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  • 1. 3 CE CreditsBlastomycosis Allison Werner, DVM Brykerwood Veterinary Clinic Austin, Texas Frank Norton, DVM, MS, DACVIM VCA Berwyn Berwyn, Illinois Abstract: For more than 100 years, blastomycosis has been recognized as causing significant morbidity and mortality in people and dogs. The disease is rare in cats. Isolation of the organism is difficult, and novel methods to culture environmental samples are forthcoming. The most significant clinical dilemma is the inability to make a timely diagnosis when multiple cytologic samples are unrewarding. This article reviews the literature on advances in epidemiology and serology, clinical presentations, new antifungal drugs, and progress in formulating a vaccine. B lastomyces dermatitidis is a well-known, infectious, fungal isolation for epidemiologists at sites of outbreaks as well as possibly organism. Blastomycosis has been characterized for more replacing animal inoculation techniques.2 than 100 years and affects almost all mammalian species, Areas from which the organism has been successfully isolated most commonly dogs and humans. Although reported world- generally have acidic or sandy soil, decaying wood, and animal wide, the organism is endemic in North America. Research feces.7 Humidity, fog, rain, and heavy dew are thought to facilitate interests in the veterinary and human medical fields include fungal sporulation and loosening of conidia from conidiophores.4,7 environmental detection, serologic diagnosis, new treatments, Proximity to waterways has also been implicated as a risk factor and vaccine formulation.1–3 for infection.7 Signalment plays a role in the occurrence of the disease in Epidemiology dogs, with risk factors including young age, breed (Doberman Veterinarians located in the Mississippi, Missouri, and Ohio river pinschers, golden retrievers, and Labrador retrievers), and possibly valleys as well as those located in southeastern Canada should have male sex.7–9 In humans, diagnosis of blastomycosis is four to 15 a high index of suspicion for this infection. The disease is endemic times more common in males than in females.1 in most of the mid-Atlantic and southern states; states with the highest incidences include Kentucky, Louisiana, Mississippi, Pathogenesis and Clinical Presentation South Carolina, Virginia, and Washington.4 Northern Illinois The organism is primarily transmitted by inhalation of conidia that and southern Wisconsin also have high incidence rates. In such are in the mycelial phase.7 Infection occurs when these conidia are hyperendemic areas, >1% of the total population of dogs is deposited into the alveoli, phagocytized by pulmonary macrophages, affected.2 Sporadic cases have also been reported in Colorado and transported to the pulmonary interstitium,7 where normal body and New York State, suggesting a wider range of endemic areas temperatures promote transformation to the yeast phase.3 The than previously thought.5,6 disease may stay localized in the lungs or may spread hematoge- There are very few reports of the organism being isolated from nously or lymphatically to other body systems.7 Dermal or lingual nature, all using animal inoculation techniques, with thousands inoculation of the organism has also been reported, causing a of cultures unsuccessfully attempted.2 Investigating sources of localized granulomatous disease; however, this form of transmission outbreaks is thus difficult. A soil isolation method using poly- is uncommon.8 The infection is not transmissible between humans, merase chain reaction–based detection of B. dermatitidis DNA between animals, or from animals to humans and, therefore, is was developed in 2006.4 This test yielded positive results in three not considered contagious or zoonotic.1,4 out of eight soil samples near a dog kennel in Lexington, Kentucky, A typical case presentation is a young, male, large-breed dog where 35 of 100 dogs had reportedly contracted the disease the presenting with coughing, tachypnea, or dyspnea. Skin lesions that year before. This is the first reported detection of B. dermatitidis appear papular or plaque-like are commonly present, occasionally DNA from a natural source, possibly providing a means of rapid with draining cutaneous tracts7,9 (FIGURE 1). Other | August 2011 | Compendium: Continuing Education for Veterinarians® E1©Copyright 2011 MediMedia Animal Health. This document is for internal purposes only. Reprinting or posting on an external website without written permission from MMAH is a violation of copyright laws.
  • 2. Blastomycosis physical examination find- ings are lymphadenopathy, ocular abnormalities such as uveitis, and pyrexia.7,8 The disease is usually pulmo- nary in origin and self-lim- iting.9 However, dissemi- nation is possible, producing a systemic, pyogranuloma- tous infection that can affect the lymphatics, eyes, bones, skin, central nervous and urogenital systems, and many organs, including the heart.4,10 Dogs may present with respiratory signs, a heart murmur, and a historyFigure 1. Draining tract on the lateral hock of Figure 2. Prostate fine-needle aspirate from an intact male dog with prostatitis due of syncope suggestive ofa German shepherd. B. dermatitidis to B. dermatitidis (arrows). Courtesy of Frank Norton, DVM.organisms were confirmed on cytology. heart failure.10 Heart lesions caused by blastomycosis, although rare, can range from myocarditis to endocarditis due to pyogranulomatous and fibrous masses in and around the heart.10 Blastomycosis is very rare in cats. To date, three review articles account for all of the reported cases in cats. The presentation is similar to that in dogs and does not appear to be related to immunosuppression caused by retroviruses.11,12 A 2006 study11 of eight cases of blastomycosis in cats revealed respiratory prob- lems as the most common chief complaint, which is consistent with previous reports. Respiratory signs were primarily dyspnea, tachypnea, and coughing. Lymphadenopathy is generally not appreciated in cats; however, fever and skin lesions are prominent physical examination findings.11 Skin lesions reported in cats are mostly dermal masses on the head and trunk.11 Ocular abnor- malities such as retinal granulomas and retinal detachment are reported to occur in 18% to 32% of cases.11–13 Central nervous Figure 3. Lateral thoracic radiograph of a dog with pulmonary blastomycosis. system disease is relatively common in cats with systemic blasto- Courtesy of Frank Norton, DVM. mycosis and carries a poor prognosis.11,12 Diagnosis Radiology Hematology A diffuse miliary or nodular interstitial pattern has been reported Routine hematologic screens are nonspecific for the diagnosis of as the most common radiographic manifestation of pulmonary blastomycosis. However, high band neutrophil counts have been blastomycosis7,8 (FIGURE 3). In a 2008 study of 125 dogs with pul- correlated with decreased survivability in canine patients with monary blastomycosis, most dogs (59%) had localized infiltrates pulmonary blastomycosis.14 rather than diffuse, nodular, interstitial disease.15 These nondiffuse patterns could mimic bacterial pneumonia or neoplasia, high- Cytology lighting the need for a confirmatory diagnosis. Tracheobronchial Cytologic identification of blastomycosis organisms is the gold lymphadenopathy is seen in 25% to 29% of cases and is not standard and most common method of diagnosis. However, this correlated with extent of lung disease or survival times.7,15 In the method has variable sensitivity, and multiple cytologic or histologic study of 125 dogs, the number of affected lung lobes was the only samples may be needed for a diagnosis to be confirmed (FIGURE 2). radiographic finding that was found to be significantly correlated A 2008 study indicated that transthoracic fine-needle aspiration is with decreased survivability.15 Of the 125 dogs in the study, 88% more sensitive (81%) than transtracheal washing (69%) for obtaining of dogs with fewer than four lobes affected survived compared a diagnostic sample in dogs with pulmonary blastomycosis.14 with 52% of dogs with four or more lobes | August 2011 | Compendium: Continuing Education for Veterinarians® E2
  • 3. Blastomycosis Table 1. Summary of Treatment Studiesa Total Number Number Drug and Dosage of Dogs Number Cured Mortality Relapsed Study Ketoconazole, 10 mg/kg/d for 60 days 9 3 (33%) 3 (33%) 3 (33%) Legendre 1984b Amphotericin B, 1 mg/kg/dose for 8–9 mg/kg 35 20 (57%) 8 (23%) 5 (20%) Legendre 1984b Amphotericin B, 1 mg/kg/d for four doses, then 18 11 (61%) 4 (22%) 3 (17%) Legendre 1984b ketoconazole, 10 mg/kg/d for 60 days Amphotericin B and ketoconazole, 10 mg/kg/d 19 12 (63%) 7 (37%) Not stated Arceneaux 19987 for 60 days Itraconazole, 10 mg/kg/d for 60 days 56 30 (54%) 14 (25%) 12 (21%) Legendre 199621 Itraconazole, 5 mg/kg/d with food for 60 days 35 19 (54%) 9 (26%) 7 (20%) Legendre 199621 Itraconazole, 10 mg/kg/d for 60–90 days 31 16 (52%) 10 (32%) 5 (16%) Arceneaux 19987 Overall with amphotericin B, amphotericin B + 195 108 (55%) 52 (27%) 35 (18%) Arceneaux 1998,7 ketoconazole, or itraconazole Legendre 1996,21 Legendre 1984b a Wheat J, Legendre A. Blastomycosis in dogs. Accessed March 2011 at Used with permission. b Legendre AM, Selcer BA, Edwards DF, Stevens R. Treatment of canine blastomycosis with amphotericin B and ketoconazole. JAVMA 1984;184:1249-1254. Serology quantitative antigen EIA).17,19 Urine specimens from people with Antibody Detection blastomycosis and other fungal infections were used in studying Serologic tests that detect antibodies evaluate the humoral immune this test.19 In the study, the test was highly sensitive, detecting response, which is not always indicative of active infection and varies almost 93% of blastomycosis cases. Furthermore, none of the urine among patients. The most widely available serologic tests to detect samples from healthy people yielded positive results. However, antibodies in veterinary medicine is agar gel immunodiffusion the test was not specific for B. dermatitidis, having significant cross- (AGID), which has a reported sensitivity ranging from 17.4% to reactivity with Histoplasma capsulatum, Paracoccidioides brasiliensis, 90%.4,9,16,17 A study testing the antibody responses of dogs with and Penicillium marneffei. Although this test is imperfect, the confirmed blastomycosis used a novel radioimmunoassay (RIA) benefit of diagnosing a fungal infection and initiating treatment and compared the results with those from the traditional AGID early may outweigh the ability to differentiate organisms. test.16 The reported difference in sensitivity was striking: 92% and A competitive binding inhibition ELISA was 100% successful 41% for the RIA and AGID methods, respectively. The specificity in detecting B. dermatitidis antigen in urine samples from dogs of both tests was 100% when tested against negative controls. The with blastomycosis in one study3 and has been used in university RIA method detected antibodies up to 1545 days after initial settings. Cross-reactivity with H. capsulatum and a positive result diagnosis, whereas the AGID method detected <10% of positive in a negative control were infections after day 10.16 Although this study revealed that the issues with this test. Re- RIA method is superior to the AGID method of antibody detection, search is still in progress to Key Facts the RIA is unavailable for commercial use. increase the specificity of Another, more recent study17 compared the sera antibody de- this test and to define its • The epidemiologic study of tection rates of an enzyme immunoassay (EIA; MVista Blastomyces optimal parameters. Blastomyces dermatitidis is dermatitidis antibody EIA, MiraVista Diagnostics) and the AGID The study that compared precluded by the difficulty in test (Meridian Bioscience) in dogs with confirmed blastomycosis. the AGID and EIA methods culturing the organism from nature. The sensitivity of the EIA and AGID test was 76.1% and 17.4%, of detecting antibodies17 also • The “classic” radiographic pattern of respectively. evaluated the EIA method pulmonary blastomycosis is being of antigen detection in dogs. recharacterized. Antigen Detection The study used paired canine Because up to 30% of dogs lack detectable antibodies at the time urine and serum specimens • Recent advances in the antigen of presentation, studies are now looking at antigen assays as a method of 46 confirmed blastomy- detection of B. dermatitidis are of detecting B. dermatitidis infection.18 MiraVista Diagnostics cosis cases and 44 control improving the reliability of serologic (Indianapolis, IN) has developed an EIA for detecting antigen in cases negative for fungal diagnosis. serum and urine specimens (MVista Blastomyces dermatitidis infection. Urine | August 2011 | Compendium: Continuing Education for Veterinarians® E3
  • 4. Blastomycosis yielded a sensitivity of 93%, whereas serum specimens yielded a A recombinant, live attenuated vaccine has also been formulated. sensitivity of 87%. The specificity was excellent (100%) for both Mice injected subcutaneously with live yeast of this mutant strain specimen types using the negative controls. Cross-reactivity with of B. dermatitis had significantly improved survival when challenged other fungal organisms was not investigated in this study. The with nonmutant B. dermatitidis.30 This genetically engineered findings of this study are promising for the use of EIA antigen strain of B. dermatitidis shows promise in the future of vaccines testing in the early diagnosis of blastomycosis in dogs. against the organism, both therapeutically and preventively. This vaccine is being evaluated for trials in human volunteers.1 Treatment The treatment for blastomycosis depends on the severity of disease. References If significant pulmonary compromise is present, amphotericin B 1. Pappas P. Blastomycosis. Semin Respir Crit Care Med 2004;25(2):113-121. 2. Burgess J, Schwan W, Volk T. PCR based detection of DNA from the human pathogen is recommended along with itraconazole for the first 4 to 7 days, Blastomyces dermatitidis from natural soil samples. Med Mycol 2006;44:741-748. followed by itraconazole for 4 to 6 months or 1 month past radio- 3. Shurley J, Legendre A, Scalarone G. Blastomyces dermatitidis antigen detection in graphic resolution.14,20 In less severe cases, itraconazole alone is urine specimens from dogs with blastomycosis using a competitive binding inhibition recommended for at least 60 days or 1 month past resolution of ELISA. Mycopathologia 2005;160(2):137-142. clinical or radiographic signs of disease.21 Ketoconazole is less 4. Legendre A. Blastomycoses. In: Greene CE, ed. Infectious Diseases of the Dog and effective than itraconazole; however, if cost of treatment is a concern, Cat. St. Louis: Saunders; 2006:569-576. 5. De Groote MA, Bjerke R, Smith H, Rhodes LV III. Expanding epidemiology of blas- using amphotericin B for the first 4 days along with ketoconazole tomycosis: clinical features and investigation of 2 cases in Colorado. Clin Infect Dis results in similar response rates to use of itraconazole alone.20 2000;30:582-584. Fluconazole is another azole antifungal that is minimally protein 6. Côté E, Barr SC, Allen C, Eaglefeather E. Blastomycosis in six dogs in New York State. bound and highly water soluble, penetrating the blood–brain JAVMA 1997;210(4):502-504. 7. Arceneaux KA, Taboada J, Hosgood G. Blastomycosis in dogs: 115 cases (1980- and prostatic barriers in higher concentrations than other azoles. 1995). JAVMA 1998;213(5):658-664. This drug may play a role in treating central nervous system or 8. Kerl ME. Update on canine and feline fungal diseases. Vet Clin North Am Small Anim prostatic blastomycosis; however, itraconazole is more effective Pract 2003;33:721-747. in most cases. Corticosteroids are reserved for dogs with dyspnea 9. Rudmann DG, Coolman BR, Perez CM, Glickman LT. Evaluation of risk factors for and should only be used after treatment with antifungals has blastomycosis in dogs: 857 cases (1980-1990). JAVMA 1992;201(11):1754-1759. 10. Schmiedt C, Kellum H, Legendre AM, et al. Cardiovascular involvement in 8 dogs been initiated.4 In general, 25% of cases fail to respond to treatment, with Blastomyces dermatitidis infection. J Vet Intern Med 2006;20:1351-1354. and of the cases that respond to treatment, 25% relapse when 11. Gilor C, Graves TK, Barger AM, O’Dell-Anderson K. Clinical aspects of natural infec- medication is discontinued. The overall treatment success rate is tion Blastomyces dermatitidis in cats: 8 cases (1991-2005). JAVMA 2006;229(1):96-99. about 70% to 80%.4,8,21 A summary of treatment studies is outlined 12. Miller PE, Miller LM, Schoster JV. Feline blastomycosis: A report of 3 cases and a in TABLE 1. literature review (1961-1988). JAAHA 1990;26(4):417-424. 13. Davies C, Troy GC. Deep mycotic infections in cats. JAAHA 1996;32:380-391. Alternative treatments include the newer triazoles voriconazole 14. Crews LJ, Feeney DA, Jessen CR, et al. Utility of diagnostic tests for and med- and posaconazole.22 Both show promising results in humans and ical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006). JAVMA mice.23–26 Voriconazole, a derivative of fluconazole, has shown to 2008;232(2): 222-227. lengthen the life of mice infected with pulmonary blastomycosis 15. Crews LJ, Feeney DA, Jessen CR, Newman AB. Radiographic findings in dogs with in a dose-dependent fashion.24 With its wide tissue distribution, pulmonary blastomycosis: 125 cases (1989-2006). JAVMA 2008;232(2):215-221. 16. Klein BS, Squires RA, Lloyd JK, et al. Canine antibody response to Blastomyces this drug may be effective in treating central nervous system dermatitidis WI-1 antigen. Am J Vet Res 2000;61(5):554-558. blastomycosis; it has been successful in treating a human case of 17. Spector D, Legendre AM, Wheat J, et al. Antigen and antibody testing for the diagno- cerebral blastomycosis.27 Posaconazole is an analogue of itracon- sis of blastomycosis in dogs. J Vet Intern Med 2008;22(4):839-843. azole. This drug improved survivability in mice infected with 18. Spector D, Wheat J, Bemis D, et al. Antigen testing for the diagnosis of blastomyco- B. dermatitis compared with itraconazole, fluconazole, and am- sis. Proc 24th Annu ACVIM Forum 2006:731. 19. Durkin M, Witt J, LeMonte A, et al. Antigen assay with the potential to aid in diagno- photericin B.23 Also, samples of lung tissue that were obtained sis of blastomycosis. J Clin Microbiol 2004;42(10):4873-4875. and cultured after treatment with posaconazole were negative for 20. Wheat J, Legendre A. Blastomycosis in dogs. B. dermatitis, in contrast to the other three drugs.23 pdf/BlastomycosisinDogs2007.pdf. Accessed March 2011. 21. Legendre AM, Rohrbach BW, Toal RL, et al. Treatment of blastomycosis with itracon- Vaccine azole in 112 dogs. J Vet Intern Med 1996;10:365-371. 22. Whelan N. Voriconazole, posaconazole, ravuconazole: an update on emerging azole Studies are ongoing in formulating an effective and safe vaccine antifungal agents. Proc 20th Annu ACVIM Forum 2002:468-470. against blastomycosis. Early studies used a recombinant BAD1 23. Sugar AM, Liu XP. In vitro and in vivo activities of SCH 56592 against Blastomyces (an immunodominant surface antigen) vaccine to initiate an dermatitidis. Antimicrob Agents Chemother 1996;40(5):1314-1316. immune response.28 The increase in survival time of vaccinated 24. Sugar AM, Liu XP. Efficacy of voriconazole in treatment of murine pulmonary blas- mice compared with unvaccinated control mice was modest. tomycosis. Antimicrob Agents Chemother 2001;45(2):601-604. 25. Jeu L, Piacenti FJ, Lyakhovetskiy AG, Fung HB. Voriconazole. Clin Ther 2003;25(5): Monoclonal antibodies against BAD1 were then investigated for 1321-1381. their protective value.29 None of the mice was protected against 26. Nagappan V, Deresinski S. Reviews of anti-infective agents: posaconazole: a broad- experimental pulmonary infection, indicating that inducing an spectrum triazole antifungal agent. Clin Infect Dis 2007;45(12):1610-1617. antibody response is not protective.29 27. Bakleh M, Aksamit AJ, Tleyjeh IM, Marshall WF. Successful treatment of | August 2011 | Compendium: Continuing Education for Veterinarians® E4
  • 5. Blastomycosis blastomycosis with voriconazole. Clin Infect Dis 2005;40:e69-e71. tion in experimental pulmonary blastomycosis. J Infect Dis 2000;181:1720-1728. 28. Wüthrich M, Chang WL, Klein BS. Immunogenicity and protective efficacy of the 30. Wüthrich M, Filutowicz HI, Klein BS. Mutation of the WI-1 gene yields an at- WI-1 adhesin of Blastomyces dermatitidis. Infect Immun 1998;66(10):5443-5449. tenuated Blastomyces dermatitidis strain that induces host resistance. J Clin Invest 29. Wüthrich M, Klein BS. Investigation of anti-WI-1 adhesin antibody-mediated protec- 2000;106:1381-1389. This article qualifies for 3 contact hours of continuing education credit from the Auburn University College of Veterinary Medicine. CE tests must be taken online at; test results and CE certificates are available immediately. Those who wish to apply this credit to 3 CE Credits fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program. 1. What currently available test method is the most sensitive 6. What is the overall treatment success rate for blastomycosis? for diagnosing B. dermatitidis infection? a. 25% to 35% a. AGID antibody test b. 45% to 55% b. EIA antigen test c. 70% to 80% c. cytology of lung aspirate d. 90% to 100% d. chest radiography 7. In cats, the most common physical examination finding 2. Patients with blastomycosis may present with related to blastomycosis is a. uveitis. a. lymphadenopathy. b. neurologic signs. b. neurologic impairment. c. heart murmur. c. ocular abnormalities. d. all of the above d. respiratory problems. 3. Blastomycosis is transmitted primarily by 8. Which is the drug of choice for treatment of uncomplicated a. dermal inoculation blastomycosis? b. contact with other infected animals a. itraconazole c. inhalation of fungal conidia b. amphotericin B d. ingestion of fungal conidia c. fluconazole d. voriconazole 4. Which diagnostic test is most commonly used in clinical practice to diagnose blastomycosis? 9. A negative prognostic indicator for dogs with pulmonary a. serology blastomycosis is b. histopathology a. an alveolar pattern. c. fungal culture b. tracheobronchial lymphadenopathy. d. cytology c. involvement of four or more lung lobes. d. an interstitial pattern. 5. Which method is most likely to obtain a diagnostic sample for cytology? 10. The most common radiographic finding(s) in pulmonary a. transtracheal wash blastomycosis is/are b. transthoracic fine-needle aspiration a. a diffuse interstitial pattern. c. impression smear of nasal discharge b. a localized infiltrative pattern. d. pharyngeal swab c. tracheobronchial lymphadenopathy. d. a and | August 2011 | Compendium: Continuing Education for Veterinarians® E5