infection to determine treatment efficacy and resolution.
      Both EIA and agar gel immunodiffusion provide results with a quick turnaround time. However, controversy arises over the accuracy of IgM antibodies determined by EIA: 100% were judged to be true positives in one
      • Blair J.E.
      • Currier J.T.
      Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis.
      but 82% were regarded as false positive in another
      • Kuberski T.
      • Herrig J.
      • Pappagianis D.
      False-positive IgM serology in coccidioidomycosis.
      report. An isolated positive IgM should be confirmed by additional diagnostic testing.
      • Blair J.E.
      • Currier J.T.
      Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis.
      Additionally, the antibody test may be falsely negative early in the course of infection or in immunosuppressed patients
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      • DiTomasso J.P.
      • Ampel N.M.
      • Sobonya R.E.
      • et al.
      Bronchoscopic diagnosis of pulmonary coccidioidomycosis. Comparison of cytology, culture, and transbronchial biopsy.
      • Blair J.E.
      • Coakley B.
      • Santelli A.C.
      • et al.
      Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts.
      • Sarosi G.A.
      • Lawrence J.P.
      • Smith D.K.
      • et al.
      Rapid diagnostic evaluation of bronchial washings in patients with suspected coccidioidomycosis.
      • Vucicevic D.
      • Blair J.E.
      • Binnicker M.J.
      • et al.
      The utility of Coccidioides polymerase chain reaction testing in the clinical setting.
      False negative EIA was noted in 13% of healthy patients and 33% of immunosuppressed patients, declining to 5% and 17%, respectively when confirmatory tests were performed.
      • Blair J.E.
      • Coakley B.
      • Santelli A.C.
      • et al.
      Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts.
      Antibody tests also may be negative early in the disease,
      • Blair J.E.
      • Coakley B.
      • Santelli A.C.
      • et al.
      Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts.
      as noted in half of cases in one study.
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      Thus, negative antibody tests cannot exclude coccidioidomycosis.
      • Saubolle M.A.
      Laboratory aspects in the diagnosis of coccidioidomycosis.
      Coccidioides galactomannan antigen testing is available in select reference laboratories. Antigenuria was detected in 50% of patients with moderate
      • Durkin M.
      • Estok L.
      • Hospenthal D.
      • et al.
      Detection of Coccidioides antigenemia following dissociation of immune complexes.
      and 71% with moderate to severe disease, among whom tests for antibodies were positive in 54%.
      • Durkin M.
      • Connolly P.
      • Kuberski T.
      • et al.
      Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay.
      Antigenemia was detected in 73% of patients with mild to moderate disease, identifying an additional 29% of cases that would have been missed if only urine was tested.
      • Durkin M.
      • Estok L.
      • Hospenthal D.
      • et al.
      Detection of Coccidioides antigenemia following dissociation of immune complexes.
      Thus, the greatest sensitivity may be achieved by testing both urine and serum. Antigen also has been detected in BAL in patients with negative results in urine.
      • Kuberski T.
      • Myers R.
      • Wheat L.J.
      • et al.
      Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen.
      Real-time PCR targeting the internal transcribed spacer region 2 sequences exhibited a sensitivity of 100% on respiratory samples, 93% on fresh tissue and 73% on paraffin-embedded tissue, with a specificity of 98–100%.
      • Binnicker M.J.
      • Buckwalter S.P.
      • Eisberner J.J.
      • et al.
      Detection of Coccidioides species in clinical specimens by real-time PCR.
      In clinical testing PCR was positive in respiratory specimens in five of nine patients, most of whom were immunosuppressed and culture positive.
      • Vucicevic D.
      • Blair J.E.
      • Binnicker M.J.
      • et al.
      The utility of Coccidioides polymerase chain reaction testing in the clinical setting.
      The relative sensitivity of real-time PCR and antigen detection remains to be determined.

      Management

      In the context of community acquired pneumonia, the decision of whether or not to treat with anti-fungal therapy is based on clinical context and severity of symptoms. When treatment is deemed necessary, azole therapy is preferred. In most cases of acute pulmonary coccidioidomycosis presenting as CAP, fluconazole or itraconazole 400 mg daily for 3–6 months is sufficient. Fluconazole is often used as itraconazole requires closer monitoring with drug levels and careful consideration of drug interactions.
      • Galgiani J.N.
      • Catanzaro A.
      • Cloud G.A.
      • et al.
      Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group.
      Longer therapy (12–18 months) is recommended for cavitary, diffuse pulmonary or disseminated disease.
      Lipid formulation of amphotericin B is recommended in patients with extensive, bilateral, or “miliary” pneumonia, or disseminated disease in immunocompromised patients. Patients are frequently transitioned to fluconazole or itraconazole after a week or two and therapy continued for at least 12 months,
      • Galgiani J.N.
      • Ampel N.M.
      • Blair J.E.
      • et al.
      Coccidioidomycosis.
      Table 3. Concomitant steroid therapy may be appropriate if paradoxical worsening or delayed improvement occurs with anti-fungal therapy alone for severe pulmonary coccidioidomycosis. Amphotericin should be used in pregnancy due to concerns regarding the teratogenicity of azole anti-fungal agents, especially in the first trimester.
      Table 3Guidelines for treatment of endemic mycoses based on consensus group recommendations.
      ParameterCoccidioidomycosis
      • Galgiani J.N.
      • Ampel N.M.
      • Blair J.E.
      • et al.
      Coccidioidomycosis.
      • Limper A.H.
      • Knox K.S.
      • Sarosi G.A.
      • et al.
      An official American thoracic society statement: treatment of fungal infections in adult pulmonary and critical care patients.
      Blastomycosis
      • Chapman S.W.
      • Dismukes W.E.
      • Proia L.A.
      • et al.
      Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.
      • Limper A.H.
      • Knox K.S.
      • Sarosi G.A.
      • et al.
      An official American thoracic society statement: treatment of fungal infections in adult pulmonary and critical care patients.
      Histoplasmosis
      • Limper A.H.
      • Knox K.S.
      • Sarosi G.A.
      • et al.
      An official American thoracic society statement: treatment of fungal infections in adult pulmonary and critical care patients.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Severe (ICU)Lipid amphotericin B 1–2 week then fluconazole or itraconazoleLipid amphotericin B, 1–2 week then itraconazoleLipid amphotericin B 1–2 week then itraconazole
      Consider systemic corticosteroids in patients with ARDS.
      Moderately severe (hospitalize)Lipid amphotericin B 1–2 week then fluconazole or itraconazoleLipid amphotericin B 1–2 week then itraconazoleLipid amphotericin B 1–2 week then itraconazole
      Consider systemic corticosteroids in patients with ARDS.
      Mild (not hospitalize)Fluconazole or itraconazoleItraconazoleItraconazole
      a Consider systemic corticosteroids in patients with ARDS.
      Asymptomatic pulmonary nodules and small thin walled cavities are not typically treated with antifungals. Occasionally nodules change size and extirpate their contents. However, they can be confused with malignancy when a diagnosis of coccidioidomycosis was not previously secured. When unclear, residual nodules frequently lead to biopsy or excision.

      Blastomycosis

      Epidemiology

      The endemic area for blastomycosis overlaps with that of histoplasmosis, but stretches further north into Minnesota, Wisconsin, the Canadian provinces adjacent to the great lakes and the areas surrounding St. Lawrence Seaway in New York and Canada.
      • Baddley J.W.
      • Winthrop K.L.
      • Patkar N.M.
      • et al.
      Geographic distribution of endemic fungal infections among older persons, United States.
      Blastomycosis is less common than histoplasmosis and coccidioidomycosis.
      • Chu J.H.
      • Feudtner C.
      • Heydon K.
      • et al.
      Hospitalizations for endemic mycoses: a population-based national study.
      Recent excavation activity and residence near waterways are risk factors for blastomycosis, (Table 1).
      • Baumgardner D.J.
      • Brockman K.
      Epidemiology of human blastomycosis in Vilas County, Wisconsin. II: 1991–1996.
      Point source outbreaks have been reported where most patients present with an acute illness after heavy exposure to contaminated excavation sites. The incubation period ranges from 21 to 106 days with a median of 45 days.
      • Klein B.S.
      • Vergeront J.M.
      • Weeks R.J.
      • et al.
      Isolation of Blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in Wisconsin.

      Clinical

      The lungs are the most commonly affected organs in blastomycosis.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Chapman S.W.
      • Dismukes W.E.
      • Proia L.A.
      • et al.
      Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.
      The majority of infected individuals are either asymptomatic or manifest a mild self-limited illness.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Also, most patients are otherwise healthy.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Acute pulmonary blastomycosis is commonly seen in the setting of an outbreak following heavy, point source exposure. Symptoms are abrupt and include cough productive of purulent sputum, fever, night sweats, dyspnea, chest pain, weight loss, myalgia and occasionally hemoptysis, (Table 1). The illness is often confused with bacterial community acquired pneumonia, and the diagnosis is suspected only after failure to respond to antibacterial therapy.
      • Kralt D.
      • Light B.
      • Cheang M.
      • et al.
      Clinical characteristics and outcomes in patients with pulmonary blastomycosis.
      • Carlos W.G.
      Seeing is believing.
      In one series, diagnosis took more than 30 days in 43% of the cases, with only one quarter diagnosed within a week of presentation.
      • Chapman S.W.
      • Lin A.C.
      • Hendricks K.A.
      • et al.
      Endemic blastomycosis in Mississippi: epidemiological and clinical studies.
      The illness may rapidly progresses to acute respiratory distress syndrome (ARDS) and shock in about 10% of cases
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Smith J.A.
      • Kauffman C.A.
      Blastomycosis.
      with up to 60% mortality.
      • Kralt D.
      • Light B.
      • Cheang M.
      • et al.
      Clinical characteristics and outcomes in patients with pulmonary blastomycosis.
      Delays in considering and testing for blastomycosis contribute to this poor outcome. Severe pulmonary blastomycosis is more common in young immunocompromised patients
      • Lemos L.B.
      • Baliga M.
      • Guo M.
      Blastomycosis: the great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients.
      • Pappas P.G.
      • Threlkeld M.G.
      • Bedsole G.D.
      • et al.
      Blastomycosis in immunocompromised patients.
      and those with diabetes mellitus.
      • Kralt D.
      • Light B.
      • Cheang M.
      • et al.
      Clinical characteristics and outcomes in patients with pulmonary blastomycosis.
      Chronic pulmonary blastomycosis is usually gradual in onset, and symptoms include cough productive of purulent sputum, fever, night sweats, malaise, and weight loss.
      • Davies S.F.
      • Sarosi G.A.
      Epidemiological and clinical features of pulmonary blastomycosis.
      The illness can be mistaken for tuberculosis or lung cancer, and is progressive if untreated.
      • Davies S.F.
      • Sarosi G.A.
      Epidemiological and clinical features of pulmonary blastomycosis.
      Extrapulmonary dissemination occurs in up to third of cases,
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Lemos L.B.
      • Guo M.
      • Baliga M.
      Blastomycosis: organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi.
      most commonly involving skin, bone, and the genitourinary system. Cutaneous or bone lesions in a patient with community acquired pneumonia who resides in the endemic area should raise the suspicion for blastomycosis. Dissemination to the central nervous system may also occur.
      • Bariola J.R.
      • Perry P.
      • Pappas P.G.
      • et al.
      Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era.

      Radiographic

      No specific radiographic findings are characteristic enough to suggest the diagnosis of blastomycosis. The most common findings in acute pulmonary blastomycosis include lobar consolidation, air bronchogram, and nodular infiltrates,
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Patel R.G.
      • Patel B.
      • Petrini M.F.
      • et al.
      Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases.
      • Ronald S.
      • Strzelczyk J.
      • Moore S.
      • et al.
      Computed tomographic scan evaluation of pulmonary blastomycosis.
      Table 1. Miliary nodules and interstitial infiltrates are common in severe cases.
      • Ronald S.
      • Strzelczyk J.
      • Moore S.
      • et al.
      Computed tomographic scan evaluation of pulmonary blastomycosis.
      Mediastinal or hilar lymphadenopathy
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      and pleural effusions are infrequent.
      • Winer-Muram H.T.
      • Beals D.H.
      • Cole Jr., F.H.
      Blastomycosis of the lung: CT features.
      Mass like lesions, often mistaken as malignancy, and cavities within areas of consolidation can be seen in chronic cases.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.

      Diagnosis

      The diagnosis is often delayed because of failure to consider blastomycosis in patients with community acquired pneumonia.
      • Chapman S.W.
      • Lin A.C.
      • Hendricks K.A.
      • et al.
      Endemic blastomycosis in Mississippi: epidemiological and clinical studies.
      If suspected, the diagnosis usually can be made rapidly by microscopic visualization of the organism or detection of antigen in body fluids,
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Grim S.A.
      • Proia L.
      • Miller R.
      • et al.
      A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.
      (Table 2). The yield of cytopathology ranges from 38% to 97%.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Lemos L.B.
      • Soofi M.
      • Amir E.
      Blastomycosis and pregnancy.
      • Martynowicz M.A.
      • Prakash U.B.S.
      Pulmonary blastomycosis: an appraisal of diagnostic techniques.
      Histopathology of lung tissue biopsy specimen may provide a diagnosis in some cases with negative cytology.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Taxy J.B.
      Blastomycosis: contributions of morphology to diagnosis: a surgical pathology, cytopathology, and autopsy pathology study.
      Definitive diagnosis requires the isolation of the organism by culture which is positive in 67–86% of cases,
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Patel A.J.
      • Gattuso P.
      • Reddy V.B.
      Diagnosis of blastomycosis in surgical pathology and cytopathology: correlation with microbiologic culture.
      often within one week of incubation.
      Blastomyces antigen can be detected in serum, urine and BAL fluid, often providing the initial basis for diagnosis,
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Grim S.A.
      • Proia L.
      • Miller R.
      • et al.
      A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.
      positive in 85%–93% of patients.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Bariola J.R.
      • Hage C.A.
      • Durkin M.
      • et al.
      Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis.
      • Durkin M.
      • Witt J.
      • Lemonte A.
      • et al.
      Antigen assay with the potential to aid in diagnosis of blastomycosis.
      Testing both serum and urine may improve the sensitivity for diagnosis by antigen detection. Cross reactions occur in histoplasmosis (96–100%),
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Bariola J.R.
      • Hage C.A.
      • Durkin M.
      • et al.
      Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis.
      • Durkin M.
      • Witt J.
      • Lemonte A.
      • et al.
      Antigen assay with the potential to aid in diagnosis of blastomycosis.
      paracoccidioidomycosis (100%), and penicilliosis marneffei (70%); otherwise specificity is 98% with other mycoses (cryptococcosis, aspergillosis, coccidioidomycosis, and candidiasis).
      • Durkin M.
      • Witt J.
      • Lemonte A.
      • et al.
      Antigen assay with the potential to aid in diagnosis of blastomycosis.
      PCR methods are promising. Excellent sensitivity and specificity was reported using a real-time method on isolates and clinical specimen.
      • Babady N.E.
      • Buckwalter S.P.
      • Hall L.
      • et al.
      Detection of Blastomyces dermatitidis and Histoplasma capsulatum from culture isolates and clinical specimens by use of real-time PCR.
      This finding requires validation before the role of PCR is known.
      Available tests for antibodies to Blastomyces are not used commonly because of poor sensitivity (<50%)
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      and specificity, however accuracy may be improved using certain Blastomyces antigens.
      • Soufleris A.J.
      • Klein B.S.
      • Courtney B.T.
      • et al.
      Utility of anti-WI-1 serological testing in the diagnosis of blastomycosis in Wisconsin residents.

      Management

      Treatment is recommended unless clinical resolution has occurred before the diagnosis is made.
      • Chapman S.W.
      • Dismukes W.E.
      • Proia L.A.
      • et al.
      Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.
      • Limper A.H.
      • Knox K.S.
      • Sarosi G.A.
      • et al.
      An official American thoracic society statement: treatment of fungal infections in adult pulmonary and critical care patients.
      A lipid formulation of Amphotericin B is recommended for patients with severe or CNS disease, (Table 3). Amphotericin B is usually administered until there is clinical improvement (1–2 weeks) except in patients with CNS diseases, in which 4–6 weeks is recommended. Itraconazole is administered for 6–12 months after discontinuation of amphotericin B.
      Itraconazole is the treatment of choice for non-severe cases.
      • Dismukes W.E.
      • Bradsher Jr., R.W.
      • Cloud G.C.
      • et al.
      Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group.
      The recommended dose is 200 mg three times a day for three days followed by 200 mg twice a day for at least six months. A Longer treatment is recommended for immunosuppressed patients, those with bone disease, and those who relapse. Fluconazole is less effective and is not recommended except in patients who do not tolerate itraconazole, and then should be administered at high doses (800 mg/day). Voriconazole has been used
      • Freifeld A.
      • Proia L.
      • Andes D.
      • et al.
      Voriconazole use for endemic fungal infections.
      but its role remains unclear. Corticosteroids may be useful adjuncts to anti-fungal therapy in patients with ARDS.
      • Lahm T.
      • Neese S.
      • Thornburg A.T.
      • et al.
      Corticosteroids for blastomycosis-induced ARDS: a report of two patients and review of the literature.
      • Plamondon M.
      • Lamontagne F.
      • Allard C.
      • et al.
      Corticosteroids as adjunctive therapy in severe blastomycosis-induced acute respiratory distress syndrome in an immunosuppressed patient.

      Histoplasmosis

      Epidemiology

      Histoplasmosis is a community acquired infection, most often presenting as pneumonia. Most cases are first treated with antibiotics and the diagnosis is not suspected until they fail to improve. Except in outbreak settings where multiple individuals become ill following a shared activity and present acutely with diffuse pulmonary infiltrates, a history of exposure to sites likely to harbor Histoplasma mold is uncommon. Some epidemiologic clues are listed in Table 1.

      Clinical

      There are no unique clinical findings to alert the physician to suspect histoplasmosis. Patients present with cough, chest pain, fever, sweats and malaise, usually occurring between one and three weeks following a high-inoculum exposure,
      • Hage C.A.
      • Wheat L.J.
      • Loyd J.
      • et al.
      Pulmonary histoplasmosis.
      • Wheat L.J.
      • Conces D.
      • Allen S.D.
      • et al.
      Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management.
      described as the “epidemic” type of acute pulmonary histoplasmosis, Table 1
      • Rubin H.
      • Lehan P.H.
      • Furcolow M.L.
      Severe nonfatal histoplasmosis; report of a typical case, with comments on therapy.
      . Severe cases may culminate in respiratory failure
      • Ronald S.
      • Strzelczyk J.
      • Moore S.
      • et al.
      Computed tomographic scan evaluation of pulmonary blastomycosis.
      • Sollod N.
      Acute fulminating disseminated histoplasmosis. Report of an unusual outbreak.
      and death.
      • Sollod N.
      Acute fulminating disseminated histoplasmosis. Report of an unusual outbreak.
      Low-level exposure causes mild flu-like illness often lasting for more than a month, referred to herein as subacute pulmonary histoplasmosis.
      • Wheat L.J.
      • Conces D.
      • Allen S.D.
      • et al.
      Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management.
      • Hage C.A.
      • Wheat L.J.
      Diagnosis of pulmonary histoplasmosis using antigen detection in the bronchoalveolar lavage.
      • Wheat L.J.
      • Slama T.G.
      • Eitzen H.E.
      • et al.
      A large urban outbreak of histoplasmosis: clinical features.
      Although self-limited, patients often undergo unneeded invasive procedures, receive repeated courses of antibiotic therapy, and miss school or work, at a substantial cost.
      Patients with underlying obstructive lung disease typically experience chronic pulmonary symptoms accompanied by progressive lung infiltrates with cavitation, termed chronic pulmonary histoplasmosis.
      • Wheat L.J.
      • Conces D.
      • Allen S.D.
      • et al.
      Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management.
      Cavitation and chronicity may suggest anaerobic infection, for which repeated courses antibiotics are prescribed without clinical benefit before histoplasmosis is suspected.

      Radiographic

      Chest radiographs or CT scans in acute pulmonary histoplasmosis show diffuse reticulonodular or miliary infiltrates, at times accompanied by mediastinal or hilar lymphadenopathy
      • Rubin H.
      • Lehan P.H.
      • Furcolow M.L.
      Severe nonfatal histoplasmosis; report of a typical case, with comments on therapy.
      Table 4. Similar findings may be seen in patients with progressive disseminated histoplasmosis,
      • Conces Jr., D.J.
      • Stockberger S.M.
      • Tarver R.D.
      • et al.
      Disseminated histoplasmosis in AIDS: findings on chest radiographs.
      which should be suspected in the absence of an acute exposure or the presence of immunosuppression. Findings in subacute pulmonary histoplasmosis include hilar or mediastinal lymphadenopathy with localized or patchy infiltrates.
      • Wheat L.J.
      • Conces D.
      • Allen S.D.
      • et al.
      Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management.
      With healing infiltrates may regress into nodules, which eventually calcify but may cavitate. Imaging studies in chronic pulmonary histoplasmosis show changes of underlying emphysema, upper lobes infiltrates, pleural thickening, volume loss and cavitation, resembling those seen in tuberculosis.
      • Wheat L.J.
      • Conces D.
      • Allen S.D.
      • et al.
      Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management.
      Table 4Diagnostic tests in histoplasmosis.
      ParameterAcute pulmonary histoplasmosisSubacute pulmonary histoplasmosisChronic pulmonary histoplasmosis
      Cytopathology2/10
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      8/19
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      3/4
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      0/2
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      1/11
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      1/6
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      2/24
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      0/5
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Culture8/19
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      14/26
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      4/4
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      0/3
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      5/34
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      11/13
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      11/128
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      11/17
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Antibody18/28
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      39/41
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      5/6
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      4/6
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      67/68
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      14/14
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      151/176
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      14/15
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Antigenemia23/29
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      5/20
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      1/5
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Antigenuria13/29
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      14/46
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      4/5
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      5/6
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      22/65
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      2/14
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      Antigen BAL3/4
      • Hage C.A.
      • Davis T.E.
      • Fuller D.
      • et al.
      Diagnosis of histoplasmosis by antigen detection in BAL fluid.
      2/2
      • Hage C.A.
      • Knox K.S.
      • Davis T.E.
      • et al.
      Antigen detection in bronchoalveolar lavage fluid for diagnosis of fungal pneumonia.
      5/5
      • Hage C.A.
      • Davis T.E.
      • Fuller D.
      • et al.
      Diagnosis of histoplasmosis by antigen detection in BAL fluid.

      Diagnosis

      Demonstration of yeast by cytology or histopathology may provide a rapid diagnosis with high specificity but with lower sensitivity than antigen or antibody detection. Isolation of the organism by culture may provide the only laboratory basis for diagnosis in some patients, but requires at least one week and often up to four weeks to detect positive results. The role of PCR remains to be determined. Good sensitivity and specificity was reported,
      • Babady N.E.
      • Buckwalter S.P.
      • Hall L.
      • et al.
      Detection of Blastomyces dermatitidis and Histoplasma capsulatum from culture isolates and clinical specimens by use of real-time PCR.
      but only six BAL specimens and five other respiratory specimens were tested, of which four BALs were negative. Other studies have shown that PCR was not sensitive when testing BAL
      • Tang Y.W.
      • Li H.
      • Durkin M.M.
      • et al.
      Urine polymerase chain reaction is not as sensitive as urine antigen for the diagnosis of disseminated histoplasmosis.
      • Wheat L.J.
      Improvements in diagnosis of histoplasmosis.
      and that PCR was less sensitive than pathology when applied to tissues.
      • Bialek R.
      • Feucht A.
      • Aepinus C.
      • et al.
      Evaluation of two nested PCR assays for detection of Histoplasma capsulatum DNA in human tissue.
      Acute pulmonary histoplasmosis: Antigen detection is the most sensitive diagnostic test in acute pulmonary histoplasmosis (Table 4).
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      Both urine and serum must be tested achieve the highest sensitivity: 38% of cases would have been missed by testing urine only, based on findings in one study.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      The sensitivity of cytopathology of respiratory specimens is uncertain, but probably low, based upon a review of the findings in published studies.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      Serologic tests for anti-Histoplasma antibodies are positive in about two-thirds of cases,
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      but not during the first three weeks of infection, based on one report,
      • Wheat L.J.
      Histoplasmosis in Indianapolis.
      when diagnosis is often most valuable. Respiratory cultures are positive less than half of cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      Subacute pulmonary histoplasmosis: As most patients have been ill for more than a month before testing is performed, and antibody tests are usually positive.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Accordingly, agar gel immunodiffusion and/or complement fixing antibodies are positive in 95% of cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      The complement fixation test is positive at titers of at least 1:8 in 90%, M bands in three quarters, and H bands in one quarter of patients.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      CF titers of 1:8 or 1:16 are less helpful in differentiating active from past infection, but occur in a third of acute cases, and should not be disregarded.
      Many physicians presume antibody testing is not useful because antibodies are present in most individuals from endemic areas, mimicking skin test positivity. However, the agar gel immunodiffusion was positive in only 0.5% and complement fixation test in 4% of healthy young adults from cities where Histoplasmin skin test positivity exceeded 50%, usually at titers of 1:8 or 1:16, as noted in one report.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Tests for antigenuria are positive in about one-third of cases, histopathology or cytology in 10–40%
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      and culture in 10–50%,
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      if invasive procedures are performed. However, the diagnosis can usually be made by serology, avoiding biopsies.
      Chronic pulmonary histoplasmosis: Culture of respiratory specimens, antigen testing of BAL or bronchial washings, and tests for antibodies are most useful. Cultures were positive in 65–85% of cases.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Culture of sputum when cultures of BAL and/or bronchial washings are negative. Antibody tests are positive in over 90% of cases in most series.
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat J.
      • French M.L.
      • Kohler R.B.
      • et al.
      The diagnostic laboratory tests for histoplasmosis: analysis of experience in a large urban outbreak.
      Antigen was detected in the urine of 14% of cases in one report
      • Carlos W.G.
      • Rose A.S.
      • Wheat L.J.
      • et al.
      Blastomycosis in Indiana: digging up more cases.
      and 80% in another, using a more sensitive assay.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      Detection of high levels of antigenuria, however, suggests concurrent progressive disseminated histoplasmosis.
      • Hage C.A.
      • Ribes J.A.
      • Wengenack N.L.
      • et al.
      A multicenter evaluation of tests for diagnosis of histoplasmosis.
      • Wheat L.J.
      • Kohler R.B.
      • Tewari R.P.
      Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens.

      Management

      Lipid amphotericin B and itraconazole are preferred for treatment of histoplasmosis.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Liposomal amphotericin B was superior to the deoxycholate formulation for treatment of progressive disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome.
      • Johnson P.C.
      • Wheat L.J.
      • Cloud G.A.
      • et al.
      Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS.
      Several studies have established effectiveness of itraconazole for treatment of mild to moderately severe histoplasmosis, reviewed elsewhere.
      • Wheat J.
      • Sarosi G.
      • McKinsey D.
      • et al.
      Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America.
      Itraconazole blood level monitoring is recommended as levels are highly variable.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Drug interactions must also be considered.
      Acute pulmonary histoplasmosis: Although most patients recover without therapy,
      • Rubin H.
      • Furcolow M.L.
      • Yates J.L.
      • et al.
      The course and prognosis of histoplasmosis.
      the clinical findings may be severe, recovery may be slow, and death may occur.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      Accordingly, most patients should be treated.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      The anecdotal experience supports treatment efficacy for acute pulmonary histoplasmosis.
      • Swartzentruber S.
      • Rhodes L.
      • Kurkjian K.
      • et al.
      Diagnosis of acute pulmonary histoplasmosis by antigen detection.
      Lipid amphotericin B is recommended in those who are hypoxic, accompanied by corticosteroids for the first week or two.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Patients with milder illnesses may be treated with itraconazole alone, 200 mg once or twice daily. The optimal duration of therapy is unknown, but a six to 12 week course is recommended.
      Subacute pulmonary histoplasmosis: Most patients with have mild symptoms and have improved by the time the diagnosis is established. Thus, anti-fungal therapy is usually unnecessary. Itraconazole 200 mg once or twice daily given for six to 12 weeks may be helpful in those who remain symptomatic for more than one month.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Chronic pulmonary histoplasmosis: Treatment is indicated in all patients with chronic pulmonary histoplasmosis.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Treatment reduces symptoms, eradicates the organism from respiratory specimens, and reduces pulmonary infiltrates.
      • Furcolow M.L.
      Comparison of treated and untreated severe histoplasmosis.
      • Murray J.F.
      • Howard D.
      Histoplasmosis cooperative study. II. Chronic pulmonary histoplasmosis treated with and without amphotericin B.
      Itraconazole 200 mg once or twice daily is recommended for at least 12 months, and until the chest imaging shows no further improvement. Relapse occurs in about 15% of cases followed for 1–2 years.
      • Wheat L.J.
      • Wass J.
      • Norton J.
      • et al.
      Cavitary histoplasmosis occurring during two large urban outbreaks. Analysis of clinical, epidemiologic, roentgenographic, and laboratory features.

      Funding

      This work was supported by a VA Career Development Award (CDA-2) to C. A. Hage.

      Conflict of interest statement

      Dr. L.J. Wheat is an employee of MiraVista Diagnostics, the laboratory that provides the Histoplasma, Blastomyces and Coccidioidomyces antigens.

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