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Feline | Canine

Coccidioidomycosis

Summary

  • Systemic fungal disease caused by infection with Coccidioides immitis or Coccidioides posadasii, dimorphic soil borne fungi
  • Endemic to the southwestern portion of the United States (e.g., Arizona, California), western Mexico, and Central and South America
  • Main route of infection is by inhalation of airborne spores
  • Inhalation of arthroconidia by a host results in sporulation; endospores are phagocytized by macrophages and elicit an inflammatory response
  • Can also enter the systemic circulation and become disseminated; higher risk of dissemination in patients with compromised immunity or massive exposure
  • Can be subclinical, but clinical manifestations include respiratory disease (most common manifestation); CNS disease (granulomatous or diffuse meningoencephalopathy); and disseminated disease, which can affect multiple organ systems (e.g., bone, joints, skin, eyes, testes)
    • Disease severity depends partially on inoculation dose and the immunocompetence of the patient
  • In dogs, pneumonia typically occurs first; osteomyelitis indicates dissemination
  • In cats, dermatologic and disseminated infections are most common
  • Diagnosis is based on a combination of serology and cytology or histopathology
  • Treatment consists of antifungal therapy and appropriate supportive care as needed
  • Direct inoculation may result in infection in veterinary personnel; wounds should not be bandaged to avoid conversion of organism to the infectious, mycelial form

Causes and Risk Factors

Causes

  • Infection with Coccidioides immitis or C. posadasii
  • Main route of infection is by inhalation of airborne spores

Risk Factors

  • Residence or travel to the southwestern United States (e.g., Arizona, California), western Mexico, or Central or South America
  • Increased incidence in dogs housed outdoors and those allowed to roam
  • Digging behavior (the pathogen is soil-borne)
  • Immunocompromise or treatment with immunosuppressive medications can cause latent infections to resurface

Signalment

  • Dogs and cats
  • Higher incidence in young, male, medium- to large-breed dogs, possibly due to increased tendency to roam or have active outdoor lifestyles
  • No breed predilection

Differential Diagnosis

Diagnosis and Screening

General Points

  • In dogs, pneumonia typically occurs first; osteomyelitis indicates dissemination
  • Advanced imaging (computed tomography or magnetic resonance imaging) is valuable for distinguishing CNS coccidiosis from other differentials
  • In cats, dermatologic and disseminated infections are most common
  • Diagnosis is based on a combination of serology and cytology or histopathology
  • Some cases may be asymptomatic or have mild clinical signs that go unnoticed by the owner
  • The onset of respiratory signs is approximately 1 to 3 weeks following infection; however, low-grade respiratory signs may go unnoticed for months to years
  • Patients with compromised immunity or massive exposure may experience systemic dissemination; disseminated disease can affect bone, eyes, heart, testicles, central nervous system, and visceral organs
  • Intradermal skin testing is not reliable

Signs and History

  • In dogs, cough is the most common initial clinical sign; may be dry or moist depending on interstitial or alveolar involvement
  • In cats, skin lesions are the most common sign; respiratory signs are only occasionally noted
  • Fever
  • Decreased appetite
  • Weight loss
  • Dogs with disseminated disease may demonstrate:
    • Lameness
    • Draining skin lesions
    • Anterior uveitis
    • Seizures
    • Nonspecific pain
    • Paralysis or paresis
  • Chorioretinitis and anterior uveitis are more common in cats with disseminated disease

Physical Exam

  • Dyspnea
  • Harsh lung sounds
  • Lymphadenopathy
  • Draining skin lesions
  • In patients with CNS disease, may note:
    • Seizures
    • Vestibular signs
    • Head-pressing
    • Behavioral changes
    • Visual deficits
    • Ataxia
    • Proprioceptive deficits
    • Cervical pain
    • Hyperesthesia
  • In patients with disseminated disease, may note:
    • Anterior uveitis
    • Chorioretinitis
    • Bone pain
    • Lameness
    • Skin lesions
    • Neurologic dysfunction, seizures
    • Paralysis or paresis
    • Nonspecific pain
    • Arrhythmias

Laboratory Tests

  • Routine laboratory tests
    • Complete blood count, biochemistry panel, and urinalysis
      • Leukocytosis
      • Neutrophilia
      • Monocytosis
      • Mild (nonregenerative) anemia
      • Hypoalbuminemia
      • Hyperglobulinemia
      • Eosinophilia; variable
      • Proteinuria

  • Cytologic and histopathologic evaluation
    • Demonstration of the organism via cytology or histopathology provides a definitive diagnosis; sample collection will depend on clinical presentation
    • The organisms are often seen intracellularly; large, round to oval double-walled spherules that may contain endospores; often surrounded by pyogranulomatous inflammation
    • Sample collection via transtracheal wash or bronchoalveolar lavage may yield false negative results; diagnostic yield will be greater in patients with alveolar disease
    • The reference laboratory should be advised that fungal infection is suspected so appropriate stains can be applied to increase the chances of organism detection

  • Serum antibody detection using agar gel immunodiffusion (AGID)
    • Can be used as a presumptive test; titers ≥ 1:16, with supportive clinical signs, are suggestive of active infection
    • Has been shown to have a higher sensitivity in cats
    • False negative results are possible if tested prior to seroconversion or in patients with fulminating disease
    • Titers can’t distinguish between prior exposure and active disease
    • Extent of elevation in titer does not reliably correlate with severity of infection
    • Titers can also be evaluated in the cerebrospinal fluid (CSF) of patients with intracranial disease; CSF titers that are higher than those in the serum are diagnostic of central nervous system involvement

  • Quantitative Coccidioides antigen assay
    • Low sensitivity for detection of active infection in serum or urine
    • Cross-reactivity with Histoplasma, Blastomyces, Aspergillus spp. has been reported

  • Cerebrospinal fluid (CSF) analysis
    • CSF tap can be performed with advanced-imaging guidance
    • Sample can be submitted for PCR or antibody testing
    • Sensitivity is low
    • Cytology may show:
      • Pleocytosis (neutrophilic or monocytic)
      • Rarely, detect Coccidioides spherules
    • May be unremarkable, even if imaging studies detect inflammation

  • Ionized calcium level
    • Should be evaluated in patients with hypercalcemia
    • Will be normal in patients with hypercalcemia due to granulomatous disease

Imaging

  • Thoracic radiography
    • Findings will vary with disease severity
    • A diffuse interstitial or localized alveolar pattern may be noted
    • Miliary or nodular changes may be noted as well
    • Hilar lymphadenopathy is common
    • Pulmonary abscess, fibrosis, or bronchiectasis may be seen with severe infection
    • Lobar pneumonia
    • May also identify cardiomegaly, pleural effusion, or pericardial effusion

  • Thoracic and abdominal ultrasonography
    • Should be considered for patients with evidence of disseminated disease

  • Computed tomography (CT) or magnetic resonance imaging (MRI)
    • May be considered for patients with central nervous system signs, to look for evidence of intracranial lesions
    • May be difficult to distinguish between neoplasia and fungal granuloma; coccidioidomycosis causes mass-like central nervous system granulomas that can be mistaken for neoplasia
    • CT is helpful for identifying:
      • Obstructive hydrocephalus
      • Foraminal or transtentorial herniation
      • Masses or spinal cord lesions
    • Magnetic resonance imaging may show:
      • T2-weighted hyperintensity (particularly involving white matter) with poorly defined margins of enhancement
      • T1-weighted post-contrast enhancement
      • Focal ischemia
      • T1-weighted isointense granulomas, or T2-weighted hypointense granulomas

Prevention

  • Keep dogs and cats away from sites where soil has been disturbed
  • Discourage digging

Treatment

General Points

  • Controversy exists regarding therapy of asymptomatic or mild cases of coccidioidomycosis; some cases resolve spontaneously with no therapy
  • Therapy should be considered for any patient with supportive clinical signs, to decrease the risk of progression
  • Triazoles are the initial drug of choice for treatment
  • Amphotericin B may be considered in patients with severe, diffuse pulmonary disease where a rapid onset of action is required, and for patients who are unable to tolerate triazoles
  • Therapy may be required for 6 to 12 months, or longer; treatment for 4 to 6 months beyond clinical resolution is recommended
  • Prolonged duration of therapy and cost of medication may create financial barriers to treatment for some clients
  • A reduction in serologic levels should be noted; however, low positive titers may persist

Medications

  • Triazole therapy
    • Agents in this class are the initial drug of choice for treatment

    • Itraconazole 5 to 10 mg/kg PO every 24 hours or divided every 12 hours, with food
      • Generic formulations may have inconsistent gastrointestinal absorption
      • Does not cross the blood-brain, blood-prostate, or blood-ocular barrier well; however, may still be effective in these areas due to inflammation of the barrier
      • A trough concentration of 0.25 to 0.5 µg/ml is considered the target level if therapeutic drug monitoring is used
      • Adverse effects include gastrointestinal signs and cutaneous vasculitis
      • Hepatoxicity may also occur; liver enzymes should be evaluated every 4 weeks during therapy

    • Fluconazole
      • Dogs: 5 mg/kg PO every 12 hours; in refractory cases, increase to 10 mg/kg PO every 12 hours
      • Cats: 50 mg per cat PO every 12 to 24 hours; or 10 mg/kg PO every 12 hours
      • A maximum daily dosage of 400 mg per day is recommended for disseminated disease in dogs
      • Crosses the blood-brain, blood-prostate, and blood-ocular barrier well
      • May be considered as an alternative to itraconazole for patients with central nervous system or ocular disease

  • Amphotericin B (AMB)
    • There are limited data on the use of AMB for dogs and cats with coccidioidomycosis
    • May be considered in patients with severe, diffuse pulmonary disease where a rapid onset of action is required
    • May also be considered for patients who are unable to tolerate triazoles or those who fail to respond to triazoles
    • Nephrotoxic; blood urea nitrogen and creatinine levels should be closely monitored
    • Keep patients well hydrated before and during therapy, but avoid over-hydration

    • AMB deoxycholate
      • Dogs: 0.5 mg/kg IV every other day (e.g., Monday, Wednesday, and Friday); dilute 1:50 in 5% dextrose and administer slowly over 4 to 6 hours; cumulative dose 9 to 12 mg/kg
      • Cats: 0.25 mg/kg IV every other day (e.g., Monday, Wednesday, and Friday); dilute 1:50 in 5% dextrose and administer slowly over 4 to 6 hours; cumulative dose 6 to 9 mg/kg
      • Slow infusion rates are recommended; infusion reactions have been reported
      • Alternative dosing option:
        • Dogs: 0.5 mg/kg (up to 0.75 mg/kg) of 5 mg/mL stock solution, diluted in 350 to 500 mL of 0.45% NaCl plus 2.5% dextrose; administer SC (between the scapulae) 1 to 3 times per week, to a cumulative dose of 8 to 26 mg/kg
        • Cats: 0.5 mg/kg SC 1 to 3 times per week; dilute the calculated dose to a concentration of 5 mg/mL, then further dilute in 350 mL of 0.45% NaCl plus 2.5% dextrose; administer SC (between the scapulae) 1 to 3 times per week, to a cumulative dose of 16 to 20 mg/kg
        • This protocol has been developed to decrease the risk for nephrotoxicity or when prolonged vascular access is not possible
        • Sterile abscesses at the site of injection have been reported

    • AMB lipid complex
      • Dogs: 3 mg/kg IV once daily for either 4 doses (on days 1, 2, 3, and 10) or 5 doses (on days 1, 2, 3, 4, and 10); give as a 1 to 2 mg/mL solution in 5% dextrose over 1 to 2 hours, to a cumulative dose of 12 to 15 mg/kg
      • Cats: 1 to 3.3 mg/kg IV once daily for either 4 doses (on days 1, 2, 3, and 10) or 5 doses (on days 1, 2, 3, 4, and 10); give as a 1 to 2 mg/mL solution in 5% dextrose over 1 to 2 hours, to a cumulative dose of 12 mg/kg
      • Slow infusion rates are recommended; infusion reactions have been reported
      • Less nephrotoxic formulation; however, blood urea nitrogen and creatinine levels should be closely monitored


Surgical Interventions

  • In cases of ocular or testicular infection, surgical removal may be considered
  • Pericardectomy may be indicated with pericardial involvement (infection, adhesions, etc.)
  • Lung lobectomy may be indicated for atelectasis or pneumothorax
  • Lumpectomy for skin or subcutaneous nodules can facilitate histopathologic diagnosis and reduce fungal population

Other Therapies

  • Corticosteroids
    • Frequently given with antifungal medication for treatment of CNS disease
    • For patients with respiratory inflammation or other systemic inflammation
    • Short-duration therapy is recommended, to reduce risk of immunosuppression; use the lowest effective dose
      • Dogs: Prednisone 0.5 to 1 mg/kg PO once daily
      • Cats: Prednisolone 1 to 2 mg/kg PO once daily

  • Non-steroidal anti-inflammatory drugs (NSAIDS) (in Dogs)
    • May help reduce fever and alleviate joint and bone pain
      • Carprofen 4.4 mg/kg PO every 24 hours
        • OR: 2.2 mg/kg SC or PO every 12 hours
      • Firocoxib 5 mg/kg PO every 24 hours
      • Meloxicam 0.1 mg/kg PO every 24 hours
      • Deracoxib 1 to 2 mg/kg PO every 24 hours

  • Analgesics
    • Alone or with corticosteroids or NSAIDs (in Dogs) for pain management
      • Tramadol:
        • Dogs: 4 to 10 mg/kg PO every 8 hours
        • Cats: 1 to 2 mg/kg PO every 12 hours

      • Gabapentin:
        • Dogs: 10 to 20 mg/kg PO every 8 to 12 hours
        • Cats: 5 to 10 mg/kg PO every 12 hours

  • Antitussives
    • For severe coughing

  • Anticonvulsants
    • For management of seizures
    • Levetiracetam is preferred over phenobarbital, due to the increased risk of hepatotoxicity when phenobarbital and triazoles are given concurrently
      • Levetiracetam:
        • Dogs: 30 mg/kg IV (slowly, over 5 to 15 minutes); or 20 mg/kg PO every 8 hours
        • Cats: 20 mg/kg IV bolus (slowly); or 20 mg/kg PO every 8 hours

  • Medication for cerebral edema
    • Mannitol: 0.5 to 1 g/kg slowly IV or IO (over 15 to 20 minutes) every 6 to 8 hours

    • Hypertonic saline: 7% to 7.5% NaCl: 2 to 8 mL/kg IV; do not exceed 1 mL/kg per minute
      • Start at the low end of dosage range for cats

    • Dexamethasone sodium phosphate: 2.2 to 4.4 mg/kg IV

  • Hepatoprotective supplements
    • May have benefits, due to prolonged treatment with antifungal medication and associated risk of hepatotoxicity
      • SAMe and Silybin (Denamarin®) 20 mg/kg PO once daily
        • Use appropriate canine and feline formulations, packaged based on body weight
        • Give on an empty stomach; follow with a small amount of water

Follow-up

General Points

  • Pet owners should be cautioned that long-term therapy for 12 months or longer is likely
  • Clinical signs may recur after the antifungal medication is stopped – especially in pets with CNS disease

Diagnostic Follow-up

  • Periodic reevaluation of thoracic radiographs and serologic findings should be considered for patients undergoing therapy
  • Repeat MRI (if possible) may show resolution of CNS lesions

Therapeutic Follow-up

  • In patients receiving itraconazole, liver enzymes should be evaluated every 4 weeks during therapy
  • Blood urea nitrogen and creatinine levels should be closely monitored during treatment with amphotericin B

Prognosis

  • Prognosis for dogs with localized respiratory disease is good
  • Dogs with severe or disseminated disease are less likely to experience complete recovery
  • Patients with central nervous system involvement have a good-to-excellent prognosis, with early detection and appropriate treatment; the prognosis becomes guarded to poor if the response to treatment is poor and/or the pet deteriorates despite therapy
  • Untreated CNS infection that reaches the brain is likely fatal
  • Resistance to future reinfection is uncertain
  • Prolonged duration of therapy and cost of medication may create financial barriers to treatment for some clients

Evidence

Guidelines and Consensus Statements

  • Lloret A, Hartmann K, Pennisi MG, et al. Rare systemic mycoses in cats: blastomycosis, histoplasmosis and coccidioidomycosis: ABCD guidelines on prevention and management. J Feline Med Surg. 2013 Jul;15(7):624-7. Level C Abstract

Systematic Reviews/Meta-analyses

  • None available

Randomized, Controlled Trials (RCTs)

  • None available

Other Studies or Reviews

  • Plumb’s Veterinary Drugs (online database), Tulsa, OK: Brief Media; 2024. Accessed January 5, 2024. Level 3
  • Kelley AJ, Stainback LB, Knowles KE, et al. Clinical characteristics, magnetic resonance imaging features, treatment, and outcome for presumed intracranial coccidioidomycosis in 45 dogs (2009-2019). J Vet Intern Med. 2021 Sep;35(5):2222-2231. Level 3
  • Papich MG. Papich Handbook of Veterinary Drugs, 5th Edition. St Louis, MO: Elsevier; 2021. Level 3
  • Davidson AP, Shubitz LF, Alcott CJ, et al. Selected clinical features of Coccidioidomycosis in dogs. Med Mycol. 2019 Feb 1;57(Supplement_1):S67-S75. Level 3
  • Gunstra A, Steurer JA, Seibert RL, et al. Sensitivity of Serologic Testing for Dogs Diagnosed with Coccidioidomycosis on Histology: 52 Cases (2012-2013). J Am Anim Hosp Assoc. 2019 Sep/Oct;55(5):238-42. Level 3
  • Bentley RT, Taylor AR, Thomovsky SA. Fungal infections of the central nervous system in small animals: clinical features, diagnosis, and management. Vet Clin North Am Small Anim Pract. 2018 Jan;48(1):63-83. Epub 2017 Oct 6. Level 3
  • Sykes, JE. Coccidioidomycosis. In: Ettinger SJ, Feldman EC, Côte E, ed.’s. Textbook of Veterinary Internal Medicine, 8th Edition. St. Louis: Saunders Elsevier; 2017:1024-7. Level 3
  • Simoes DM, Dial SM, Coyner KS, 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 Oct;27(5):346-e87. Epub 2016 Jul 10. Level 3
  • Bentley RT, Heng HG, Thompson C, et al. Magnetic resonance imaging features and outcome for solitary central nervous system coccidioides granulomas in 11 dogs and cats. Vet Radiol Ultrasound. 2015 Sep-Oct;56(5):520-30. Level 3
  • Sykes JE, Grooters AM, Taboada J. Systemic antifungal therapy. In: Bonagura JD, Twedt DC, ed.'s. Kirk's Current Veterinary Therapy. 15th ed. St. Louis: Elsevier Saunders; 2014:1234-8. Level 3
  • Greene RT. Coccidioidomycosis and paracoccidioidomycosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. Elsevier Saunders; 2012:634-45. Level 3
  • Kirsch EJ, Greene RT, Prahl A, et al. Evaluation of Coccidioides antigen detection in dogs with coccidioidomycosis. Clin Vaccine Immunol. 2012 Mar;19(3):343-5. Level 3 (IND)
  • Davidson AP. Coccidioidomycosis. In: Ettinger SJ, Feldman EC, ed.'s. Textbook of Veterinary Internal Medicine. 7th ed. St. Louis: Saunders Elsevier; 2010:992-6. Level 3
  • Gaidici A, Saubolle MA. Transmission of coccidioidomycosis to a human via a cat bite. J Clin Microbiol. 2009 Feb;47(2):505-6. Level 3
  • Graupmann-Kuzma A, Valentine BA, Shibitiz LF, et al. Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp Assoc. 2008 Sep-Oct;44(5):226-35. Level 3
  • Greene RT, Troy GC. Coccidioidomycosis in 48 cats: a retrospective study (1984-1993). J Vet Inter Med. 1995 Mar-Apr;9(2):86-91. Level 3

Additional Reading

  • Schlacks S, Vishkautsan P, Butkiewicz C, et al. Evaluation of a commercially available, point-of-care Coccidioides antibody lateral flow assay to aid in rapid diagnosis of coccidioidomycosis in dogs. Med Mycol. 2020 Apr 1;58(3):328-332.
  • Mehrkens LR, Mohr FC, Sykes JE. Clinicopathologic and histopathologic renal abnormalities in dogs with coccidioidomycosis. J Vet Intern Med. 2016 Sep;30(5):1667-71.
  • Shubitz LF, Roy ME, Nix DE, et al. Efficacy of Nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs. Med Mycol. 2013 Oct;51(7):747-54.