Coccidioidomycosis

Heather Largura DDS, MS, Janelle Renschler DVM, PhD, Joe Wheat MD

See Sykes, J.E. for more detailed information [1Sykes, J.E., Canine and Feline Infectious Diseases. 2014, St. Louis, MO: Elsevier. 915.].

Background

Areas Endemic for Coccidioidomycosis

A map of Areas Endemic for CoccidioidomycosisA Map of Areas Endemic for Coccidioidomycosis

Clinical Findings in Dogs: most infections are subclinical ~70% [9Shubitz, L.E., et al., Incidence of coccidioides infection among dogs residing in a region in which the organism is endemic. J Am Vet. Med Assoc, 2005. 226(11): p. 1846-1850. Davidson, A.P., et al., Selected Clinical Features of Coccidioidomycosis in Dogs. Med Mycol, 2019. 57(Supplement_1): p. S67-S75., 10Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65.]

Pulmonary: most common form of coccidioidomycosis, and often accompanied by disseminated findings.

Disseminated (extrapulmonary): 25%, may be accompanied by pulmonary involvement [2Johnson, L.R., et al., Clinical, clinicopathologic, and radiographic findings in dogs with coccidioidomycosis: 24 cases (1995-2000). J. Am. Vet. Med. Assoc, 2003. 222(4): p. 461-466., 10Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65.]

  • Other: cardiac, gastrointestinal, kidneys, bladder, testes, prostate, liver, spleen, GI tract, urinary tract

Clinical findings in cats

Pulmonary

Disseminated (extrapulmonary): 60% present with disseminated infection, perhaps due to delay in seeking care or recognition of infection [6Arbona, N., et al., Clinical features of cats diagnosed with coccidioidomycosis in Arizona, 2004-2018. J Feline Med Surg, 2019: p.1098612X19829910.].

Laboratory abnormalities

Diagnosis

Histology and cytology:

Antigen detection:

Antibody Detection:

Culture:

Molecular: inadequate information to determine usefulness

  • Advantage: fast turnaround time, although no peer-reviewed publications available to assess sensitivity and specificity (making interpretation of the results difficult).
  • Disadvantage: low incidence of fungemia so whole blood unlikely a desirable specimen, invasive procedure to obtain respiratory or tissue specimens, expensive.

Treatment

General

Amphotericin B: 1 – 3mg/kg every other day, 3 times weekly. Deoxycholate or lipid formulation of amphotericin B are recommended as initial treatment for 3-7 days for cases with severe disease followed by itraconazole to complete therapy. Risk of nephrotoxicity.

Fluconazole: 10mg/kg q24h or 5mg/kg q12h. Fluconazole is the first drug of choice for coccidioidomycosis, with high bioavailability and low toxicity; however, resistance to fluconazole has developed in humans and cats with histoplasmosis [10Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65., 27Sorensen, K.N., et al., Comparative efficacies of terbinafine and fluconazole in treatment of experimental coccidioidal meningitis in a rabbit model. Antimicrob. Agents Chemother, 2000. 44(11): p. 3087-3091.].

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.

Terbinafine: no published canine studies to support terbinafine, not recommended in humans. A rabbit model comparing terbinafine and fluconazole showed terbinafine to be ineffective in survival, histology and reduction in numbers of colony forming units 28Galgiani, J.N., et al., Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis – A randomized, double-blind trial. Annals of Internal Medicine, 2000. 133(9): p. 676-686.]; no information on whether adequate tissue concentration achieved [10Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65., 28Galgiani, J.N., et al., Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis – A randomized, double-blind trial. Annals of Internal Medicine, 2000. 133(9): p. 676-686.].

Ancillary therapy: glucocorticoids at anti-inflammatory doses for animals with respiratory distress or severe inflammation; however, for short duration [10Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65.]. Nonsteroidal anti-inflammatory drugs, tramadol or gabapentin when NSAIDS insufficient, cough suppressants or short-term bronchodilator therapy, antiepileptics for dogs with seizures. Caution should be used with combination of phenobarbital, prednisone, and fluconazole [10Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65.]. Drugs metabolized by cytochrome P450 such as phenobarbital will have increased blood levels when used concomitantly with azoles, and glucocorticosteroids can have suppressive effects to the immune system and contribute to hepatopathy in conjunction with azoles.

Surgical management: amputation for persistent osteomyelitis, pericardectomy in tamponade, and enucleation may be required for endopthalmitis [1Sykes, J.E., Canine and Feline Infectious Diseases. 2014, St. Louis, MO: Elsevier. 915.].

Monitoring response to treatment

Resolution of clinical signs and reduction in serological titers, though decision to terminate treatment should not be based on titer alone since titers may plateau or decrease slightly after recovery [23LF, B.C.a.S. A RETROSPECTIVE REVIEW OF CANINE COCCIDIOIDOMYCOSIS CASES AT A TERTIARY CARE CENTER IN TUCSON. in 62nd Annual Coccidioidomycosis Study Group Meeting. 2018. Flagstaff, AZ., 31Kriesel, J.D., et al., Persistent pulmonary infection with an azole-resistant Coccidioides species. Med Mycol, 2008: p. 1-4.].

Coccidioides antibody testing at 3-month intervals during and at 3, 6- and 12-months following discontinuation of treatment, until negative.

If Coccidioides antigen in serum or urine was initially positive, may be useful as a monitoring tool (treat until negative).

Imaging: resolution or marked improvement in radiographs, CT or MRI scans.

Antifungal susceptibility testing may be performed on cultured isolates. Services available at UT Health San Antonio Fungus Testing Lab.

Relapse: up to 25% of dogs relapse [23LF, B.C.a.S. A RETROSPECTIVE REVIEW OF CANINE COCCIDIOIDOMYCOSIS CASES AT A TERTIARY CARE CENTER IN TUCSON. in 62nd Annual Coccidioidomycosis Study Group Meeting. 2018. Flagstaff, AZ.]

Diagnosis: recurrent signs and increase in antibody titer or antigen concentration.

Causes: use of non-FDA approved itraconazole, subtherapeutic levels of itraconazole, development of resistance to fluconazole and inadequate duration of treatment [30Greene, R.T., Coccidioidomycosis, IN: Greene CE, ed. Infectious Diseases of the Dog and Cat. 1998, Philadelphia: WB Saunders., 32Thompson, G.R., 3rd, B.M. Barker, and N.P. Wiederhold, LargeScale Evaluation of In Vitro Amphotericin B, Triazole, and Echinocandin Activity against Coccidioides Species from U.S. Institutions. Antimicrob Agents Chemother, 2017. 61(4). , 33].

Treatment

  • Repeat itraconazole adhering to guidelines above.
  • Chronic suppression with itraconazole 5mg/kg administered 3 times weekly may prevent relapse.

REFERENCES:

  1. Sykes, J.E., Canine and Feline Infectious Diseases. 2014, St. Louis, MO: Elsevier. 915.
  2. Johnson, L.R., et al., Clinical, clinicopathologic, and radiographic findings in dogs with coccidioidomycosis: 24 cases (1995-2000). J. Am. Vet. Med. Assoc, 2003. 222(4): p. 461-466.
  3. Maddy, K.T., Disseminated coccidioidomycosis of the dog. J Am Vet. Med Assoc, 1958. 132(11): p. 483-489.
  4. Butkiewicz, C.D., L.E. Shubitz, and S.M. Dial, Risk factors associated with Coccidioides infection in dogs. J Am Vet. Med Assoc, 2005. 226(11): p. 1851-1854.
  5. Greene, R.T. and G.C. Troy, Coccidioidomycosis in 48 cats: a retrospective study (1984-1993). J Vet. Intern Med, 1995. 9(2): p. 86-91.
  6. Arbona, N., et al., Clinical features of cats diagnosed with coccidioidomycosis in Arizona, 2004-2018. J Feline Med Surg, 2019: p.1098612X19829910.
  7. Marsden-Haug, N., et al., Coccidioidomycosis Acquired in Washington State. Clin. Infect. Dis, 2013.
  8. Lockhart, S.R., O.Z. McCotter, and T.M. Chiller, Emerging Fungal Infections in the Pacific Northwest: The Unrecognized Burden and Geographic Range of Cryptococcus gattii and Coccidioides immitis. Microbiol Spectr, 2016. 4(3).
  9. Shubitz, L.E., et al., Incidence of coccidioides infection among dogs residing in a region in which the organism is endemic. J Am Vet. Med Assoc, 2005. 226(11): p. 1846-1850.
    Davidson, A.P., et al., Selected Clinical Features of Coccidioidomycosis in Dogs. Med Mycol, 2019. 57(Supplement_1): p. S67-S75.
  10. Millman, T.M., Coccidioidomycosis in the dog: its radiographic diagnosis. J Am Vet Radiol Soc., 1979(20): p. 50-65.
  11. Angell, J.A., et al., Ocular coccidioidomycosis in a cat. J Am Vet. Med Assoc, 1985. 187(2): p. 167-169.
  12. Shively, J.N. and C.E. Whiteman, Ocular lesions in disseminated coccidioidomycosis in 2 dogs. Pathol Vet, 1970. 7(1): p. 1-6.
  13. Burtch, M., Granulomatous meningitis caused by Coccidioides immitis in a dog. J Am Vet. Med Assoc, 1998. 212(6): p. 827-829.
  14. Pryor, W.H., Jr., et al., Coccidioides immitis encephalitis in two dogs. J Am Vet Med Assoc, 1972. 161(10): p. 1108-12.
  15. Tofflemire, K. and C. Betbeze, Three cases of feline ocular coccidioidomycosis: presentation, clinical features, diagnosis, and treatment. Vet. Ophthalmol, 2010. 13(3): p. 166-172.
  16. Gaidici, A. and M.A. Saubolle, Transmission of coccidioidomycosis to a human via a cat bite. J Clin Microbiol, 2009. 47(2): p. 505-6.
  17. Shubitz, L.F. and S.M. Dial, Coccidioidomycosis: a diagnostic challenge. Clin. Tech. Small Anim Pract, 2005. 20(4): p. 220-226.
  18. Simoes, D.M., et al., Retrospective analysis of cutaneous lesions in 23 canine and 17 feline cases of coccidiodomycosis seen in Arizona, USA (2009-2015). Vet Dermatol, 2016. 27(5): p. 346-e87.
  19. Wolf, A.M., Primary cutaneous coccidioidomycosis in a dog and a cat. J Am Vet. Med Assoc, 1979. 174(5): p. 504-506.
  20. Holbrook, E.D., et al., Novel canine anti-Coccidioides immunoglobulin G enzyme immunoassay aids in diagnosis of coccidioidomycosis in dogs. Med Mycol, 2019.
  21. Kirsch, E.J., et al., Evaluation of Coccidioides antigen detection in dogs with coccidioidomycosis. Clin Vaccine Immunol, 2012. 19(3): p. 343-5.
  22. Graupmann-Kuzma, A., et al., Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp. Assoc, 2008. 44(5): p. 226-235.
  23. LF, B.C.a.S. A RETROSPECTIVE REVIEW OF CANINE COCCIDIOIDOMYCOSIS CASES AT A TERTIARY CARE CENTER IN TUCSON. in 62nd Annual Coccidioidomycosis Study Group Meeting. 2018. Flagstaff, AZ.
  24. Crabtree, A.C., D.G. Keith, and H.L. Diamond, Relationship between radiographic hilar lymphadenopathy and serologic titers for Coccidioides sp. in dogs in an endemic region. Vet. Radiol. Ultrasound, 2008. 49(6): p. 501-503.
  25. Pappagianis, D., Serologic studies in coccidioidomycosis. Semin. Respir. Infect, 2001. 16(4): p. 242-250.
  26. Renschler, J.S., et al., Reduced susceptibility to fluconazole in a cat with histoplasmosis. JFMS Open Rep, 2017. 3(2): p. 2055116917743364.
  27. Sorensen, K.N., et al., Comparative efficacies of terbinafine and fluconazole in treatment of experimental coccidioidal meningitis in a rabbit model. Antimicrob. Agents Chemother, 2000. 44(11): p. 3087-3091.
  28. Galgiani, J.N., et al., Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis – A randomized, double-blind trial. Annals of Internal Medicine, 2000. 133(9): p. 676-686.
  29. Renschler, J., et al., Comparison of Compounded, Generic, and Innovator-Formulated Itraconazole in Dogs and Cats. J Am Anim Hosp Assoc, 2018. 54(4): p. 195-200.
  30. Greene, R.T., Coccidioidomycosis, IN: Greene CE, ed. Infectious Diseases of the Dog and Cat. 1998, Philadelphia: WB Saunders.
  31. Kriesel, J.D., et al., Persistent pulmonary infection with an azole-resistant Coccidioides species. Med Mycol, 2008: p. 1-4.
  32. Thompson, G.R., 3rd, B.M. Barker, and N.P. Wiederhold, LargeScale Evaluation of In Vitro Amphotericin B, Triazole, and Echinocandin Activity against Coccidioides Species from U.S. Institutions. Antimicrob Agents Chemother, 2017. 61(4).