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Blastomycosis in Indiana
CHEST
Original Research PNEUMONIA
Blastomycosis in Indiana Digging Up More Cases W. Graham Carlos, MD; Anthony S. Rose, MD; L. Joseph Wheat, MD; Steven Norris, MD; George A. Sarosi, MD, FCCP; Kenneth S. Knox, MD, FCCP; and Chadi A. Hage, MD, FCCP
Background: The endemic region of blastomycosis historically has included the state of Indiana. However, few published reports of blastomycosis exist to substantiate this distinction. A surge of patients with blastomycosis in central Indiana (Indianapolis and surrounding counties) beginning in 2005 prompted us to review our local experience. We propose that this surge was related to major highway construction around Indianapolis. Methods: We reviewed all microbiologically confirmed cases from four hospitals serving central Indiana. Chart review was completed for adult patients, and data were collected on clinical presentations, methods of diagnosis, comorbidities, radiologic findings, treatment, and outcomes. We plotted patient residence addresses with sites of highway construction. Results: Fifty-nine patients were identified from laboratory results and physician referral. Interestingly, a surge of blastomycosis incidence occurred in 34 patients between 2005 and 2008 during which time major highway projects were under way around the Indianapolis metropolitan area. The majority of these patients presented acutely and with pulmonary involvement. Fungal culture and antigen testing were the most sensitive means to diagnosis. Antifungal therapy was highly effective. Conclusions: This urban outbreak of blastomycosis in Indianapolis should prompt clinicians to consider blastomycosis in this highly endemic area of histoplasmosis. CHEST 2010; 138(6):1377–1382
riginally described by Gilchrist for its cutaneous Omanifestations in 1894, Blastomyces dermatitidis, 1
the causative organism of blastomycosis, is now recognized as a thermal dimorphic fungus causing systemic granulomatous disease in humans. The epiManuscript received March 6, 2010; revision accepted May 13, 2010. Affiliations: From Pulmonary-Critical Care and Infectious Diseases (Drs Carlos and Hage), Richard L. Roudebush VA Hospital and Indiana University School of Medicine, Indianapolis, IN; Respiratory and Critical Care Consultants (Dr Rose), Clarian Health Partners, Indianapolis, IN; MiraVista Laboratories (Dr Wheat), Indianapolis, IN; Community Infectious Diseases (Dr Norris), Indianapolis, IN; University of Minnesota School of Medicine (Dr Sarosi), Minneapolis VA Medical Center, Minneapolis, MN; and Southern Arizona VA Health Care System (Dr Knox), University of Arizona, Tucson, AZ. Funding/Support: This study was supported by a Department of Veterans Affairs–Career Development Award-2 (to Dr Hage) and Indiana University School of Medicine Internal funding (to Dr Hage). Correspondence to: Chadi A. Hage, MD, FCCP, PulmonaryCritical Care and Infectious Diseases, Roudebush VA Medical Center and Indiana University, 1481 W 10th St, 111P-IU, Indianapolis, IN 46202; e-mail: [email protected].
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demiologic classification of blastomycosis has proven difficult because of a lack of accurate skin testing, serologic assays, and methods for isolation from the soil.2,3 Clinical cases have contributed to most of our current understanding of blastomycosis as an endemic mycosis. To our knowledge, no published case series from the state of Indiana exist, and only a few cases have been reported in Indianapolis.4 Despite this, Indiana traditionally has been included in the endemic classification that stretches from the states surrounding the Great Lakes southward and eastward along the Mississippi and Ohio River basins.5-8 Within the past 5 years, the Indianapolis metropolitan area has undergone extensive excavation along major interstate highways. During this time, we observed an increase in the frequency of diagnosis of © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-0627 CHEST / 138 / 6 / DECEMBER, 2010
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blastomycosis in Indianapolis. This increase prompted a retrospective analysis of our local experience. We sought to classify demographics, disease characteristics, radiologic findings, and response to treatment. In addition, methods of diagnosis were compared as were clinical characteristics between the intervals of 1985 to 2004 and 2005 to 2008. Herein, we report the first series of blastomycosis in central Indiana and identify a recent surge in patients with this condition suggestive of an outbreak. This investigation supports Indiana’s designation as an endemic area for blastomycosis.
Materials and Methods This retrospective chart review was approved by the Indiana University Institutional Review Board (#0610-66). We searched the Regenstrief medical record database and microbiology laboratory records for positive results for blastomycosis from the following: fungal culture or stain, pathology, cytopathology, and fungal antigen testing. We also solicited patients from local infectious diseases and pulmonary specialists. Review of medical records was completed to determine the age at diagnosis, exposure history (if known), medical comorbidities, methods of diagnosis, chest radiograph and CT imaging findings, treatment, and outcomes. The time of diagnosis was defined as the date of the first positive diagnostic test. Exposure history was taken from clinical records, specifically noting exposure to birds, excavation and construction sites, hunting, and farming. Radiographic findings were obtained from thoracic radiologist interpretations recorded in the medical records. Antigen assays (MiraVista Diagnostics; Indianapolis, IN) were performed as part of the clinical evaluation as directed by the clinician. A portion of the antigen data describing the diagnostic value of Blastomyces antigen has been reported by Bariola et al.9 In addition, we identified the home addresses of patients who received a diagnosis of blastomycosis between 2005 and 2009 and mapped them using Google maps (http://maps.google.com/maps) to assess proximity to excavation sites. Disease manifestations were clinically classified into one of the following three groups: acute pulmonary blastomycosis, chronic pulmonary blastomycosis, and extrapulmonary blastomycosis. Acute presentations included symptoms that would be expected in community-acquired pneumonia or acute flu-like illnesses such as myalgias and arthralgias, fever, headache, pleuritic chest pains, and sputum production.10,11 Chronic infections were characterized by persistent cough; constitutional symptoms; and a relative lack of pulmonary symptoms, usually with a mass-like lung lesion suggestive of lung cancer.10,12 We did not track symptom duration to differentiate acute vs chronic infections because of inconsistencies noted in the medical records with regard to start and duration of illness, as previously reported.13 Extrapulmonary disease was defined as microbiologic or pathologic evidence of Blastomyces infection outside the lungs. The x2 test was used to compare the proportions among the different tests.
Results Fifty-nine patients were identified as having microbiologically confirmed blastomycosis between the years 1985 and 2009 (through March of 2009) of which 34 were seen between 2005 and 2009. This
cohort included 38 male and 21 female patients with a mean age of 44 years (range, 19-89 years). General patient characteristics are shown in Table 1. Pulmonary involvement was seen in 52 (88%) patients. In addition to pulmonary infection, extrapulmonary involvement was seen in 26 (44%) patients as follows: skin (n 5 15), bone (n 5 9), CNS (n 5 3), joint (n 5 2), prostate (n 5 1), pericardium (n 5 1), and larynx (n 5 1). Of the seven patients in whom no pulmonary involvement was seen, skin was the most common site involved (n 5 6). Diabetes was the most common underlying condition (22%). Compared with the entire cohort, patients with diabetes were more likely to present acutely (77% vs 53%; P 5 .194), were significantly more likely to receive care in the ICU at diagnosis (46% vs 17%; P 5 .054), and were more likely to die (50% vs 7%; P 5 .049). Two patients with HIV were included of whom one died. A full list of underlying conditions is included in Table 1. Acute presentations were more frequent than chronic for the entire cohort. In the subset of patients receiving a diagnosis between 2005 and 2009 (Fig 1, Table 2), 22 (65%) of 34 presented in an acute fashion compared with nine (38%) of 25 between 1985 and 2004 (P = .055). ARDS was seen in seven patients of whom three had underlying conditions (Table 3) as follows: diabetes (n 5 2) and corticosteroid use (n 5 1). Four patients with ARDS were seen between 2005 and 2009. Fewer than one-half (22 of 59) of patients received a chest CT scan during their work-up. In four patients, the chest CT scan revealed cavitation, and fractures of thoracic vertebrae were seen in two. Table 4 summarizes the radiologic manifestations of our cohort, including anatomic distributions of infiltrates. Out of 34 subjects in whom antigen testing was completed (serum, urine, and BAL), we observed a sensitivity of 76% for positive antigen testing for either histoplasmosis or blastomycosis (Table 4). The current antigen test does not differentiate histoplasmosis from blastomycosis.14 Samples yielding a positive antigen (some patients provided multiple sample sites) were urine (n 5 31), serum (n 5 6), and BAL (n 5 5). With one exception (a patient from 2009), every positive antigen test was associated with positive cultures, cytopathology, or histopathology. All together, blastomycosis antigen testing was performed on 57 samples, and 42 (74%) were positive. Blastomyces serology (immunodiffusion) was performed in 25 patients; eight were positive, and 17 were negative. Fungal culture demonstrated the highest sensitivity (42 [86%] of 49) in our series. Sources for positive cultures included BAL fluid (n 5 15), lung tissue (n 5 11), skin (n 5 5), bone (n 5 3), synovial fluid (n 5 2), urine (n 5 1), and cerebrospinal fluid (n 5 1).
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Table 1—Patient Demographics, Underlying Conditions, Place of Care, and Associated Exposures Demographic Characteristic (N 5 59) Race/ethnicity White Black Hispanic Underlying condition Diabetes Asthma, COPD, IPF Corticosteroid use Cancer HIV/AIDS Collagen vascular disease Pregnancy Kidney transplant IgG deficiency Cirrhosis Place of care Inpatient ICU Medical ward Outpatient Unknown Associated exposure Landscaping Farming Construction Hunting
No. (%) 33 (56) 18 (31) 6 (10) 26 (45) 13 (22) 4 (7) 4 (7) 3 (, 1) 2 (, 1) 2 (, 1) 1 (, 1) 1 (, 1) 1 (, 1) 1 (, 1) 35 (59) 10 (17) 25 (42) 21 (36) 3 (, 1) 11 (19) 4 (, 1) 3 (, 1) 3 (, 1) 1 (, 1)
IPF 5 idiopathic pulmonary fibrosis.
Cytopathology was the least sensitive (14 [38%] of 37; P , .001) compared with fungal culture. Sources for positive cytopathology included BAL fluid (n 5 9), lung tissue (n 5 2), sputum (n 5 1), skin (n 5 1), and bone (n 5 1). Stains that were applied to BAL samples were Diff-Quik, Giemsa, Gram stain-modified Kinyoun, Gomori methenamine silver, calcofluor white, and auramine-rhodamine stain, as previously described.15 Non-BAL samples were routinely subjected to Diff-Quik and Papanicolaou stains. Table 4
summarizes the different microbiologic and pathologic diagnostic tests used to identify patients. Using census data, we calculated the incidence within Marion county (the locale for Indianapolis) and observed an increase from 2003 to 2008 in the incidence of patients with blastomycosis per 100,000 population as follows: 2003, 0.12; 2004, 0.35; 2005, 0.58; 2006, 1.15; 2007, 1.03; and 2008, 0.68. This time frame correlated with major interstate highway construction around the Indianapolis metropolitan area that was part of Indiana’s Major Moves transportation plan initiated in 2005. The excavation and construction work started with the east side of highway 465, followed by the east part of interstate 70, and then by the west side of highway 465 (Fig 2). Treatment and outcome information was available on 53 patients, 47 of whom received antifungal therapy (acute blastomycosis, 29 of 31; chronic blastomycosis, 18 of 27). Amphotericin B was administered to 25 (47%) patients as follows: amphotericin deoxycholate (n 5 20), liposomal amphotericin B (n 5 3), and amphotericin B lipid complex (n 5 2). Patients with acute presentations were more likely to receive amphotericin (18 [58%] of 31) compared with those with chronic presentations (three [11%] of 27; P , .001). Average duration of treatment with amphotericin was 24 days (range, 2-70 days). Azoles were used in 47 (87%) patients as follows: itraconazole (n 5 44), voriconazole (n 5 2), fluconazole (n 5 1), and ketoconazole (n 5 1). Azoles were used following amphotericin B therapy in 23 patients and alone in 24 patients. Of the patients with acute blastomycosis, 27 of 31 received azoles compared with 18 of 27 for chronic presentations. We observed seven patients presenting with ARDS of whom three were successfully treated with corticosteroids in addition to amphotericin B. We were unable to determine whether steroids were given
Figure 1. Distribution of the 59 patients with blastomycosis over time. *Years of major highway construction in the Indianapolis metropolitan area. www.chestpubs.org
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Table 2—Case Characteristic Comparisons of Intervals 1985 to 2004 and 2005 to 2009 Characteristic Total patients, No. Acute ARDS Pneumonia Chronic
1985-2004
2005-2009a
P Value
25 9 (38) 3 (12) 5 (20) 15 (60)
34 22 (65) 4 (12) 18 (53) 12 (35)
… .055 .704 .022 .106
Data are presented as No. (%), unless otherwise indicated. This time frame correlated with major highway construction projects around the Indianapolis metropolitan area. x2 was used to compare the proportions between the two intervals. a
to the patient who presented with ARDS and subsequently died. The overall mortality rate was 7.5% (four of 59). Only one (1.9%) fatality could be directly attributed to blastomycosis. This patient presented with an acute pneumonia with ARDS and died 5 days later of progressive disease. The remaining three fatalities included one patient who died of bacterial (Pseudomonas) endocarditis 3 weeks after diagnosis, one with HIV infection and extrapulmonary blastomycosis who died of recurrent bacterial pneumonia 3 years after diagnosis, and one who died of an acute myocardial infarction (diagnosis of blastomycosis was made postmortem). Discussion This series of 59 patients with microbiologically confirmed blastomycosis infection represents the largest from Indiana to date. Indiana, bordering Lake Michigan to the north and the Ohio River to the south, sits in the middle of the blastomycosis endemic region. Despite its location, no publications describing blastomycosis in Indiana exist to our knowledge. We were prompted to analyze our local data after noticing a surge in cases after 2005, particularly those presenting acutely with pneumonia. Excavation at contaminated construction sites has been noted to cause aerosolization of the fungus leading to exposure.3,16,17 We suspect that this surge is related to major highway construction that took place in the Indianapolis metropolitan area beginning in 2005. We also found the Table 3—Type of Presentation (N 5 58)a Presentation
No. (%)
Acute Pneumonia ARDS Disseminated Chronic Disseminated
31 (53) 23 (40) 7 (12) 7 (12) 27 (46) 17 (29)
One patient could not be classified as acute or chronic.
a
primary residence of most new patients was located near these construction sites (Fig 2). Additionally, recent reviews have observed that blastomycosis often localizes to specific counties.12,18 Although we documented a surge, we likely underestimated the incidence of blastomycosis in central Indiana. Our analysis included active surveillance of four hospitals that serve central Indiana. There are at least seven more hospitals that serve the same geographical area that were not included in this analysis. The epidemiologic classification of blastomycosis in Indiana is further hindered by the fact that the state does not require reporting of blastomycosis. Radiologic findings of pulmonary blastomycosis are highly variable.19,20 Radiologic characteristics (Table 4) were consistent with previous publications in that airspace consolidation was a common finding19 especially in those patients presenting with acute disease (63%).21,22 Upper-lobe involvement was more frequent in our series as has been described previously.23,24 Adenopathy was noted in 25% of our patients, similar to Sheflin et al,24 and higher than the 6% rate reported by others.23,25 Our observed frequency of adenopathy may be attributed to detection bias. Of the 13 cases of adenopathy we observed, eight were detected exclusively by chest CT scan. Cavitation was detected in six patients (four of six on CT scan alone), always appeared in the upper lobes, and was associated with acute disease 83% of the time. Our findings are similar to a previous report in which two of 16 patients had cavitation, both in the upper lobes, with one presenting acutely.20 A rapid diagnosis of blastomycosis can be made by visualizing the yeast organism in respiratory specimens or sites of extrapulmonary involvement using calcofluor white stain, potassium hydroxide wet mount, cytology, or histopathology.26 In our study, Blastomyces yeast was demonstrated by microscopic evaluation (cytopathology or histopathology) in 80% of subjects. Antigen detection also has been used for the diagnosis of blastomycosis and was positive in 74% of our cases. Although the highest sensitivity for diagnosis in our study was obtained by culture (86%), culture may not yield a rapid diagnosis because of the delay in recognizing growth of the organism. As such, antigen testing provides a reliable method to make an accurate and rapid diagnosis of blastomycosis, particularly when a large burden of disease is present and when cytologic analysis is performed at lessexperienced centers.12 Although antigen testing was completed on subjects from our cohort beginning in 2005, around the time highway construction was initiated, we do not have any evidence that antigen testing created detection bias. The Blastomyces antigen test became available for clinical use in June 2003. All but one patient were diagnosed using traditional
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Table 4—Results of Diagnostic Methods Used by Presentation Type Diagnostic Method Radiologic feature (n 5 51) Consolidation Adenopathy Interstitial infiltrates Mass Nodules Cavitation Negative Pleural effusion Unilobar disease Right upper lobe Left upper lobe Left lower lobe Right lower lobe Right middle lobe Initial diagnostic source (n 5 58)a BAL Lung biopsy Transbronchial biopsy Percutaneous FNA Open lung biopsy Lobectomy Skin or soft tissue biopsy Bone or joint biopsy Sputum Urine (antigen) Microbiologic tests Fungal culture (n 5 49) Fungal antigen ELISA (n 5 57) Blastomyces or Histoplasmab Blastomyces serology (n 5 25) Histopathology (n 5 42) Cytopathology (n 5 37)
Total, No. Acute (n 5 31), Chronic (%) No. (n 5 27), No. 24 (47) 13 (25) 11 (22) 8 (16) 6 (12) 6 (12) 4 (8) 3 (6) 19 (37) 9 6 2 1 1
15 8 8 4 2 4 0 3 12 … … … … …
9 5 3 4 4 2 4 0 7 … … … … …
23 (40) 16 (28) 7 5 4 1 15 (26) 8 (14) 3 1
20 9 3 2 1 0 5 2 1 1
3 7 4 3 3 1 10 6 2 0
42 (86)
28
14
42 (74)
35
7
8 (32)
4
4
34 (81) 14 (38)
18 11
16 3
ELISA 5 enzyme-linked immunosorbent assay; FNA 5 fine needle aspiration. aSeveral subjects had multiple positive specimens. bWe observed 100% cross-reactivity between assays. Several patients had samples from different sources (urine, serum, and BAL fluid).
methods of culture and cytopathology, and antigen testing was performed concomitantly. The cross-reactivity between the Blastomyces and Histoplasma antigen is well recognized.13 We observed a 100% cross-reactivity rate in the samples tested for both antigens from the same source. Differentiating between histoplasmosis and blastomycosis usually can be made based on epidemiologic, clinical, histopathologic, culture, or serologic differences. However, early differentiation may not be clinically as important in critically ill patients because management is similar between both conditions.26,27 Several publications have discussed the characteristics of blastomycosis in immunosuppressed patients. This population typically has severe infections associwww.chestpubs.org
Figure 2. Geographic plot of the Indianapolis metropolitan area highlighting the major interstate highways and the primary residences of patients with blastomycosis seen between the years 2005 and 2009.
ated with high mortality rates, especially in patients with AIDS.12,28 Diabetes mellitus was the most commonly reported comorbidity in our series, and compared with the entire cohort, these patients were more likely to present acutely (77% vs 53%; P 5 .216) and to die (15% vs 7%; P 5 .644). Our findings are consistent with other studies that have noted an increase of fungal disease prevalence in patients with diabetes, including blastomycosis,13 cryptococcosis,29 and coccidioidomycosis.30 We recognize several limitations in our study. First, we collected data from fewer than one-half (four of 11) of the hospitals serving central Indiana and most likely underestimated the true incidence of blastomycosis. Second, this retrospective analysis relied solely on review of medical records, which may not have documented exposure history and duration of illness accurately. Finally, the fact that blastomycosis is not a reportable disease in Indiana limits our ability to generate an accurate estimate of prevalence. The clinical presentation of blastomycosis is notoriously variable, and diagnosis often is delayed secondary to limited diagnostic methods and a low index of suspicion. Although blastomycosis is the rarest of endemic fungal diseases, this report should alert clinicians in the endemic area to be mindful of blastomycosis outbreaks during periods of construction. Blastomycosis should be considered in the differential diagnosis of community-acquired pneumonia in endemic areas, especially when antibacterial therapy is not effective. Acknowledgments Author contributions: Dr Carlos: contributed to the study concept and design, acquisition of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual CHEST / 138 / 6 / DECEMBER, 2010
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content. He had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Dr Rose: contributed to the acquisition of data. Dr Wheat: contributed to critical revision of the manuscript for important intellectual content. Dr Norris: contributed to acquisition of data. Dr Sarosi: contributed to critical revision of the manuscript for important intellectual content. Dr Knox: contributed to the study design and concept and critical revision of the manuscript for important intellectual content. Dr Hage: contributed to the study concept and design, acquisition of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. He had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflict of interest: Dr Wheat is an employee of MiraVista Diagnostics, the laboratory that developed and performs MVista Histoplasma and Blastomyces antigen enzyme immunoassay. Drs Carlos, Rose, Norris, Sarosi, Knox, and Hage have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank Dr Mitchell Goldman for his critical review of the manuscript.
References 1. Gilchrist TC. Protozoan dermatitis. J Cutan Genitourin Dis. 1894;12:496-499. 2. Chick EW, Baum GL, Furcolow ML, Huppert M, Kaufman L, Pappagianis R. Scientific Assembly statement. The use of skin tests and serologic tests in histoplasmosis, coccidioidomycosis, and blastomycosis, 1973. Am Rev Respir Dis. 1973;108(1):156-159. 3. Davies SF, Sarosi GA. Epidemiological and clinical features of pulmonary blastomycosis. Semin Respir Infect. 1997;12(3): 206-218. 4. Lahm T, Neese S, Thornburg AT, Ober MD, Sarosi GA, Hage CA. Corticosteroids for blastomycosis-induced ARDS: a report of two patients and review of the literature. Chest. 2008;133(6):1478-1480. 5. Baumgardner DJ, Buggy BP, Mattson BJ, Burdick JS, Ludwig D. Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis. 1992;15(4):629-635. 6. Bradsher RW. Clinical features of blastomycosis. Semin Respir Infect. 1997;12(3):229-234. 7. Watts B, Argekar P, Saint S, Kauffman CA. Clinical problemsolving. Building a diagnosis from the ground up—a 49-yearold man came to the clinic with a 1-week history of suprapubic pain and fever. N Engl J Med. 2007;356(14):1456-1462. 8. Sarosi GA, Davies SF. Blastomycosis. Am Rev Respir Dis. 1979;120(4):911-938. 9. Bariola JR, Hage CA, Durkin M, et al. Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis. Diagn Microbiol Infect Dis. In press. 10. Davies SF. An overview of pulmonary fungal infections. Clin Chest Med. 1987;8(3):495-512. 11. Sarosi GA. Community-acquired fungal diseases. Clin Chest Med. 1991;12(2):337-347.
12. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239. 13. Kralt D, Light B, Cheang M, et al. Clinical characteristics and outcomes in patients with pulmonary blastomycosis. Mycopathologia. 2009;167(3):115-124. 14. Durkin M, Witt J, Lemonte A, Wheat B, Connolly P. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol. 2004;42(10):4873-4875. 15. Hage CA, Davis TE, Fuller D, et al. Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest. 2010;137(3): 623-628. 16. Kitchen MS, Reiber CD, Eastin GB. An urban epidemic of North American blastomycosis. Am Rev Respir Dis. 1977; 115(6):1063-1066. 17. Tosh FE, Hammerman KJ, Weeks RJ, Sarosi GA. A common source epidemic of North American blastomycosis. Am Rev Respir Dis. 1974;109(5):525-529. 18. Hussein R, Khan S, Levy F, Mehta JB, Sarubbi FA. Blastomycosis in the mountainous region of northeast Tennessee. Chest. 2009;135(4):1019-1023. 19. Fang W, Washington L, Kumar N. Imaging manifestations of blastomycosis: a pulmonary infection with potential dissemination. Radiographics. 2007;27(3):641-655. 20. Winer-Muram HT, Beals DH, Cole FH Jr. Blastomycosis of the lung: CT features. Radiology. 1992;182(3):829-832. 21. Masood A, Bensadoun ES. A 62-year-old man with multiple pulmonary nodular opacities. Chest. 2002;121(3):982-984. 22. Patel RG, Patel B, Petrini MF, Carter RR III, Griffith J. Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases. South Med J. 1999;92(3):289-295. 23. Rabinowitz JG, Busch J, Buttram WR. Pulmonary manifestations of blastomycosis. Radiological support of a new concept. Radiology. 1976;120(1):25-32. 24. Sheflin JR, Campbell JA, Thompson GP. Pulmonary blastomycosis: findings on chest radiographs in 63 patients. AJR Am J Roentgenol. 1990;154(6):1177-1180. 25. Halvorsen RA, Duncan JD, Merten DF, Gallis HA, Putman CE . Pulmonary blastomycosis: radiologic manifestations . Radiology. 1984;150(1):1-5. 26. Chapman SW, Dismukes WE, Proia LA, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(12): 1801-1812. 27. Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825. 28. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1992;116(10):847-853. 29. Kiertiburanakul S, Wirojtananugoon S, Pracharktam R, Sungkanuparph S. Cryptococcosis in human immunodeficiency virus-negative patients. Int J Infect Dis. 2006;10(1):72-78. 30. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes mellitus. Am J Med. 2006;119(11): 964-969.
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Original Research PNEUMONIA
Blastomycosis in Indiana Digging Up More Cases W. Graham Carlos, MD; Anthony S. Rose, MD; L. Joseph Wheat, MD; Steven Norris, MD; George A. Sarosi, MD, FCCP; Kenneth S. Knox, MD, FCCP; and Chadi A. Hage, MD, FCCP
Background: The endemic region of blastomycosis historically has included the state of Indiana. However, few published reports of blastomycosis exist to substantiate this distinction. A surge of patients with blastomycosis in central Indiana (Indianapolis and surrounding counties) beginning in 2005 prompted us to review our local experience. We propose that this surge was related to major highway construction around Indianapolis. Methods: We reviewed all microbiologically confirmed cases from four hospitals serving central Indiana. Chart review was completed for adult patients, and data were collected on clinical presentations, methods of diagnosis, comorbidities, radiologic findings, treatment, and outcomes. We plotted patient residence addresses with sites of highway construction. Results: Fifty-nine patients were identified from laboratory results and physician referral. Interestingly, a surge of blastomycosis incidence occurred in 34 patients between 2005 and 2008 during which time major highway projects were under way around the Indianapolis metropolitan area. The majority of these patients presented acutely and with pulmonary involvement. Fungal culture and antigen testing were the most sensitive means to diagnosis. Antifungal therapy was highly effective. Conclusions: This urban outbreak of blastomycosis in Indianapolis should prompt clinicians to consider blastomycosis in this highly endemic area of histoplasmosis. CHEST 2010; 138(6):1377–1382
riginally described by Gilchrist for its cutaneous Omanifestations in 1894, Blastomyces dermatitidis, 1
the causative organism of blastomycosis, is now recognized as a thermal dimorphic fungus causing systemic granulomatous disease in humans. The epiManuscript received March 6, 2010; revision accepted May 13, 2010. Affiliations: From Pulmonary-Critical Care and Infectious Diseases (Drs Carlos and Hage), Richard L. Roudebush VA Hospital and Indiana University School of Medicine, Indianapolis, IN; Respiratory and Critical Care Consultants (Dr Rose), Clarian Health Partners, Indianapolis, IN; MiraVista Laboratories (Dr Wheat), Indianapolis, IN; Community Infectious Diseases (Dr Norris), Indianapolis, IN; University of Minnesota School of Medicine (Dr Sarosi), Minneapolis VA Medical Center, Minneapolis, MN; and Southern Arizona VA Health Care System (Dr Knox), University of Arizona, Tucson, AZ. Funding/Support: This study was supported by a Department of Veterans Affairs–Career Development Award-2 (to Dr Hage) and Indiana University School of Medicine Internal funding (to Dr Hage). Correspondence to: Chadi A. Hage, MD, FCCP, PulmonaryCritical Care and Infectious Diseases, Roudebush VA Medical Center and Indiana University, 1481 W 10th St, 111P-IU, Indianapolis, IN 46202; e-mail: [email protected].
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demiologic classification of blastomycosis has proven difficult because of a lack of accurate skin testing, serologic assays, and methods for isolation from the soil.2,3 Clinical cases have contributed to most of our current understanding of blastomycosis as an endemic mycosis. To our knowledge, no published case series from the state of Indiana exist, and only a few cases have been reported in Indianapolis.4 Despite this, Indiana traditionally has been included in the endemic classification that stretches from the states surrounding the Great Lakes southward and eastward along the Mississippi and Ohio River basins.5-8 Within the past 5 years, the Indianapolis metropolitan area has undergone extensive excavation along major interstate highways. During this time, we observed an increase in the frequency of diagnosis of © 2010 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.10-0627 CHEST / 138 / 6 / DECEMBER, 2010
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blastomycosis in Indianapolis. This increase prompted a retrospective analysis of our local experience. We sought to classify demographics, disease characteristics, radiologic findings, and response to treatment. In addition, methods of diagnosis were compared as were clinical characteristics between the intervals of 1985 to 2004 and 2005 to 2008. Herein, we report the first series of blastomycosis in central Indiana and identify a recent surge in patients with this condition suggestive of an outbreak. This investigation supports Indiana’s designation as an endemic area for blastomycosis.
Materials and Methods This retrospective chart review was approved by the Indiana University Institutional Review Board (#0610-66). We searched the Regenstrief medical record database and microbiology laboratory records for positive results for blastomycosis from the following: fungal culture or stain, pathology, cytopathology, and fungal antigen testing. We also solicited patients from local infectious diseases and pulmonary specialists. Review of medical records was completed to determine the age at diagnosis, exposure history (if known), medical comorbidities, methods of diagnosis, chest radiograph and CT imaging findings, treatment, and outcomes. The time of diagnosis was defined as the date of the first positive diagnostic test. Exposure history was taken from clinical records, specifically noting exposure to birds, excavation and construction sites, hunting, and farming. Radiographic findings were obtained from thoracic radiologist interpretations recorded in the medical records. Antigen assays (MiraVista Diagnostics; Indianapolis, IN) were performed as part of the clinical evaluation as directed by the clinician. A portion of the antigen data describing the diagnostic value of Blastomyces antigen has been reported by Bariola et al.9 In addition, we identified the home addresses of patients who received a diagnosis of blastomycosis between 2005 and 2009 and mapped them using Google maps (http://maps.google.com/maps) to assess proximity to excavation sites. Disease manifestations were clinically classified into one of the following three groups: acute pulmonary blastomycosis, chronic pulmonary blastomycosis, and extrapulmonary blastomycosis. Acute presentations included symptoms that would be expected in community-acquired pneumonia or acute flu-like illnesses such as myalgias and arthralgias, fever, headache, pleuritic chest pains, and sputum production.10,11 Chronic infections were characterized by persistent cough; constitutional symptoms; and a relative lack of pulmonary symptoms, usually with a mass-like lung lesion suggestive of lung cancer.10,12 We did not track symptom duration to differentiate acute vs chronic infections because of inconsistencies noted in the medical records with regard to start and duration of illness, as previously reported.13 Extrapulmonary disease was defined as microbiologic or pathologic evidence of Blastomyces infection outside the lungs. The x2 test was used to compare the proportions among the different tests.
Results Fifty-nine patients were identified as having microbiologically confirmed blastomycosis between the years 1985 and 2009 (through March of 2009) of which 34 were seen between 2005 and 2009. This
cohort included 38 male and 21 female patients with a mean age of 44 years (range, 19-89 years). General patient characteristics are shown in Table 1. Pulmonary involvement was seen in 52 (88%) patients. In addition to pulmonary infection, extrapulmonary involvement was seen in 26 (44%) patients as follows: skin (n 5 15), bone (n 5 9), CNS (n 5 3), joint (n 5 2), prostate (n 5 1), pericardium (n 5 1), and larynx (n 5 1). Of the seven patients in whom no pulmonary involvement was seen, skin was the most common site involved (n 5 6). Diabetes was the most common underlying condition (22%). Compared with the entire cohort, patients with diabetes were more likely to present acutely (77% vs 53%; P 5 .194), were significantly more likely to receive care in the ICU at diagnosis (46% vs 17%; P 5 .054), and were more likely to die (50% vs 7%; P 5 .049). Two patients with HIV were included of whom one died. A full list of underlying conditions is included in Table 1. Acute presentations were more frequent than chronic for the entire cohort. In the subset of patients receiving a diagnosis between 2005 and 2009 (Fig 1, Table 2), 22 (65%) of 34 presented in an acute fashion compared with nine (38%) of 25 between 1985 and 2004 (P = .055). ARDS was seen in seven patients of whom three had underlying conditions (Table 3) as follows: diabetes (n 5 2) and corticosteroid use (n 5 1). Four patients with ARDS were seen between 2005 and 2009. Fewer than one-half (22 of 59) of patients received a chest CT scan during their work-up. In four patients, the chest CT scan revealed cavitation, and fractures of thoracic vertebrae were seen in two. Table 4 summarizes the radiologic manifestations of our cohort, including anatomic distributions of infiltrates. Out of 34 subjects in whom antigen testing was completed (serum, urine, and BAL), we observed a sensitivity of 76% for positive antigen testing for either histoplasmosis or blastomycosis (Table 4). The current antigen test does not differentiate histoplasmosis from blastomycosis.14 Samples yielding a positive antigen (some patients provided multiple sample sites) were urine (n 5 31), serum (n 5 6), and BAL (n 5 5). With one exception (a patient from 2009), every positive antigen test was associated with positive cultures, cytopathology, or histopathology. All together, blastomycosis antigen testing was performed on 57 samples, and 42 (74%) were positive. Blastomyces serology (immunodiffusion) was performed in 25 patients; eight were positive, and 17 were negative. Fungal culture demonstrated the highest sensitivity (42 [86%] of 49) in our series. Sources for positive cultures included BAL fluid (n 5 15), lung tissue (n 5 11), skin (n 5 5), bone (n 5 3), synovial fluid (n 5 2), urine (n 5 1), and cerebrospinal fluid (n 5 1).
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Table 1—Patient Demographics, Underlying Conditions, Place of Care, and Associated Exposures Demographic Characteristic (N 5 59) Race/ethnicity White Black Hispanic Underlying condition Diabetes Asthma, COPD, IPF Corticosteroid use Cancer HIV/AIDS Collagen vascular disease Pregnancy Kidney transplant IgG deficiency Cirrhosis Place of care Inpatient ICU Medical ward Outpatient Unknown Associated exposure Landscaping Farming Construction Hunting
No. (%) 33 (56) 18 (31) 6 (10) 26 (45) 13 (22) 4 (7) 4 (7) 3 (, 1) 2 (, 1) 2 (, 1) 1 (, 1) 1 (, 1) 1 (, 1) 1 (, 1) 35 (59) 10 (17) 25 (42) 21 (36) 3 (, 1) 11 (19) 4 (, 1) 3 (, 1) 3 (, 1) 1 (, 1)
IPF 5 idiopathic pulmonary fibrosis.
Cytopathology was the least sensitive (14 [38%] of 37; P , .001) compared with fungal culture. Sources for positive cytopathology included BAL fluid (n 5 9), lung tissue (n 5 2), sputum (n 5 1), skin (n 5 1), and bone (n 5 1). Stains that were applied to BAL samples were Diff-Quik, Giemsa, Gram stain-modified Kinyoun, Gomori methenamine silver, calcofluor white, and auramine-rhodamine stain, as previously described.15 Non-BAL samples were routinely subjected to Diff-Quik and Papanicolaou stains. Table 4
summarizes the different microbiologic and pathologic diagnostic tests used to identify patients. Using census data, we calculated the incidence within Marion county (the locale for Indianapolis) and observed an increase from 2003 to 2008 in the incidence of patients with blastomycosis per 100,000 population as follows: 2003, 0.12; 2004, 0.35; 2005, 0.58; 2006, 1.15; 2007, 1.03; and 2008, 0.68. This time frame correlated with major interstate highway construction around the Indianapolis metropolitan area that was part of Indiana’s Major Moves transportation plan initiated in 2005. The excavation and construction work started with the east side of highway 465, followed by the east part of interstate 70, and then by the west side of highway 465 (Fig 2). Treatment and outcome information was available on 53 patients, 47 of whom received antifungal therapy (acute blastomycosis, 29 of 31; chronic blastomycosis, 18 of 27). Amphotericin B was administered to 25 (47%) patients as follows: amphotericin deoxycholate (n 5 20), liposomal amphotericin B (n 5 3), and amphotericin B lipid complex (n 5 2). Patients with acute presentations were more likely to receive amphotericin (18 [58%] of 31) compared with those with chronic presentations (three [11%] of 27; P , .001). Average duration of treatment with amphotericin was 24 days (range, 2-70 days). Azoles were used in 47 (87%) patients as follows: itraconazole (n 5 44), voriconazole (n 5 2), fluconazole (n 5 1), and ketoconazole (n 5 1). Azoles were used following amphotericin B therapy in 23 patients and alone in 24 patients. Of the patients with acute blastomycosis, 27 of 31 received azoles compared with 18 of 27 for chronic presentations. We observed seven patients presenting with ARDS of whom three were successfully treated with corticosteroids in addition to amphotericin B. We were unable to determine whether steroids were given
Figure 1. Distribution of the 59 patients with blastomycosis over time. *Years of major highway construction in the Indianapolis metropolitan area. www.chestpubs.org
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Table 2—Case Characteristic Comparisons of Intervals 1985 to 2004 and 2005 to 2009 Characteristic Total patients, No. Acute ARDS Pneumonia Chronic
1985-2004
2005-2009a
P Value
25 9 (38) 3 (12) 5 (20) 15 (60)
34 22 (65) 4 (12) 18 (53) 12 (35)
… .055 .704 .022 .106
Data are presented as No. (%), unless otherwise indicated. This time frame correlated with major highway construction projects around the Indianapolis metropolitan area. x2 was used to compare the proportions between the two intervals. a
to the patient who presented with ARDS and subsequently died. The overall mortality rate was 7.5% (four of 59). Only one (1.9%) fatality could be directly attributed to blastomycosis. This patient presented with an acute pneumonia with ARDS and died 5 days later of progressive disease. The remaining three fatalities included one patient who died of bacterial (Pseudomonas) endocarditis 3 weeks after diagnosis, one with HIV infection and extrapulmonary blastomycosis who died of recurrent bacterial pneumonia 3 years after diagnosis, and one who died of an acute myocardial infarction (diagnosis of blastomycosis was made postmortem). Discussion This series of 59 patients with microbiologically confirmed blastomycosis infection represents the largest from Indiana to date. Indiana, bordering Lake Michigan to the north and the Ohio River to the south, sits in the middle of the blastomycosis endemic region. Despite its location, no publications describing blastomycosis in Indiana exist to our knowledge. We were prompted to analyze our local data after noticing a surge in cases after 2005, particularly those presenting acutely with pneumonia. Excavation at contaminated construction sites has been noted to cause aerosolization of the fungus leading to exposure.3,16,17 We suspect that this surge is related to major highway construction that took place in the Indianapolis metropolitan area beginning in 2005. We also found the Table 3—Type of Presentation (N 5 58)a Presentation
No. (%)
Acute Pneumonia ARDS Disseminated Chronic Disseminated
31 (53) 23 (40) 7 (12) 7 (12) 27 (46) 17 (29)
One patient could not be classified as acute or chronic.
a
primary residence of most new patients was located near these construction sites (Fig 2). Additionally, recent reviews have observed that blastomycosis often localizes to specific counties.12,18 Although we documented a surge, we likely underestimated the incidence of blastomycosis in central Indiana. Our analysis included active surveillance of four hospitals that serve central Indiana. There are at least seven more hospitals that serve the same geographical area that were not included in this analysis. The epidemiologic classification of blastomycosis in Indiana is further hindered by the fact that the state does not require reporting of blastomycosis. Radiologic findings of pulmonary blastomycosis are highly variable.19,20 Radiologic characteristics (Table 4) were consistent with previous publications in that airspace consolidation was a common finding19 especially in those patients presenting with acute disease (63%).21,22 Upper-lobe involvement was more frequent in our series as has been described previously.23,24 Adenopathy was noted in 25% of our patients, similar to Sheflin et al,24 and higher than the 6% rate reported by others.23,25 Our observed frequency of adenopathy may be attributed to detection bias. Of the 13 cases of adenopathy we observed, eight were detected exclusively by chest CT scan. Cavitation was detected in six patients (four of six on CT scan alone), always appeared in the upper lobes, and was associated with acute disease 83% of the time. Our findings are similar to a previous report in which two of 16 patients had cavitation, both in the upper lobes, with one presenting acutely.20 A rapid diagnosis of blastomycosis can be made by visualizing the yeast organism in respiratory specimens or sites of extrapulmonary involvement using calcofluor white stain, potassium hydroxide wet mount, cytology, or histopathology.26 In our study, Blastomyces yeast was demonstrated by microscopic evaluation (cytopathology or histopathology) in 80% of subjects. Antigen detection also has been used for the diagnosis of blastomycosis and was positive in 74% of our cases. Although the highest sensitivity for diagnosis in our study was obtained by culture (86%), culture may not yield a rapid diagnosis because of the delay in recognizing growth of the organism. As such, antigen testing provides a reliable method to make an accurate and rapid diagnosis of blastomycosis, particularly when a large burden of disease is present and when cytologic analysis is performed at lessexperienced centers.12 Although antigen testing was completed on subjects from our cohort beginning in 2005, around the time highway construction was initiated, we do not have any evidence that antigen testing created detection bias. The Blastomyces antigen test became available for clinical use in June 2003. All but one patient were diagnosed using traditional
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Table 4—Results of Diagnostic Methods Used by Presentation Type Diagnostic Method Radiologic feature (n 5 51) Consolidation Adenopathy Interstitial infiltrates Mass Nodules Cavitation Negative Pleural effusion Unilobar disease Right upper lobe Left upper lobe Left lower lobe Right lower lobe Right middle lobe Initial diagnostic source (n 5 58)a BAL Lung biopsy Transbronchial biopsy Percutaneous FNA Open lung biopsy Lobectomy Skin or soft tissue biopsy Bone or joint biopsy Sputum Urine (antigen) Microbiologic tests Fungal culture (n 5 49) Fungal antigen ELISA (n 5 57) Blastomyces or Histoplasmab Blastomyces serology (n 5 25) Histopathology (n 5 42) Cytopathology (n 5 37)
Total, No. Acute (n 5 31), Chronic (%) No. (n 5 27), No. 24 (47) 13 (25) 11 (22) 8 (16) 6 (12) 6 (12) 4 (8) 3 (6) 19 (37) 9 6 2 1 1
15 8 8 4 2 4 0 3 12 … … … … …
9 5 3 4 4 2 4 0 7 … … … … …
23 (40) 16 (28) 7 5 4 1 15 (26) 8 (14) 3 1
20 9 3 2 1 0 5 2 1 1
3 7 4 3 3 1 10 6 2 0
42 (86)
28
14
42 (74)
35
7
8 (32)
4
4
34 (81) 14 (38)
18 11
16 3
ELISA 5 enzyme-linked immunosorbent assay; FNA 5 fine needle aspiration. aSeveral subjects had multiple positive specimens. bWe observed 100% cross-reactivity between assays. Several patients had samples from different sources (urine, serum, and BAL fluid).
methods of culture and cytopathology, and antigen testing was performed concomitantly. The cross-reactivity between the Blastomyces and Histoplasma antigen is well recognized.13 We observed a 100% cross-reactivity rate in the samples tested for both antigens from the same source. Differentiating between histoplasmosis and blastomycosis usually can be made based on epidemiologic, clinical, histopathologic, culture, or serologic differences. However, early differentiation may not be clinically as important in critically ill patients because management is similar between both conditions.26,27 Several publications have discussed the characteristics of blastomycosis in immunosuppressed patients. This population typically has severe infections associwww.chestpubs.org
Figure 2. Geographic plot of the Indianapolis metropolitan area highlighting the major interstate highways and the primary residences of patients with blastomycosis seen between the years 2005 and 2009.
ated with high mortality rates, especially in patients with AIDS.12,28 Diabetes mellitus was the most commonly reported comorbidity in our series, and compared with the entire cohort, these patients were more likely to present acutely (77% vs 53%; P 5 .216) and to die (15% vs 7%; P 5 .644). Our findings are consistent with other studies that have noted an increase of fungal disease prevalence in patients with diabetes, including blastomycosis,13 cryptococcosis,29 and coccidioidomycosis.30 We recognize several limitations in our study. First, we collected data from fewer than one-half (four of 11) of the hospitals serving central Indiana and most likely underestimated the true incidence of blastomycosis. Second, this retrospective analysis relied solely on review of medical records, which may not have documented exposure history and duration of illness accurately. Finally, the fact that blastomycosis is not a reportable disease in Indiana limits our ability to generate an accurate estimate of prevalence. The clinical presentation of blastomycosis is notoriously variable, and diagnosis often is delayed secondary to limited diagnostic methods and a low index of suspicion. Although blastomycosis is the rarest of endemic fungal diseases, this report should alert clinicians in the endemic area to be mindful of blastomycosis outbreaks during periods of construction. Blastomycosis should be considered in the differential diagnosis of community-acquired pneumonia in endemic areas, especially when antibacterial therapy is not effective. Acknowledgments Author contributions: Dr Carlos: contributed to the study concept and design, acquisition of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual CHEST / 138 / 6 / DECEMBER, 2010
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content. He had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Dr Rose: contributed to the acquisition of data. Dr Wheat: contributed to critical revision of the manuscript for important intellectual content. Dr Norris: contributed to acquisition of data. Dr Sarosi: contributed to critical revision of the manuscript for important intellectual content. Dr Knox: contributed to the study design and concept and critical revision of the manuscript for important intellectual content. Dr Hage: contributed to the study concept and design, acquisition of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. He had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflict of interest: Dr Wheat is an employee of MiraVista Diagnostics, the laboratory that developed and performs MVista Histoplasma and Blastomyces antigen enzyme immunoassay. Drs Carlos, Rose, Norris, Sarosi, Knox, and Hage have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank Dr Mitchell Goldman for his critical review of the manuscript.
References 1. Gilchrist TC. Protozoan dermatitis. J Cutan Genitourin Dis. 1894;12:496-499. 2. Chick EW, Baum GL, Furcolow ML, Huppert M, Kaufman L, Pappagianis R. Scientific Assembly statement. The use of skin tests and serologic tests in histoplasmosis, coccidioidomycosis, and blastomycosis, 1973. Am Rev Respir Dis. 1973;108(1):156-159. 3. Davies SF, Sarosi GA. Epidemiological and clinical features of pulmonary blastomycosis. Semin Respir Infect. 1997;12(3): 206-218. 4. Lahm T, Neese S, Thornburg AT, Ober MD, Sarosi GA, Hage CA. Corticosteroids for blastomycosis-induced ARDS: a report of two patients and review of the literature. Chest. 2008;133(6):1478-1480. 5. Baumgardner DJ, Buggy BP, Mattson BJ, Burdick JS, Ludwig D. Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis. 1992;15(4):629-635. 6. Bradsher RW. Clinical features of blastomycosis. Semin Respir Infect. 1997;12(3):229-234. 7. Watts B, Argekar P, Saint S, Kauffman CA. Clinical problemsolving. Building a diagnosis from the ground up—a 49-yearold man came to the clinic with a 1-week history of suprapubic pain and fever. N Engl J Med. 2007;356(14):1456-1462. 8. Sarosi GA, Davies SF. Blastomycosis. Am Rev Respir Dis. 1979;120(4):911-938. 9. Bariola JR, Hage CA, Durkin M, et al. Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis. Diagn Microbiol Infect Dis. In press. 10. Davies SF. An overview of pulmonary fungal infections. Clin Chest Med. 1987;8(3):495-512. 11. Sarosi GA. Community-acquired fungal diseases. Clin Chest Med. 1991;12(2):337-347.
12. McKinnell JA, Pappas PG. Blastomycosis: new insights into diagnosis, prevention, and treatment. Clin Chest Med. 2009;30(2):227-239. 13. Kralt D, Light B, Cheang M, et al. Clinical characteristics and outcomes in patients with pulmonary blastomycosis. Mycopathologia. 2009;167(3):115-124. 14. Durkin M, Witt J, Lemonte A, Wheat B, Connolly P. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol. 2004;42(10):4873-4875. 15. Hage CA, Davis TE, Fuller D, et al. Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest. 2010;137(3): 623-628. 16. Kitchen MS, Reiber CD, Eastin GB. An urban epidemic of North American blastomycosis. Am Rev Respir Dis. 1977; 115(6):1063-1066. 17. Tosh FE, Hammerman KJ, Weeks RJ, Sarosi GA. A common source epidemic of North American blastomycosis. Am Rev Respir Dis. 1974;109(5):525-529. 18. Hussein R, Khan S, Levy F, Mehta JB, Sarubbi FA. Blastomycosis in the mountainous region of northeast Tennessee. Chest. 2009;135(4):1019-1023. 19. Fang W, Washington L, Kumar N. Imaging manifestations of blastomycosis: a pulmonary infection with potential dissemination. Radiographics. 2007;27(3):641-655. 20. Winer-Muram HT, Beals DH, Cole FH Jr. Blastomycosis of the lung: CT features. Radiology. 1992;182(3):829-832. 21. Masood A, Bensadoun ES. A 62-year-old man with multiple pulmonary nodular opacities. Chest. 2002;121(3):982-984. 22. Patel RG, Patel B, Petrini MF, Carter RR III, Griffith J. Clinical presentation, radiographic findings, and diagnostic methods of pulmonary blastomycosis: a review of 100 consecutive cases. South Med J. 1999;92(3):289-295. 23. Rabinowitz JG, Busch J, Buttram WR. Pulmonary manifestations of blastomycosis. Radiological support of a new concept. Radiology. 1976;120(1):25-32. 24. Sheflin JR, Campbell JA, Thompson GP. Pulmonary blastomycosis: findings on chest radiographs in 63 patients. AJR Am J Roentgenol. 1990;154(6):1177-1180. 25. Halvorsen RA, Duncan JD, Merten DF, Gallis HA, Putman CE . Pulmonary blastomycosis: radiologic manifestations . Radiology. 1984;150(1):1-5. 26. Chapman SW, Dismukes WE, Proia LA, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(12): 1801-1812. 27. Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825. 28. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1992;116(10):847-853. 29. Kiertiburanakul S, Wirojtananugoon S, Pracharktam R, Sungkanuparph S. Cryptococcosis in human immunodeficiency virus-negative patients. Int J Infect Dis. 2006;10(1):72-78. 30. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes mellitus. Am J Med. 2006;119(11): 964-969.
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