Download Blastomycosis

3 CE Credits
Blastomycosis
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
organism. Blastomycosis has been characterized for more
than 100 years and affects almost all mammalian species,
most commonly dogs and humans. Although reported worldwide, the organism is endemic in North America. Research
interests in the veterinary and human medical fields include
environmental detection, serologic diagnosis, new treatments,
and vaccine formulation.1–3
Epidemiology
Veterinarians located in the Mississippi, Missouri, and Ohio river
valleys as well as those located in southeastern Canada should have
a high index of suspicion for this infection. The disease is endemic
in most of the mid-Atlantic and southern states; states with the
highest incidences include Kentucky, Louisiana, Mississippi,
South Carolina, Virginia, and Washington.4 Northern Illinois
and southern Wisconsin also have high incidence rates. In such
hyperendemic areas, >1% of the total population of dogs is
affected.2 Sporadic cases have also been reported in Colorado
and New York State, suggesting a wider range of endemic areas
than previously thought.5,6
There are very few reports of the organism being isolated from
nature, all using animal inoculation techniques, with thousands
of cultures unsuccessfully attempted.2 Investigating sources of
outbreaks is thus difficult. A soil isolation method using polymerase chain reaction–based detection of B. dermatitidis DNA
was developed in 2006.4 This test yielded positive results in three
out of eight soil samples near a dog kennel in Lexington, Kentucky,
where 35 of 100 dogs had reportedly contracted the disease the
year before. This is the first reported detection of B. dermatitidis
DNA from a natural source, possibly providing a means of rapid
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isolation for epidemiologists at sites of outbreaks as well as possibly
replacing animal inoculation techniques.2
Areas from which the organism has been successfully isolated
generally have acidic or sandy soil, decaying wood, and animal
feces.7 Humidity, fog, rain, and heavy dew are thought to facilitate
fungal sporulation and loosening of conidia from conidiophores.4,7
Proximity to waterways has also been implicated as a risk factor
for infection.7
Signalment plays a role in the occurrence of the disease in
dogs, with risk factors including young age, breed (Doberman
pinschers, golden retrievers, and Labrador retrievers), and possibly
male sex.7–9 In humans, diagnosis of blastomycosis is four to 15
times more common in males than in females.1
Pathogenesis and Clinical Presentation
The organism is primarily transmitted by inhalation of conidia that
are in the mycelial phase.7 Infection occurs when these conidia are
deposited into the alveoli, phagocytized by pulmonary macrophages,
and transported to the pulmonary interstitium,7 where normal body
temperatures promote transformation to the yeast phase.3 The
disease may stay localized in the lungs or may spread hematogenously or lymphatically to other body systems.7 Dermal or lingual
inoculation of the organism has also been reported, causing a
localized granulomatous disease; however, this form of transmission
is uncommon.8 The infection is not transmissible between humans,
between animals, or from animals to humans and, therefore, is
not considered contagious or zoonotic.1,4
A typical case presentation is a young, male, large-breed dog
presenting with coughing, tachypnea, or dyspnea. Skin lesions that
appear papular or plaque-like are commonly present, occasionally
with draining cutaneous tracts7,9 (FIGURE 1). Other common
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Blastomycosis
physical examination findings are lymphadenopathy,
ocular abnormalities such
as uveitis, and pyrexia.7,8 The
disease is usually pulmonary in origin and self-limiting.9 However, dissemination is possible, producing
a systemic, pyogranulomatous 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 history
Figure 1. Draining tract on the lateral hock of
of syncope suggestive of
a German shepherd. B. dermatitidis
heart failure.10 Heart lesions
organisms were confirmed on cytology.
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 problems 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 abnormalities such as retinal granulomas and retinal detachment are
reported to occur in 18% to 32% of cases.11–13 Central nervous
system disease is relatively common in cats with systemic blastomycosis and carries a poor prognosis.11,12
Diagnosis
Hematology
Routine hematologic screens are nonspecific for the diagnosis of
blastomycosis. However, high band neutrophil counts have been
correlated with decreased survivability in canine patients with
pulmonary blastomycosis.14
Cytology
Cytologic identification of blastomycosis organisms is the gold
standard and most common method of diagnosis. However, this
method has variable sensitivity, and multiple cytologic or histologic
samples may be needed for a diagnosis to be confirmed (FIGURE 2).
A 2008 study indicated that transthoracic fine-needle aspiration is
more sensitive (81%) than transtracheal washing (69%) for obtaining
a diagnostic sample in dogs with pulmonary blastomycosis.14
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Figure 2. Prostate fine-needle aspirate from an intact male dog with prostatitis due
to B. dermatitidis (arrows). Courtesy of Frank Norton, DVM.
Figure 3. Lateral thoracic radiograph of a dog with pulmonary blastomycosis.
Courtesy of Frank Norton, DVM.
Radiology
A diffuse miliary or nodular interstitial pattern has been reported
as the most common radiographic manifestation of pulmonary
blastomycosis7,8 (FIGURE 3). In a 2008 study of 125 dogs with pulmonary blastomycosis, most dogs (59%) had localized infiltrates
rather than diffuse, nodular, interstitial disease.15 These nondiffuse
patterns could mimic bacterial pneumonia or neoplasia, highlighting the need for a confirmatory diagnosis. Tracheobronchial
lymphadenopathy is seen in 25% to 29% of cases and is not
correlated with extent of lung disease or survival times.7,15 In the
study of 125 dogs, the number of affected lung lobes was the only
radiographic finding that was found to be significantly correlated
with decreased survivability.15 Of the 125 dogs in the study, 88%
of dogs with fewer than four lobes affected survived compared
with 52% of dogs with four or more lobes affected.
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Blastomycosis
Table 1. Summary of Treatment Studiesa
Total Number
of Dogs
Number Cured
Mortality
Number
Relapsed
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
ketoconazole, 10 mg/kg/d for 60 days
18
11 (61%)
4 (22%)
3 (17%)
Legendre 1984b
Amphotericin B and ketoconazole, 10 mg/kg/d
for 60 days
19
12 (63%)
7 (37%)
Not stated
Arceneaux 19987
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 +
ketoconazole, or itraconazole
195
108 (55%)
52 (27%)
35 (18%)
Arceneaux 1998,7
Legendre 1996,21
Legendre 1984b
Drug and Dosage
a
Wheat J, Legendre A. Blastomycosis in dogs. Accessed March 2011 at http://www.miravistalabs.com/Files/pdf/BlastomycosisinDogs2007.pdf. 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
Antibody Detection
Serologic tests that detect antibodies evaluate the humoral immune
response, which is not always indicative of active infection and varies
among patients. The most widely available serologic tests to detect
antibodies in veterinary medicine is agar gel immunodiffusion
(AGID), which has a reported sensitivity ranging from 17.4% to
90%.4,9,16,17 A study testing the antibody responses of dogs with
confirmed blastomycosis used a novel radioimmunoassay (RIA)
and compared the results with those from the traditional AGID
test.16 The reported difference in sensitivity was striking: 92% and
41% for the RIA and AGID methods, respectively. The specificity
of both tests was 100% when tested against negative controls. The
RIA method detected antibodies up to 1545 days after initial
diagnosis, whereas the AGID method detected <10% of positive
infections after day 10.16 Although this study revealed that the
RIA method is superior to the AGID method of antibody detection,
the RIA is unavailable for commercial use.
Another, more recent study17 compared the sera antibody detection rates of an enzyme immunoassay (EIA; MVista Blastomyces
dermatitidis antibody EIA, MiraVista Diagnostics) and the AGID
test (Meridian Bioscience) in dogs with confirmed blastomycosis.
The sensitivity of the EIA and AGID test was 76.1% and 17.4%,
respectively.
Antigen Detection
Because up to 30% of dogs lack detectable antibodies at the time
of presentation, studies are now looking at antigen assays as a method
of detecting B. dermatitidis infection.18 MiraVista Diagnostics
(Indianapolis, IN) has developed an EIA for detecting antigen in
serum and urine specimens (MVista Blastomyces dermatitidis
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Study
quantitative antigen EIA).17,19 Urine specimens from people with
blastomycosis and other fungal infections were used in studying
this test.19 In the study, the test was highly sensitive, detecting
almost 93% of blastomycosis cases. Furthermore, none of the urine
samples from healthy people yielded positive results. However,
the test was not specific for B. dermatitidis, having significant crossreactivity with Histoplasma capsulatum, Paracoccidioides brasiliensis,
and Penicillium marneffei. Although this test is imperfect, the
benefit of diagnosing a fungal infection and initiating treatment
early may outweigh the ability to differentiate organisms.
A competitive binding inhibition ELISA was 100% successful
in detecting B. dermatitidis antigen in urine samples from dogs
with blastomycosis in one study3 and has been used in university
settings. Cross-reactivity with H. capsulatum and a positive result
in a negative control were
issues with this test. Research is still in progress to
Key Facts
increase the specificity of
• The epidemiologic study of
this test and to define its
Blastomyces dermatitidis is
optimal parameters.
precluded by the difficulty in
The study that compared
culturing the organism from nature.
the AGID and EIA methods
of detecting antibodies17 also
• The “classic” radiographic pattern of
evaluated the EIA method
pulmonary blastomycosis is being
of antigen detection in dogs.
recharacterized.
The study used paired canine
• Recent advances in the antigen
urine and serum specimens
detection of B. dermatitidis are
of 46 confirmed blastomyimproving the reliability of serologic
cosis cases and 44 control
diagnosis.
cases negative for fungal
infection. Urine specimens
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Blastomycosis
yielded a sensitivity of 93%, whereas serum specimens yielded a
sensitivity of 87%. The specificity was excellent (100%) for both
specimen types using the negative controls. Cross-reactivity with
other fungal organisms was not investigated in this study. The
findings of this study are promising for the use of EIA antigen
testing in the early diagnosis of blastomycosis in dogs.
Treatment
The treatment for blastomycosis depends on the severity of disease.
If significant pulmonary compromise is present, amphotericin B
is recommended along with itraconazole for the first 4 to 7 days,
followed by itraconazole for 4 to 6 months or 1 month past radiographic resolution.14,20 In less severe cases, itraconazole alone is
recommended for at least 60 days or 1 month past resolution of
clinical or radiographic signs of disease.21 Ketoconazole is less
effective than itraconazole; however, if cost of treatment is a concern,
using amphotericin B for the first 4 days along with ketoconazole
results in similar response rates to use of itraconazole alone.20
Fluconazole is another azole antifungal that is minimally protein
bound and highly water soluble, penetrating the blood–brain
and prostatic barriers in higher concentrations than other azoles.
This drug may play a role in treating central nervous system or
prostatic blastomycosis; however, itraconazole is more effective
in most cases. Corticosteroids are reserved for dogs with dyspnea
and should only be used after treatment with antifungals has
been initiated.4 In general, 25% of cases fail to respond to treatment,
and of the cases that respond to treatment, 25% relapse when
medication is discontinued. The overall treatment success rate is
about 70% to 80%.4,8,21 A summary of treatment studies is outlined
in TABLE 1.
Alternative treatments include the newer triazoles voriconazole
and posaconazole.22 Both show promising results in humans and
mice.23–26 Voriconazole, a derivative of fluconazole, has shown to
lengthen the life of mice infected with pulmonary blastomycosis
in a dose-dependent fashion.24 With its wide tissue distribution,
this drug may be effective in treating central nervous system
blastomycosis; it has been successful in treating a human case of
cerebral blastomycosis.27 Posaconazole is an analogue of itraconazole. This drug improved survivability in mice infected with
B. dermatitis compared with itraconazole, fluconazole, and amphotericin B.23 Also, samples of lung tissue that were obtained
and cultured after treatment with posaconazole were negative for
B. dermatitis, in contrast to the other three drugs.23
Vaccine
Studies are ongoing in formulating an effective and safe vaccine
against blastomycosis. Early studies used a recombinant BAD1
(an immunodominant surface antigen) vaccine to initiate an
immune response.28 The increase in survival time of vaccinated
mice compared with unvaccinated control mice was modest.
Monoclonal antibodies against BAD1 were then investigated for
their protective value.29 None of the mice was protected against
experimental pulmonary infection, indicating that inducing an
antibody response is not protective.29
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A recombinant, live attenuated vaccine has also been formulated.
Mice injected subcutaneously with live yeast of this mutant strain
of B. dermatitis had significantly improved survival when challenged
with nonmutant B. dermatitidis.30 This genetically engineered
strain of B. dermatitidis shows promise in the future of vaccines
against the organism, both therapeutically and preventively. This
vaccine is being evaluated for trials in human volunteers.1
References
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
Blastomyces dermatitidis from natural soil samples. Med Mycol 2006;44:741-748.
3. Shurley J, Legendre A, Scalarone G. Blastomyces dermatitidis antigen detection in
urine specimens from dogs with blastomycosis using a competitive binding inhibition
ELISA. Mycopathologia 2005;160(2):137-142.
4. Legendre A. Blastomycoses. In: Greene CE, ed. Infectious Diseases of the Dog and
Cat. St. Louis: Saunders; 2006:569-576.
5. De Groote MA, Bjerke R, Smith H, Rhodes LV III. Expanding epidemiology of blastomycosis: clinical features and investigation of 2 cases in Colorado. Clin Infect Dis
2000;30:582-584.
6. Côté E, Barr SC, Allen C, Eaglefeather E. Blastomycosis in six dogs in New York State.
JAVMA 1997;210(4):502-504.
7. Arceneaux KA, Taboada J, Hosgood G. Blastomycosis in dogs: 115 cases (19801995). JAVMA 1998;213(5):658-664.
8. Kerl ME. Update on canine and feline fungal diseases. Vet Clin North Am Small Anim
Pract 2003;33:721-747.
9. Rudmann DG, Coolman BR, Perez CM, Glickman LT. Evaluation of risk factors for
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
with Blastomyces dermatitidis infection. J Vet Intern Med 2006;20:1351-1354.
11. Gilor C, Graves TK, Barger AM, O’Dell-Anderson K. Clinical aspects of natural infection Blastomyces dermatitidis in cats: 8 cases (1991-2005). JAVMA 2006;229(1):96-99.
12. Miller PE, Miller LM, Schoster JV. Feline blastomycosis: A report of 3 cases and a
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.
14. Crews LJ, Feeney DA, Jessen CR, et al. Utility of diagnostic tests for and medical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006). JAVMA
2008;232(2): 222-227.
15. Crews LJ, Feeney DA, Jessen CR, Newman AB. Radiographic findings in dogs with
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
dermatitidis WI-1 antigen. Am J Vet Res 2000;61(5):554-558.
17. Spector D, Legendre AM, Wheat J, et al. Antigen and antibody testing for the diagnosis of blastomycosis in dogs. J Vet Intern Med 2008;22(4):839-843.
18. Spector D, Wheat J, Bemis D, et al. Antigen testing for the diagnosis of blastomycosis. Proc 24th Annu ACVIM Forum 2006:731.
19. Durkin M, Witt J, LeMonte A, et al. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol 2004;42(10):4873-4875.
20. Wheat J, Legendre A. Blastomycosis in dogs. http://www.miravistalabs.com/Files/
pdf/BlastomycosisinDogs2007.pdf. Accessed March 2011.
21. Legendre AM, Rohrbach BW, Toal RL, et al. Treatment of blastomycosis with itraconazole in 112 dogs. J Vet Intern Med 1996;10:365-371.
22. Whelan N. Voriconazole, posaconazole, ravuconazole: an update on emerging azole
antifungal agents. Proc 20th Annu ACVIM Forum 2002:468-470.
23. Sugar AM, Liu XP. In vitro and in vivo activities of SCH 56592 against Blastomyces
dermatitidis. Antimicrob Agents Chemother 1996;40(5):1314-1316.
24. Sugar AM, Liu XP. Efficacy of voriconazole in treatment of murine pulmonary blastomycosis. Antimicrob Agents Chemother 2001;45(2):601-604.
25. Jeu L, Piacenti FJ, Lyakhovetskiy AG, Fung HB. Voriconazole. Clin Ther 2003;25(5):
1321-1381.
26. Nagappan V, Deresinski S. Reviews of anti-infective agents: posaconazole: a broadspectrum triazole antifungal agent. Clin Infect Dis 2007;45(12):1610-1617.
27. Bakleh M, Aksamit AJ, Tleyjeh IM, Marshall WF. Successful treatment of cerebral
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blastomycosis with voriconazole. Clin Infect Dis 2005;40:e69-e71.
28. Wüthrich M, Chang WL, Klein BS. Immunogenicity and protective efficacy of the
WI-1 adhesin of Blastomyces dermatitidis. Infect Immun 1998;66(10):5443-5449.
29. Wüthrich M, Klein BS. Investigation of anti-WI-1 adhesin antibody-mediated protec-
3 CE Credits
tion in experimental pulmonary blastomycosis. J Infect Dis 2000;181:1720-1728.
30. Wüthrich M, Filutowicz HI, Klein BS. Mutation of the WI-1 gene yields an attenuated Blastomyces dermatitidis strain that induces host resistance. J Clin Invest
2000;106:1381-1389.
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1. What currently available test method is the most sensitive
for diagnosing B. dermatitidis infection?
6. What is the overall treatment success rate for blastomycosis?
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
2. Patients with blastomycosis may present with
7. In cats, the most common physical examination finding
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
a. dermal inoculation
8. Which is the drug of choice for treatment of uncomplicated
blastomycosis?
b. contact with other infected animals
a. itraconazole
c. inhalation of fungal conidia
b. amphotericin B
d. ingestion of fungal conidia
c. fluconazole
4. Which diagnostic test is most commonly used in clinical
practice to diagnose blastomycosis?
a. serology
d. voriconazole
9. A negative prognostic indicator for dogs with pulmonary
blastomycosis is
b. histopathology
a. an alveolar pattern.
c. fungal culture
b. tracheobronchial lymphadenopathy.
d. cytology
c. involvement of four or more lung lobes.
5. Which method is most likely to obtain a diagnostic sample
for cytology?
a. transtracheal wash
d. an interstitial pattern.
10.The most common radiographic finding(s) in pulmonary
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 b
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