Cutaneous and Systemic Blastomycosis, Hypercalcemia, and Excess Synthesis of Calcitriol in a Domestic Shorthair Cat

Introduction

Systemic blastomycosis is uncommon in cats, and ionized hypercalcemia with this condition has not previously been reported in domestic cats. ¹ Blastomycosis infection occurs in domestic cats housed only indoors; however, the source of infection is unknown.² Hypercalcemia associated with blastomycosis has been reported in domestic cats, dogs, and in nondomestic felids; however, ionized calcium, vitamin D metabolites, and calcium regulation have not been explored in any previous report.^3–7 A reported 5.3–13.7% of dogs with blastomycosis have hypercalcemia associated with granulomatous disease.^4–6 Sterile pyogranulomatous dermatitis and panniculitis have been described in a dog associated with increased ionized calcium, but calcitriol was not measured.⁸ To the authors’ knowledge, this is the first domestic cat reported with blastomycosis, ionized hypercalcemia, and evaluation of calcium-regulatory hormones.

Case Report

A 9 yr old, castrated, male, domestic shorthair cat presented to the veterinary teaching hospital for evaluation of ulcerative skin lesions of 3 wk duration. The first ulcerative lesion noted by the pet owner was on the left hind limb. An additional lesion on the left forelimb was noted 3 days later. The cat weighed 9.0 kg and was initially evaluated by the referring veterinarian and treated with clindamycin (75 mg per os [PO] q 12 hr). Despite clindamycin therapy, the cat's lesions became progressively larger with associated alopecia of surrounding skin and increased exudate. After 5 days of clindamycin therapy, the patient was hospitalized by the referring veterinarian and treated with intravenous enrofloxacin (45 mg q 24 hr), daily hydrotherapy, and wound management. While on this treatment regimen, no new lesions were identified, but no improvement was noted. The patient was discharged from the referring veterinary hospital on oral enrofloxacin (45 mg q 24 hr), clindamycin (75 mg q 12 hr), and topical gentamicin/betamethasone spray (q 12 hr) and referred for evaluation to the authors’ hospital. The cat maintained normal water and food intake during this 3 wk history. His activity level was slightly decreased and increased hiding activity was observed by his owner. He was an indoor only cat with no travel history outside of Ohio.

At initial evaluation, there were ulcerative lesions on the cat's ventrum (Figure 1). Temperature, heart rate, respiratory rate, and pulse quality were within normal limits. The cat weighed 9.0 kg. Cardiac and respiratory auscultations were unremarkable. Grade IV/V dental disease was observed. Cytology of the exudates from the ulcerative lesions was reported as pyogranulomatous cytology with multiple blue, broad-based, budding, yeast-like organisms consistent with Blastomyces organisms.

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Ocular examination, including fundic evaluation, was within normal limits, and no inflammatory changes consistent with fungal infections were identified. Thoracic radiographs were obtained, and the presence of a mass in the left caudal lung lobe was observed. The mass extended from the level of the lung lobe hilus ventrally, laterally, and caudally to involve most of the ventral aspect of the left caudal lung lobe. The cranial and medial margins of the mass were defined by lobar signs adjacent to the caudal subsegment of the left cranial and accessory lung lobes, respectively. Additionally, several small, ill-defined pulmonary nodules were identified dorsal to the mass on the right lateral radiograph. These findings were compatible with blastomycosis (Figure 2). No bone lysis or associated bone lesions were seen on radiographs of the left tarsus. Complete blood count was interpreted as an inflammatory leukogram with a left shift (1,800 total band neutrophils). Biochemical profile abnormalities included a total calcium level of 13.8 mg/dL (normal range, 8.4–10.1 mg/dL) and elevated globulins of 5.0 g/dL (normal range, 3.1–4.1 g/dL). Ionized calcium was increased at 7.02 mg/dL (normal range, 5–5.5 mg/dL) (Table 1). Feline leukemia and feline immunodeficiency virus snap tests were negative. Organisms consistent with blastomycosis and associated pyogranulomatous inflammation effacing the lymph node were seen on left popliteal lymph node aspiration cytology (Figure 3). Tissue culture was submitted from a 6 mm punch biopsy of the lesions to the Ohio Department of Health^a and later reported as DNA probe positive for Blastomyces dermatitidis.

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TABLE 1 Serial Calcium and Vitamin D Metabolite Measures in a Cat with Blastomycosis

N, normal range; PTHrP, parathyroid hormone related polypeptide.

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Therapy was initiated for blastomycosis, which included wound cleaning and debridement with saline flushing, fentanyl patch placement for pain (25 μg to be removed in 3–4 days upon re-evaluation), and Sporonox oral itraconazole suspension (45 mg q 12 hr). Enrofloxacin and clindamycin were discontinued. An Elizabethan collar was placed, and client education for provision of good hygiene (isolation from others pets, housed on cleansable surfaces only, limiting contact, utilizing examination gloves for medication application) and description of zoonotic potential (spread to humans through inhalation and direct contact, varied severity of disease in humans) of blastomycosis were provided. A switch to paper litter in the litter box was recommended to avoid wound contamination with clay litter.

The patient was re-evaluated in 4 days, at which time deeper ulceration of the hindlimb lesion was observed secondary to sloughing of necrotic tissue. He was observed to tolerate oral itraconazole well, and his wounds were clipped free of hair and flushed gently with sterile saline. His therapy was modified to include topical bacitracin/neomycin/polymyxin B ointment to all open lesions on legs once daily after cleaning of any exudates with a warm, moist, soft cloth to promote a moist environment for re-epithelialization while discouraging secondary bacterial infection and providing a mechanical barrier. The itraconazole prescription was modified to a 100 mg generic capsule administered once daily after the initial suspension was finished (7 day course) due to financial considerations. Hill's a/d diet^b was dispensed to encourage adequate caloric intake because decreased appetite was reported.

Two week re-evaluation revealed several new small ulcerative and nodular lesions surrounding the original left forelimb and hind limb lesions. The patient was inappetent at home; however, his activity level remained unchanged. Patient weight was 7.9 kg. Rod and cocci organisms were seen on cytology of ulcerative lesions, suggesting a secondary bacterial infection. There were concerns about liver toxicity, but the liver enzymes were normal. Current therapy was maintained. Marbofloxacin therapy was instituted to combat the secondary bacterial infection at 25 mg PO q 24 hr. The owner was dispensed Hill's a/d diet and instructed on syringe feeding recommendations if inappetence continued.

Three week re-evaluation revealed little change from previous 2 wk re-evaluation. Complete blood count was re-evaluated and a progressive inflammatory leukogram with left shift was observed (22,700 total leukocytes, normal range 4,000–14,500; 2,700 total band neutrophils, normal range, 0–100). Serum total calcium elevation increased slightly from the last visit at 14.1 mg/dL (normal range, 8.5–10.1 mg/dL) (Table 1). Current therapy was continued with all previously prescribed medications and syringe feeding.

Six week re-evaluation revealed minor resolution of some lesions, whereas others progressed to further ulceration, including abscessation of the left popliteal lymph node region. Inappetence continued at home; however, continued syringe feeding of >30 mL of Hill's a/d diet q 8 hr was maintained. Patient weight was 7.2 kg. Therapy for the persistent hypercalcemia was recommended (hospitalization, intravenous fluid therapy, furosemide, possible pamidronate infusion) and declined due to financial considerations. There was concern that the hypercalcemia was contributing to the cat's poor overall condition, inappetence, lethargy, and weight loss. Repeated measures of calcium status and vitamin D metabolite measures were paid for by research funds. Vitamin D metabolites were measured; 1,25-dihydroxy-vitamin-D^c was 102.0 pg/mL (normal range, 20–40 pg/mL) and 25-hydroxy-vitamin-D^d was 52 nmol/L (normal range, 65–170 nmol/L) (Table 1). Marbofloxacin therapy was discontinued as secondary infection resolution was seen on cytology. Topical 2% chlorhexidene solution spray on lesions q 24 hr was prescribed as a preventative measure to reduce incidence of secondary bacterial infection. The therapy was continued with a dose reduction to 50 mg itraconazole PO q 24 hr in the hope that some of the anorexia was related to the drug.

Seven week re-evaluation revealed the cat's appetite improved on the reduced dose of itraconazole. No new skin lesions were observed, and mild resolution and reduction of discharge from wounds was noted. Lesions decreased in size through contraction and re-epithelialization. Thoracic radiographs revealed reduction in size of hilar mass and subtle nodules as previously described. Current therapy was maintained. Parathyroid hormone–related polypeptide (PTHrP) level was measured^d at 0.0 pmol/L (Table 1). Ionized calcium was measured at 5.50 mg/dL (normal range, 5–5.5 mg/dL) (Table 1).

The 12 wk re-evaluation revealed substantial improvement. No ulcerative lesions remained, all lesions demonstrated re-epithelialization, and wound size was substantially reduced through contraction. The cat's appetite returned to normal and activity level increased. Patient weight was 7.7 kg. No new skin lesions were observed, and some regrowth of hair was seen. No exudate remained; the main limb lesions had closed, and resultant scar tissue was noted. Therapy was continued with 50 mg of oral itraconazole q 24 hr, and all topical therapy was discontinued.

At 19 wk re-evaluation, complete resolution of all skin lesions with continued hair regrowth was observed. All lesions were completely re-epithelialized and significantly contracted. Patient appetite and activity level remained normal. Patient weight was 8.2 kg. Thoracic radiographs revealed continued resolution of pulmonary lesions. The left caudal lobar fungal granuloma was decreased in size, and tracheobronchial lymphadenopathy was unchanged compared with previous studies. Ionized calcium was measured at 5.22 mg/dL (normal range, 5–5.5 mg/dL) (Table 1). Vitamin D metabolites were measured at 1,25-dihydroxy-vitamin D^b (65.6 pg/mL) and 25-hydroxy-vitamin D^d (119 nmol/L) (Table 1). PTHrP measured^d 0.0 pmol/L (Table 1). Clinical blastomycosis was considered resolved at this re-evaluation, and therapy was continued with only itraconazole 50 mg PO q 24 hr for a final 4 wk. No future hospital evaluations were planned due to financial limitations, and the reported normal health was by phone consultation with the owner.

Discussion

The hypercalcemia identified in this patient was consistent with hypercalcemia of granulomatous disease characterized by an elevated calcitriol level (1,25-dihydroxy-vitamin-D).^9,10 PTHrP concentrations were low, suggesting that the cause of the hypercalcemia was not driven by neoplastic production of PTHrP, which often occurs in humoral hypercalcemia of malignancy. The degree of hypercalcemia paralleled the clinical response to therapy observed in cutaneous and lung lesions as well as the calcitriol levels. Further calcitriol levels were not measured when the cat was in complete remission.

The initial 25-hydroxy-vitamin-D concentration was low, indicating no role for this metabolite in the generation of hypercalcemia; this low concentration was likely the combined result of poor nutritional intake and conversion of 25-hydroxy-vitamin-D to 1,25-dihydroxy-vitamin-D by macrophages. The increased 1,25-dihyroxy-vitamin-D was attributed to unregulated conversion of 25-hydroxy-vitamin-D to 1,25-dihydroxy-vitamin-D by macrophages associated with the granulomatous inflammation of blastomycosis. 1,25D is normally tightly regulated by activity of 1-α-hydroxylase within the kidneys. Macrophages do not have this regulatory control; therefore, as the mass of macrophages increased, so did the capacity to convert 25-hydroxy vitamin-D to 1,25-dihyroxy-vitamin-D. Hypercalcemia develops during exposure to increased concentrations of circulating 1,25-dihyroxyvitamin-D after increased gastrointestinal calcium absorption, bone resorption, and renal tubular reabsorption of calcium.^9,10

The authors attributed the initial systemic signs in this cat to the effects of the blastomycosis infection and resultant inflammation, as well as the toxic effects of ionized hypercalcemia. Ideally, the degree of hypercalcemia would reduce with treatment designed to lower serum calcium. In other forms of vitamin D metabolite, toxicity associated with hypercalcemia in dogs; IV treatment with the bisphosphonate pamidronate was an effective method to decrease circulating calcium.^11–13

The most common association with hypercalcemia in cats is idiopathic hypercalcemia followed by cats with azotemic chronic kidney disease.^14,15 Hypercalcemia of malignancy is far less common in cats than dogs.^14,15 Granulomatous inflammation is an uncommon cause of hypercalcemia in cats. One cat with hypercalcemia and increased concentration of circulating calcitriol was reported in association with granulomatous disease caused by atypical Mycobacterium.¹⁶ Three of seven domestic cats that developed severe granulomatous reactions at injection sites of immunocontraceptives also developed serum total hypercalcemia associated with increased concentrations of circulating calcitriol.¹⁷ Two of eight cats with histoplasmosis in one report were noted with hypercalcemia based on total serum calcium, but measurement of vitamin D metabolites was not reported.¹⁸ Granulomatous disease of cryptococcosis and actinomyces rhinitis was described as causes of hypercalcemia in 2 of 71 feline cases; however, neither ionized calcium nor vitamin D metabolites were measured.¹⁵ Moderate hypercalcemia based on serum total calcium (without evaluation of vitamin D metabolites) was described in association with blastomycosis in nondomestic felids.⁷ Mild total serum hypercalcemia was reported in two of eight domestic cats in a retrospective case series of naturally occurring blastomycosis infection; however, no ionized calcium or vitamin D metabolites were measured.³

Ideally, PTHrP concentrations should be measured in patients with hypercalcemia to determine whether the hypercalcemia is parathyroid gland dependent. Measurement of ionized calcium is important because total calcium often fails to predict ionized calcium concentrations accurately in cats.¹⁹ PTHrP concentration should be suppressed when ionized hypercalcemia is due to excess vitamin D metabolites or malignancy if the parathyroid glands are normal.⁹ Although not measured in this report, PTHrP would likely have been normal to low in concentration because the hypercalcemia resolved as the fungal lesions resolved and the calcitriol concentrations declined. If a parathyroid adenoma was the cause of the hypercalcemia, hypercalcemia would have persisted as the fungal lesions resolved.

This was the first report of ionized hypercalcemia secondary to blastomycosis in the domestic cat. Evaluation of vitamin D metabolites demonstrated excessive production of calcitriol, which supports the concept for the development of hypercalcemia secondary to granulomatous disease described previously in many species.^{8–10,14,16,20} Resolution of ionized hypercalcemia was found in association with decreased circulating calcitriol and effective treatment of blastomycosis.