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provided by Elsevier - Publisher Connector Respiratory Medicine (2012) 106, 769e776

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REVIEW Endemic mycoses: Overlooked causes of community acquired

Chadi A. Hage a,*, Kenneth S. Knox b, Lawrence J. Wheat c

a Pulmonary-Critical Care and Infectious Diseases, Indiana University and Richard L. Roudebush VA Medical Center, 1481 W. 10th St., 111P-IU, Indianapolis, IN, USA b University of Arizona, Tucson, AZ, USA c MiraVista Diagnostics and Mirabella Technologies, Indianapolis, IN, USA

Received 31 October 2011; accepted 10 February 2012 Available online 3 March 2012

KEYWORDS Summary Community acquired The endemic mycoses are important but often overlooked causes for community acquired pneumonia; pneumonia. Delays in recognition, diagnosis and proper treatment often lead to disastrous Endemic mycosis; 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 ; Coccidioidomycosis, Histo- Blastomycosis plasmosis and Blastomycosis. We discuss their epidemiology, clinical presentations, methods of diagnosis and current treatment strategies. Published by Elsevier Ltd.

Contents

Introduction ...... 770 Coccidioidomycosis ...... 770 Epidemiology ...... 770 Clinical ...... 770 Radiographic ...... 770 Diagnosis ...... 771 Management ...... 771 Blastomycosis ...... 772 Epidemiology ...... 772

* Corresponding author. Tel.: þ1 317 988 3811; fax: þ1 317 988 3976. E-mail address: [email protected] (C.A. Hage).

0954-6111/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.rmed.2012.02.004 770 C.A. Hage et al.

Clinical ...... 772 Radiographic ...... 772 Diagnosis ...... 772 Management ...... 773 Histoplasmosis ...... 773 Epidemiology ...... 773 Clinical ...... 773 Radiographic ...... 773 Diagnosis ...... 773 Management ...... 774 Funding ...... 774 Conflict of interest statement ...... 774 References ...... 774

Introduction symptomatic cases 95% experience a self-limited that resolves after several weeks. Approximately 1% of The endemic mycoses are important but often overlooked patients will have disseminated infection with the most common extra thoracic sites being skin, soft tissue, bone, causes for community acquired pneumonia (CAP). Of note is 6 that they often occur outside of the traditional endemic and meninges. Symptoms of acute infection resemble or pneumonia and are indistinguishable from area. For example, in a review of endemic mycoses among 3,4,7 the elderly, one quarter of cases of coccidioidomycosis other causes of community acquired pneumonia, occurred outside the southwest United States.1 Not only are Table 1. In retrospective studies, patients with coccidioi- the endemic mycoses common causes for hospitalizations, domycosis were less likely to have cough and sputum they are often severe, fatal in nearly 10% of cases.2 production but more likely to have eosinophilia, , myalgia, rash, and fatigue than patients without coccidi- Surprisingly, deaths occurred overwhelmingly (87%) in 4,5 nonimmunocompromised subjects. The failure to consider oidomycosis. Eosinophilia occurs in a quarter of cases and and delay in testing for the endemic mycoses contributes to may suggest coccidioidal pneumonia or prompt further the poor outcome. testing. Although resolution is the norm, chronic progres- sive, often apical cavitary pneumonia resembling tubercu- losis may occur, and peripheral cavities can rupture causing Coccidioidomycosis or pyopneumothorax. Pleural manifestations are more prominent in coccidioidomycosis than other Epidemiology endemic fungal diseases. Coccidioidomycosis is a common fungal cause of community acquired pneumonia in the southwest endemic areas,3e5 Radiographic Table 1. Most are acquired through soil disrup- The radiologic findings of acute coccidioidomycosis are tion and subsequent inhalation of airborne arthroconidia. diverse and nonspecific. Pulmonary infiltrates are identified As such, “haboob” sand storms near Phoenix, Arizona as in the majority of patients, and pleural effusions and well as military training exercises in California are frequent adenopathy are common,8 Table 1. Pulmonary nodules and culprits of outbreaks. cavities are identified in less than 5% of cases. Immuno- suppressed patients may manifest a diffuse “miliary” Clinical pattern.9 CT scans are more sensitive, identifying effusions, Coccidioidomycosis mimics bacterial causes of CAP in hilar lymph nodes, micronodular infiltrates, and multifocal healthy individuals and immunocompromised patients. ground glass infiltrates more readily. Mediastinal and hilar About 60% of people infected are asymptomatic, and of adenopathy is common, but not to the degree that is seen

Table 1 Epidemiologic, clinical and radiographic characteristics. Parameter Coccidioidomycosis Blastomycosis Histoplasmosis Exposure history Sand storms, construction, Outdoor activity near Exposure to soil containing military exercises, often dry waterways bat or bird droppings, period following rainy seasons usually unrecognized Clinical findings Respiratory symptoms, fever, Respiratory symptoms, Respiratory symptoms, fever, fatigue, eosinophilia skin or bone lesions arthralgia Chest radiographs/CT Focal and diffuse infiltrates, Lobar consolidation, Focal, diffuse or cavitary cavities, , diffuse infiltrates, infiltrates, hilar or mediastinal adenopathy, micronodular infiltrates nodular infiltrates lymphadenopathy Endemic mycoses CAP 771 in some patients with acute histoplasmosis. Lymph nodes 100% were judged to be true positives in one14 but 82% were and nodules exhibit varying degrees of uptake on PET scans. regarded as false positive in another15 report. An isolated Small non-calcified nodules are common residua of acute positive IgM should be confirmed by additional diagnostic Coccidioides that can be confused with malignancy. testing.14 Additionally, the antibody test may be falsely Nodules may evolve into thin walled cavities by shelling out negative early in the course of infection or in immunosup- the nodule contents. These cavities usually resolve but may pressed patients11,12,16e18 False negative EIA was noted in be sanctuary for secondary infection or mycetoma, or may 13% of healthy patients and 33% of immunosuppressed cause pneumothorax or hemoptysis. patients, declining to 5% and 17%, respectively when confirmatory tests were performed.16 Antibody tests also Diagnosis may be negative early in the disease,16 as noted in half of In a large proportion of community acquired pneumonia cases in one study.11 Thus, negative antibody tests cannot patients in the endemic area, diagnostic testing for exclude coccidioidomycosis.19 coccidioidomycosis is not performed.3 In a large retro- Coccidioides galactomannan testing is available spective cohort, patients more likely to be tested for in select reference laboratories. Antigenuria was detected coccidioidomycosis were adults and immunosuppressed in 50% of patients with moderate20 and 71% with moderate patients. Patients who experienced symptoms for >14 to severe disease, among whom tests for antibodies were days, manifest a rash, or had chest pain were also more positive in 54%.10 Antigenemia was detected in 73% of likely to be tested.3 patients with mild to moderate disease, identifying an Rapid diagnosis can be achieved by cytopathologic additional 29% of cases that would have been missed if only examination of respiratory specimens in patients with urine was tested.20 Thus, the greatest sensitivity may be infiltrates or cavitary disease, positive in one quarter10,11 to achieved by testing both urine and serum. Antigen also has two-thirds of cases,8,12 Table 2. Simultaneous trans- been detected in BAL in patients with negative results in bronchial biopsy may increase the diagnostic yield.12 urine.11 Nodules may be biopsied to exclude malignancy.13 In Real-time PCR targeting the internal transcribed spacer many patients with negative cytopathology, culture is region 2 sequences exhibited a sensitivity of 100% on positive.10,11 In patients with milder illnesses, however, respiratory samples, 93% on fresh tissue and 73% on cytopathology and culture are performed in only 40e60% of paraffin-embedded tissue, with a specificity of 98e100%.21 cases, respectively.10 Despite the availability of more rapid In clinical testing PCR was positive in respiratory specimens diagnostic methods, culture remains an important part of in five of nine patients, most of whom were immunosup- the diagnostic workup, providing the only basis for diag- pressed and culture positive.18 The relative sensitivity of nosis in some cases. real-time PCR and antigen detection remains to be Serologic tests for antibodies are the most widely used determined. method of diagnosis and are perhaps more useful in diag- nosing coccidioidal infection than the other endemic Management mycoses. IgM specific for the tube precipitin antigen and In the context of community acquired pneumonia, the IgG specific for the complement fixation antigen can be decision of whether or not to treat with anti-fungal therapy assayed locally by commercially available immunodiffusion is based on clinical context and severity of symptoms. When kits or enzyme-linked immunoassay (EIA).6 IgG antibody to treatment is deemed necessary, azole therapy is preferred. the complement fixation antigen, when positive, can be In most cases of acute pulmonary coccidioidomycosis pre- quantified at reference laboratories and reported as a titer. senting as CAP, fluconazole or itraconazole 400 mg daily for Any positive titer is considered significant and indicative of 3e6 months is sufficient. Fluconazole is often used as recent infection. Titers are often followed in symptomatic itraconazole requires closer monitoring with drug levels and patients or patients with chronic infection to determine careful consideration of drug interactions.22 Longer therapy treatment efficacy and resolution. (12e18 months) is recommended for cavitary, diffuse Both EIA and agar gel immunodiffusion provide results pulmonary or disseminated disease. with a quick turnaround time. However, controversy arises Lipid formulation of amphotericin B is recommended in over the accuracy of IgM antibodies determined by EIA: patients with extensive, bilateral, or “miliary” pneumonia, or disseminated disease in immunocompromised patients. Patients are frequently transitioned to fluconazole or itra- conazole after a week or two and therapy continued for at Table 2 Diagnostic tests in blastomycosis and least 12 months,23 Table 3. Concomitant steroid therapy coccidioidomycosis. may be appropriate if paradoxical worsening or delayed Parameter Coccidioidomycosis Blastomycosis improvement occurs with anti-fungal therapy alone for Cytopathology 25e508,10,12,17,20,a 8126 severe pulmonary coccidioidomycosis. Amphotericin should Culture 40e10010e12,17,18 8626 be used in pregnancy due to concerns regarding the tera- Antibody 50e10011,12,16e18 3226 togenicity of azole anti-fungal agents, especially in the first Antigenuria 50e7110,11,20 55e9326,45,76 trimester. Antigenemia 7020 8045 Asymptomatic pulmonary nodules and small thin walled Antigen BAL Single case11 8077 cavities are not typically treated with . Occa- PCR 56e10018,21 8647 sionally nodules change size and extirpate their contents. However, they can be confused with malignancy when a Sensitivity in percent (references). a diagnosis of coccidioidomycosis was not previously 772 C.A. Hage et al.

Table 3 Guidelines for treatment of endemic mycoses based on consensus group recommendations. Parameter Coccidioidomycosis23,49 Blastomycosis27,49 Histoplasmosis49,69 Severe (ICU) Lipid amphotericin B 1e2 Lipid amphotericin B, Lipid amphotericin B week then fluconazole or 1e2 week then 1e2 week then itraconazolea itraconazole itraconazole Moderately severe Lipid amphotericin B 1e2 Lipid amphotericin B Lipid amphotericin B (hospitalize) week then fluconazole or 1e2 week then 1e2 week then itraconazolea itraconazole itraconazole Mild (not hospitalize) Fluconazole or itraconazole Itraconazole Itraconazole a Consider systemic corticosteroids in patients with ARDS.

secured. When unclear, residual nodules frequently lead to Extrapulmonary dissemination occurs in up to third of biopsy or excision. cases,26,35 most commonly involving skin, bone, and the genitourinary system. Cutaneous or bone lesions in a patient with community acquired pneumonia who resides Blastomycosis in the endemic area should raise the suspicion for blasto- mycosis. Dissemination to the central nervous system may Epidemiology also occur.36 The endemic area for blastomycosis overlaps with that of histoplasmosis, but stretches further north into Minnesota, Radiographic Wisconsin, the Canadian provinces adjacent to the great No specific radiographic findings are characteristic enough lakes and the areas surrounding St. Lawrence Seaway in to suggest the diagnosis of blastomycosis. The most New York and Canada.1 Blastomycosis is less common than common findings in acute pulmonary blastomycosis include histoplasmosis and coccidioidomycosis.2 Recent excavation lobar consolidation, air bronchogram, and nodular infil- activity and residence near waterways are risk factors for trates,26,37,38 Table 1. Miliary nodules and interstitial infil- blastomycosis, (Table 1).24 Point source outbreaks have trates are common in severe cases.38 Mediastinal or hilar been reported where most patients present with an acute lymphadenopathy26 and pleural effusions are infrequent.39 illness after heavy exposure to contaminated excavation Mass like lesions, often mistaken as malignancy, and cavi- sites. The incubation period ranges from 21 to 106 days with ties within areas of consolidation can be seen in chronic a median of 45 days.25 cases.26

Clinical Diagnosis The are the most commonly affected organs in blas- The diagnosis is often delayed because of failure to tomycosis.26,27 The majority of infected individuals are consider blastomycosis in patients with community either asymptomatic or manifest a mild self-limited acquired pneumonia.30 If suspected, the diagnosis usually illness.26 Also, most patients are otherwise healthy.26 Acute can be made rapidly by microscopic visualization of the pulmonary blastomycosis is commonly seen in the setting of organism or detection of antigen in body fluids,26,40 (Table an outbreak following heavy, point source exposure. 2). The yield of cytopathology ranges from 38% to Symptoms are abrupt and include cough productive of 97%.26,41,42 Histopathology of lung tissue biopsy specimen purulent sputum, fever, night sweats, dyspnea, chest pain, may provide a diagnosis in some cases with negative weight loss, myalgia and occasionally hemoptysis, (Table cytology.26,43 Definitive diagnosis requires the isolation of 1). The illness is often confused with bacterial community the organism by culture which is positive in 67e86% of acquired pneumonia, and the diagnosis is suspected only cases,26,44 often within one week of incubation. after failure to respond to antibacterial therapy.28,29 In one Blastomyces antigen can be detected in serum, urine series, diagnosis took more than 30 days in 43% of the cases, and BAL fluid, often providing the initial basis for diag- with only one quarter diagnosed within a week of presen- nosis,26,40 positive in 85%e93% of patients.26,45,46 Testing tation.30 The illness may rapidly progresses to acute both serum and urine may improve the sensitivity for respiratory distress syndrome (ARDS) and shock in about diagnosis by antigen detection. Cross reactions occur in 10% of cases26,31 with up to 60% mortality.28 Delays in histoplasmosis (96e100%),26,45,46 paracoccidioidomycosis considering and testing for blastomycosis contribute to this (100%), and penicilliosis marneffei (70%); otherwise speci- poor outcome. Severe pulmonary blastomycosis is more ficity is 98% with other mycoses (cryptococcosis, aspergil- common in young immunocompromised patients32,33 and losis, coccidioidomycosis, and ).46 those with diabetes mellitus.28 PCR methods are promising. Excellent sensitivity and Chronic pulmonary blastomycosis is usually gradual in specificity was reported using a real-time method on onset, and symptoms include cough productive of purulent isolates and clinical specimen.47 This finding requires vali- sputum, fever, night sweats, malaise, and weight loss.34 dation before the role of PCR is known. The illness can be mistaken for tuberculosis or lung Available tests for antibodies to Blastomyces are not cancer, and is progressive if untreated.34 used commonly because of poor sensitivity (<50%)26 and Endemic mycoses CAP 773 specificity, however accuracy may be improved using exposure,54,55 described as the “epidemic” type of acute certain Blastomyces .48 pulmonary histoplasmosis, Table 1 56. Severe cases may culminate in respiratory failure38,57 and death.57 Low-level Management exposure causes mild flu-like illness often lasting for more Treatment is recommended unless clinical resolution has than a month, referred to herein as subacute pulmonary occurred before the diagnosis is made.27,49 A lipid formu- histoplasmosis.55,58,59 Although self-limited, patients often lation of Amphotericin B is recommended for patients with undergo unneeded invasive procedures, receive repeated severe or CNS disease, (Table 3). Amphotericin B is usually courses of antibiotic therapy, and miss school or work, at administered until there is clinical improvement (1e2 a substantial cost. weeks) except in patients with CNS diseases, in which 4e6 Patients with underlying typi- weeks is recommended. Itraconazole is administered for cally experience chronic pulmonary symptoms accompa- 6e12 months after discontinuation of amphotericin B. nied by progressive lung infiltrates with cavitation, termed Itraconazole is the treatment of choice for non-severe chronic pulmonary histoplasmosis.55 Cavitation and chro- cases.50 The recommended dose is 200 mg three times a day nicity may suggest anaerobic infection, for which repeated for three days followed by 200 mg twice a day for at least courses antibiotics are prescribed without clinical benefit six months. A Longer treatment is recommended for before histoplasmosis is suspected. immunosuppressed patients, those with bone disease, and those who relapse. Fluconazole is less effective and is not Radiographic recommended except in patients who do not tolerate Chest radiographs or CT scans in acute pulmonary histo- itraconazole, and then should be administered at high plasmosis show diffuse reticulonodular or miliary infil- doses (800 mg/day). Voriconazole has been used51 but its trates, at times accompanied by mediastinal or hilar role remains unclear. Corticosteroids may be useful lymphadenopathy56 Table 4. Similar findings may be seen in adjuncts to anti-fungal therapy in patients with ARDS.52,53 patients with progressive disseminated histoplasmosis,60 which should be suspected in the absence of an acute exposure or the presence of immunosuppression. Findings Histoplasmosis in subacute pulmonary histoplasmosis include hilar or mediastinal lymphadenopathy with localized or patchy Epidemiology infiltrates.55 With healing infiltrates may regress into Histoplasmosis is a community acquired infection, most nodules, which eventually calcify but may cavitate. often presenting as pneumonia. Most cases are first treated Imaging studies in chronic pulmonary histoplasmosis show with antibiotics and the diagnosis is not suspected until changes of underlying emphysema, upper lobes infiltrates, they fail to improve. Except in outbreak settings where pleural thickening, volume loss and cavitation, resembling multiple individuals become ill following a shared activity those seen in tuberculosis.55 and present acutely with diffuse pulmonary infiltrates, a history of exposure to sites likely to harbor Histoplasma Diagnosis mold is uncommon. Some epidemiologic clues are listed in Demonstration of yeast by cytology or histopathology may Table 1. provide a rapid diagnosis with high specificity but with lower sensitivity than antigen or antibody detection. Clinical Isolation of the organism by culture may provide the only There are no unique clinical findings to alert the physician laboratory basis for diagnosis in some patients, but requires to suspect histoplasmosis. Patients present with cough, at least one week and often up to four weeks to detect chest pain, fever, sweats and malaise, usually occurring positive results. The role of PCR remains to be determined. between one and three weeks following a high-inoculum Good sensitivity and specificity was reported,47 but only six

Table 4 Diagnostic tests in histoplasmosis. Parameter Acute pulmonary Subacute pulmonary Chronic pulmonary histoplasmosis histoplasmosis histoplasmosis Cytopathology 2/1065 8/1964 3/464 0/264 1/1126 1/626 2/2467 0/567 Culture 8/1965 14/2664 4/464 0/364 5/3426 11/1326 11/12867 11/1767 Antibody 18/2865 39/4164 5/664 4/664 67/6826 14/1426 151/17667 14/1567 Antigenemia 23/2965 5/2026 1/526 Antigenuria 13/2965 14/4664 4/564 5/664 22/6526 2/1426 Antigen BAL 3/477 2/278 5/577 774 C.A. Hage et al.

BAL specimens and five other respiratory specimens were is recommended as levels are highly variable.69 Drug tested, of which four BALs were negative. Other studies interactions must also be considered. have shown that PCR was not sensitive when testing Acute pulmonary histoplasmosis: Although most patients BAL61,62 and that PCR was less sensitive than pathology recover without therapy,72 the clinical findings may be when applied to tissues.63 severe, recovery may be slow, and death may occur.65 Acute pulmonary histoplasmosis: Antigen detection is Accordingly, most patients should be treated.69 The anec- the most sensitive diagnostic test in acute pulmonary dotal experience supports treatment efficacy for acute histoplasmosis (Table 4).64,65 Both urine and serum must be pulmonary histoplasmosis.65 Lipid amphotericin B is rec- tested achieve the highest sensitivity: 38% of cases would ommended in those who are hypoxic, accompanied by have been missed by testing urine only, based on findings in corticosteroids for the first week or two.69 Patients with one study.65 The sensitivity of cytopathology of respiratory milder illnesses may be treated with itraconazole alone, specimens is uncertain, but probably low, based upon 200 mg once or twice daily. The optimal duration of therapy a review of the findings in published studies.64,65 Serologic is unknown, but a six to 12 week course is recommended. tests for anti-Histoplasma antibodies are positive in about Subacute pulmonary histoplasmosis: Most patients with two-thirds of cases,64,65 but not during the first three weeks have mild symptoms and have improved by the time the of infection, based on one report,66 when diagnosis is often diagnosis is established. Thus, anti-fungal therapy is usually most valuable. Respiratory cultures are positive less than unnecessary. Itraconazole 200 mg once or twice daily given half of cases.64,65 for six to 12 weeks may be helpful in those who remain Subacute pulmonary histoplasmosis: As most patients symptomatic for more than one month.69 have been ill for more than a month before testing is per- Chronic pulmonary histoplasmosis: Treatment is indi- formed, and antibody tests are usually positive.26,64,67 cated in all patients with chronic pulmonary histoplas- Accordingly, agar gel immunodiffusion and/or comple- mosis.69 Treatment reduces symptoms, eradicates the ment fixing antibodies are positive in 95% of cases.64,67 The organism from respiratory specimens, and reduces pulmo- complement fixation test is positive at titers of at least 1:8 nary infiltrates.73,74 Itraconazole 200 mg once or twice daily in 90%, M bands in three quarters, and H bands in one is recommended for at least 12 months, and until the chest quarter of patients.67 CF titers of 1:8 or 1:16 are less imaging shows no further improvement. Relapse occurs in helpful in differentiating active from past infection, but about 15% of cases followed for 1e2 years.75 occur in a third of acute cases, and should not be disregarded. Funding Many physicians presume antibody testing is not useful because antibodies are present in most individuals from This work was supported by a VA Career Development endemic areas, mimicking skin test positivity. However, the Award (CDA-2) to C. A. Hage. 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.67 Conflict of interest statement Tests for antigenuria are positive in about one-third of cases, histopathology or cytology in 10e40%26,64,67 and Dr. L.J. Wheat is an employee of MiraVista Diagnostics, the culture in 10e50%,26,64,67 if invasive procedures are per- laboratory that provides the Histoplasma, Blastomyces and formed. However, the diagnosis can usually be made by Coccidioidomyces antigens. serology, avoiding biopsies. Chronic pulmonary histoplasmosis: Culture of respiratory specimens, antigen testing of BAL or bronchial washings, References and tests for antibodies are most useful. Cultures were positive in 65e85% of cases.26,64,67 Culture of sputum when 1. Baddley JW, Winthrop KL, Patkar NM, et al. Geographic cultures of BAL and/or bronchial washings are negative. distribution of endemic fungal infections among older persons, United States. Emerg Infect Dis 2011;17:1664e9. Antibody tests are positive in over 90% of cases in most 2. Chu JH, Feudtner C, Heydon K, et al. Hospitalizations for series.26,64,67 Antigen was detected in the urine of 14% of 26 endemic mycoses: a population-based national study. 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