Blastomycosis
Joe Wheat MD, Janelle Renschler DVM, PhD, Heather Largura DDS
See Sykes, J.E. for more detailed information [1
Background
- Causative agents: Dimorphic fungi Blastomyces dermatitidis, B. gilchristii (formerly a cryptic subspecies of B. dermatitidis), B. helicus (new species rarely found in the Southwest United States and parts of Canada) [2
Schwartz, I.S., et al., Blastomyces helicus, a New Dimorphic Fungus Causing Fatal Pulmonary and Systemic Disease in Humans and Animals in Western Canada and the United States. Clin Infect Dis, 2019. 68(2): p. 188-195. ]. - Route of infection: inhalation of spores, rarely cutaneous inoculation.
- At highest risk: young, large breed dogs with highest rates in Coonhounds, Pointers, and Weimaraners; higher rates in sexually intact males caused by roaming behavior or hunting.
- Endemic distribution: Mississippi, Ohio, and Missouri river valleys, VT, Eastern seaboard, Canada (primarily western ON, parts of MB and SK), and areas adjacent to Great Lakes but may occur outside of endemic areas [2
Schwartz, I.S., et al., Blastomyces helicus, a New Dimorphic Fungus Causing Fatal Pulmonary and Systemic Disease in Humans and Animals in Western Canada and the United States. Clin Infect Dis, 2019. 68(2): p. 188-195. ].
Clinical Findings
- Pulmonary: ~90% (often accompanied by disseminated findings)
- Signs: tachypnea, cough, dyspnea
- Imaging: nodular, referred to as “snowstorm pattern” or interstitial infiltrates. Less frequent: tracheobronchial lymphadenopathy, masses, or cavitary lesions.
- Disseminated (extrapulmonary): >50%; may be accompanied by pulmonary involvement
- Nonspecific signs: >75%; fever, anorexia, weight loss, lethargy, reduced activity
- Cutaneous lesions: ~50%; ulcerations with drainage, granulomas, subcutaneous abscesses; especially on nasal planum, face, and nail beds.
- Peripheral lymphadenomegaly: ~40%
- Ocular involvement: ~40%; uveitis, chorioretinitis, optic neuritis, retinal detachment, retinal granulomas, vitritis, glaucoma, lens rupture, panopthalmitis.
- Bone lesions: ~20%; lameness, draining lesions, sinus tracts. Imaging reveals osteolytic lesions with periosteal proliferation, usually solitary and distal to stifle and elbow.
- CNS involvement: ~5%; meningoencephalitis, brain lesions, ependymitis with signs of behavioral change, seizures, weakness, ataxia, paralysis, cranial nerve abnormalities.
- Other: <5%: sinonasal, cardiac, gastrointestinal, renal, bladder, testes, prostate, mammary gland.
Laboratory abnormalities
- CBC: normocytic, normochromic nonregenerative anemia, neutrophilia, monocytosis, lymphocytosis, or lymphopenia.
- Serum chemistry profile: mild to moderate hyperglobulinemia due to polyclonal gammopathy, hypoalbuminemia, and uncommonly mild hypercalcemia.
- Urinalysis: occasional proteinuria, pyuria, hematuria or cylindruria; rarely yeasts seen on sediment exam.
- CSF analysis: increased total nucleated cell counts and increased CSF protein concentration.
Diagnosis
- Cytology (FNA/impression smear or respiratory specimens) or histopathology
- Advantage: FNA or biopsy easy to perform if cutaneous lesions or lymphadenopathy present and most rapid method for diagnosis.
- Disadvantage:
- Risk and higher cost if more invasive procedure required in the absence of skin lesions or enlarged lymph nodes (i.e., respiratory specimens or surgical or ultrasound-guided biopsy)
- Sensitivity for transtracheal lavage is 69 – 76% [3
Crews, L.J., et al., Utility of diagnostic tests for and medical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006). J. Am. Vet. Med. Assoc, 2008. 232(2): p. 222-227. , 4McMillan, C.J. and S.M. Taylor, Transtracheal aspiration in the diagnosis of pulmonary blastomycosis (17 cases: 2000-2005). Can. Vet. J, 2008. 49(1): p. 53-55. ] and lung aspirate is 81% [3Crews, L.J., et al., Utility of diagnostic tests for and medical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006). J. Am. Vet. Med. Assoc, 2008. 232(2): p. 222-227. ].
- Antigen Detection
- Advantage: high sensitivity- 93.5% urine, 87% serum in pathology proven cases [5
Spector, D., et al., Antigen and antibody testing for the diagnosis of blastomycosis in dogs. J Vet. Intern Med, 2008. 22(4): p. 839-843. ,6Foy, D.S., et al., Serum and urine blastomyces antigen concentrations as markers of clinical remission in dogs treated for systemic blastomycosis. J. Vet. Intern. Med, 2014. 28(2): p. 305-310. ,7Mourning, A.C., et al., Evaluation of an enzyme immunoassay for antibodies to a recombinant Blastomyces adhesin-1 repeat antigen as an aid in the diagnosis of blastomycosis in dogs. J. Am. Vet. Med. Assoc, 2015. 247(10): p. 1133-1138. ] including those caused by B. helicus [2Schwartz, I.S., et al., Blastomyces helicus, a New Dimorphic Fungus Causing Fatal Pulmonary and Systemic Disease in Humans and Animals in Western Canada and the United States. Clin Infect Dis, 2019. 68(2): p. 188-195. ]. Has largely replaced antibody assays for serologic diagnosis. Antigen concentration correlates with severity of infection; used as a marker for monitoring response to treatment. Easy to collect specimens (urine, serum, or other body fluids). - Disadvantage: very high cross reactivity with Histoplasma antigen (96%) [8
Connolly, P., et al., Blastomyces dermatitidis Antigen Detection by Quantitative Enzyme Immunoassay. Clin. Vaccine Immunol, 2012. 19(1): p. 53-56. ]. Tests can be initially negative in mild or localized cases so negative result does not exclude diagnosis.
- Advantage: high sensitivity- 93.5% urine, 87% serum in pathology proven cases [5
- Antibody Detection:
- Advantage: useful in cases with more localized or chronic infection (false negative or very weak positive antigen) and histology or cytology not feasible. Antibody EIA has good sensitivity (76 – 95%) [7
Mourning, A.C., et al., Evaluation of an enzyme immunoassay for antibodies to a recombinant Blastomyces adhesin-1 repeat antigen as an aid in the diagnosis of blastomycosis in dogs. J. Am. Vet. Med. Assoc, 2015. 247(10): p. 1133-1138. ] and specificity - Disadvantage: No commercially available feline Ab EIA. Immunodiffusion (AGID) has low sensitivity (17.4 – 65%) [7
Mourning, A.C., et al., Evaluation of an enzyme immunoassay for antibodies to a recombinant Blastomyces adhesin-1 repeat antigen as an aid in the diagnosis of blastomycosis in dogs. J. Am. Vet. Med. Assoc, 2015. 247(10): p. 1133-1138. ]. Although the EIA is highly specific, some false positives may occur in dogs living in endemic area.
- Advantage: useful in cases with more localized or chronic infection (false negative or very weak positive antigen) and histology or cytology not feasible. Antibody EIA has good sensitivity (76 – 95%) [7
- Culture:
- Advantage: only way to prove the diagnosis. Antifungal susceptibility testing may be performed on cultured isolates.
- Disadvantages: Rarely performed in vet med. Some risk to laboratory personnel, so appropriate facilities are required. Culture requires 1- 3 weeks incubation, up to 5 weeks occasionally. Only used for basis of diagnosis in 12% of cases [9
Legendre, A.M., et al., Treatment of blastomycosis with itraconazole in 112 dogs. J. Vet. Intern. Med, 1996. 10(6): p. 365-371. ].
- Molecular
- Fast turnaround time, although no peerreviewed publications available to assess sensitivity and specificity (making interpretation of results difficult).
- Disadvantage: low incidence of fungemia so whole blood unlikely a desirable specimen. Invasive procedure to obtain respiratory or tissue specimens.
Treatment
- General
- Up to 25% die during 1st week of treatment, mostly those with severe lung disease and respiratory failure [9
Legendre, A.M., et al., Treatment of blastomycosis with itraconazole in 112 dogs. J. Vet. Intern. Med, 1996. 10(6): p. 365-371. ,10Mazepa, A.S., L.A. Trepanier, and D.S. Foy, Retrospective comparison of the efficacy of fluconazole or itraconazole for the treatment of systemic blastomycosis in dogs. J Vet. Intern Med, 2011. 25(3): p. 440-445. ].- Initial hospitalization for intravenous amphotericin B and respiratory assistance may reduce mortality
- Systemic corticosteroids may also be indicated in hospitalized cases with respiratory insufficiency [11
Plamondon, M., et al., Corticosteroids as adjunctive therapy in severe blastomycosis-induced acute respiratory distress syndrome in an immunosuppressed patient. Clin. Infect. Dis, 2010. 51(1): p. e1-e3. ].
- Outcome poor in cases with CNS involvement or severe respiratory insufficiency
- Up to 25% die during 1st week of treatment, mostly those with severe lung disease and respiratory failure [9
- Itraconazole: 5mg/kg PO q 12 hours for 3 days (loading dose) then q 24 hours for dogs; higher doses may be required for cats. Alternate-day dosing may be effective in cats [12
Middleton, S.M., et al., Alternate-day dosing of itraconazole in healthy adult cats. J Vet Pharmacol Ther, 2016. 39(1): p. 27-31. ].- Uncomplicated cases: at least 6 months and resolution of signs, resolution or marked improvement of radiographic lesions, and clearance of urine antigen. Relapse occurred in at least 20% of cases in one older study [9
Legendre, A.M., et al., Treatment of blastomycosis with itraconazole in 112 dogs. J. Vet. Intern. Med, 1996. 10(6): p. 365-371. ]. At least 6 months is recommended in humans [13Chapman, S.W., et al., Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin. Infect. Dis, 2008. 460: p. 1801-1812. ] and relapse occurred in only 5% of patients [14Dismukes, W.E., et al., Itraconazole therapy for blastomycosis and histoplasmosis. Am. J. Med, 1992. 93: p. 489-497. ]. - Complicated cases (bone, joints, CNS) or relapse despite appropriate therapy. May require 12 months or more of therapy based on resolution of signs, radiographic lesions, and antigen.
- Use only pelletized generic itraconazole or FDA approved products (Sporanox® capsules or liquid, Itrafungol®). Compounded non-FDA approved preparations have poor bioavailability[15
Renschler, J., et al., Comparison of Compounded, Generic, and InnovatorFormulated Itraconazole in Dogs and Cats. J Am Anim Hosp Assoc, 2018. 54(4): p. 195-200. 16. Renschler, J.S., et al., Reduced susceptibility to fluconazole in a cat with histoplasmosis. JFMS Open Rep, 2017. 3(2): p. 2055116917743364. ], high failure rates and are not recommended. - Testing blood concentration of itraconazole after reaching steady-state (2 weeks in dogs and 3 weeks in cats) is highly recommended [15
Renschler, J., et al., Comparison of Compounded, Generic, and InnovatorFormulated Itraconazole in Dogs and Cats. J Am Anim Hosp Assoc, 2018. 54(4): p. 195-200. 16. Renschler, J.S., et al., Reduced susceptibility to fluconazole in a cat with histoplasmosis. JFMS Open Rep, 2017. 3(2): p. 2055116917743364. ]. Some animals require higher or lower itraconazole dose to achieve therapeutic blood level.
- Uncomplicated cases: at least 6 months and resolution of signs, resolution or marked improvement of radiographic lesions, and clearance of urine antigen. Relapse occurred in at least 20% of cases in one older study [9
- Fluconazole: 10mg/kg q24h or 5mg/kg q12h. Less effective than itraconazole in prospective clinical trials in humans [13
Chapman, S.W., et al., Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin. Infect. Dis, 2008. 460: p. 1801-1812. ] and is not preferred. Resistance to fluconazole has developed in humans and cats with histoplasmosis [16Renschler, J.S., et al., Reduced susceptibility to fluconazole in a cat with histoplasmosis. JFMS Open Rep, 2017. 3(2): p. 2055116917743364. ]. Treatment failure and relapse may be more common with fluconazole in dogs (study not prospective and too small to compare accurately [10Mazepa, A.S., L.A. Trepanier, and D.S. Foy, Retrospective comparison of the efficacy of fluconazole or itraconazole for the treatment of systemic blastomycosis in dogs. J Vet. Intern Med, 2011. 25(3): p. 440-445. ]. Fluconazole is not the treatment of choice in dogs [1Sykes, J.E., Canine and Feline Infectious Diseases. 2014, St. Louis, MO: Elsevier. 915. ] or humans [13Chapman, S.W., et al., Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin. Infect. Dis, 2008. 460: p. 1801-1812. ]. - Amphotericin B: deoxycholate or lipid-complexed amphotericin B is recommended as initial treatment for cases with severe disease followed by itraconazole to complete therapy [3
Crews, L.J., et al., Utility of diagnostic tests for and medical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006). J. Am. Vet. Med. Assoc, 2008. 232(2): p. 222-227. ,4McMillan, C.J. and S.M. Taylor, Transtracheal aspiration in the diagnosis of pulmonary blastomycosis (17 cases: 2000-2005). Can. Vet. J, 2008. 49(1): p. 53-55. ]. Risk of nephrotoxicity. - Terbinafine: no published studies to support terbinafine, not recommended in humans [13
Chapman, S.W., et al., Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin. Infect. Dis, 2008. 460: p. 1801-1812. ]. Has been used anecdotally in vet med, sometimes in combination with other antifungals. PK study in dogs showed blood concentrations >MIC for Blastomyces for 18 hours after oral dose (30-35 mg/kg).
Monitoring response to treatment
- Blastomyces antigen testing at 3-month intervals during and at 3, 6 and 12-months following discontinuation of treatment, until negative.
- Imaging: resolution or marked improvement in radiographs, CT or MRI scans.
Relapse
- Diagnosis: recurrent signs and/or increase antigen concentrations
- Causes: use of compounded itraconazole, subtherapeutic levels of itraconazole, inadequate duration of treatment [9
Legendre, A.M., et al., Treatment of blastomycosis with itraconazole in 112 dogs. J. Vet. Intern. Med, 1996. 10(6): p. 365-371. ], and use of fluconazole [10Mazepa, A.S., L.A. Trepanier, and D.S. Foy, Retrospective comparison of the efficacy of fluconazole or itraconazole for the treatment of systemic blastomycosis in dogs. J Vet. Intern Med, 2011. 25(3): p. 440-445. ,13Chapman, S.W., et al., Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin. Infect. Dis, 2008. 460: p. 1801-1812. ]. - Treatment:
- Repeat itraconazole adhering to guidelines above.
- Chronic suppression with itraconazole 5mg/ kg administered 3 times weekly could be considered in cases with refractory disease or ongoing environmental exposure.
REFERENCES:
- Sykes, J.E., Canine and Feline Infectious Diseases. 2014, St. Louis, MO: Elsevier. 915.
- Schwartz, I.S., et al., Blastomyces helicus, a New Dimorphic Fungus Causing Fatal Pulmonary and Systemic Disease in Humans and Animals in Western Canada and the United States. Clin Infect Dis, 2019. 68(2): p. 188-195.
- Crews, L.J., et al., Utility of diagnostic tests for and medical treatment of pulmonary blastomycosis in dogs: 125 cases (1989-2006). J. Am. Vet. Med. Assoc, 2008. 232(2): p. 222-227.
- McMillan, C.J. and S.M. Taylor, Transtracheal aspiration in the diagnosis of pulmonary blastomycosis (17 cases: 2000-2005). Can. Vet. J, 2008. 49(1): p. 53-55.
- Spector, D., et al., Antigen and antibody testing for the diagnosis of blastomycosis in dogs. J Vet. Intern Med, 2008. 22(4): p. 839-843.
- Foy, D.S., et al., Serum and urine blastomyces antigen concentrations as markers of clinical remission in dogs treated for systemic blastomycosis. J. Vet. Intern. Med, 2014. 28(2): p. 305-310.
- Mourning, A.C., et al., Evaluation of an enzyme immunoassay for antibodies to a recombinant Blastomyces adhesin-1 repeat antigen as an aid in the diagnosis of blastomycosis in dogs. J. Am. Vet. Med. Assoc, 2015. 247(10): p. 1133-1138.
- Connolly, P., et al., Blastomyces dermatitidis Antigen Detection by Quantitative Enzyme Immunoassay. Clin. Vaccine Immunol, 2012. 19(1): p. 53-56.
- Legendre, A.M., et al., Treatment of blastomycosis with itraconazole in 112 dogs. J. Vet. Intern. Med, 1996. 10(6): p. 365-371.
- Mazepa, A.S., L.A. Trepanier, and D.S. Foy, Retrospective comparison of the efficacy of fluconazole or itraconazole for the treatment of systemic blastomycosis in dogs. J Vet. Intern Med, 2011. 25(3): p. 440-445.
- Plamondon, M., et al., Corticosteroids as adjunctive therapy in severe blastomycosis-induced acute respiratory distress syndrome in an immunosuppressed patient. Clin. Infect. Dis, 2010. 51(1): p. e1-e3.
- Middleton, S.M., et al., Alternate-day dosing of itraconazole in healthy adult cats. J Vet Pharmacol Ther, 2016. 39(1): p. 27-31.
- Chapman, S.W., et al., Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin. Infect. Dis, 2008. 460: p. 1801-1812.
- Dismukes, W.E., et al., Itraconazole therapy for blastomycosis and histoplasmosis. Am. J. Med, 1992. 93: p. 489-497.
- Renschler, J., et al., Comparison of Compounded, Generic, and InnovatorFormulated Itraconazole in Dogs and Cats. J Am Anim Hosp Assoc, 2018. 54(4): p. 195-200.
- Renschler, J.S., et al., Reduced susceptibility to fluconazole in a cat with histoplasmosis. JFMS Open Rep, 2017. 3(2): p. 2055116917743364.