Retrospective evaluation of voriconazole treatment in psittacines: 14 cases (2012–2023)

Daria Hinkle Department of Surgical Science, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI

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Christoph Mans Department of Surgical Science, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI

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 Dr med vet, MBA, DACZM

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Abstract

OBJECTIVE

To retrospectively evaluate the clinical use of voriconazole in psittacine patients for the treatment of suspected respiratory fungal infections.

ANIMALS

14 client-owned psittacine birds.

METHODS

Medical records were searched from 2012 to 2023 for voriconazole use in psittacines. Species, age, clinical signs, physical examination findings, CT reports, bloodwork results, treatment, and outcome were obtained from the records or client follow-up.

RESULTS

African grey parrots were the most prevalent species (8/14). Dyspnea (9/14) and abnormal respiratory auscultation (11/14) were the most common examination abnormalities. An initial CT was performed in all cases, and pneumonia (10/14) and air sac disease (9/14) were the most common findings, with 8 cases having both pulmonary and air sac disease. Voriconazole doses ranged from 10 to 21 mg/kg (median, 16 mg/kg), with most cases prescribed as every-12-hour frequency (12/14). Three of 14 (21%) cases died or were euthanized within 24 days of diagnosis. One case was euthanized at 311 days, and 6 cases were lost to follow-up. Four of 14 (29%) cases lived > 12 months from diagnosis. Two of these cases cleared clinical infection after receiving voriconazole at 17 to 18 mg/kg (q 12 h). No adverse effects attributable to voriconazole were reported.

CLINICAL RELEVANCE

Voriconazole can be safely used for the treatment of suspected fungal respiratory infection in psittacines. However, the prognosis for resolution is guarded, and prolonged treatment and repeated diagnostic imaging are necessary in many cases.

Abstract

OBJECTIVE

To retrospectively evaluate the clinical use of voriconazole in psittacine patients for the treatment of suspected respiratory fungal infections.

ANIMALS

14 client-owned psittacine birds.

METHODS

Medical records were searched from 2012 to 2023 for voriconazole use in psittacines. Species, age, clinical signs, physical examination findings, CT reports, bloodwork results, treatment, and outcome were obtained from the records or client follow-up.

RESULTS

African grey parrots were the most prevalent species (8/14). Dyspnea (9/14) and abnormal respiratory auscultation (11/14) were the most common examination abnormalities. An initial CT was performed in all cases, and pneumonia (10/14) and air sac disease (9/14) were the most common findings, with 8 cases having both pulmonary and air sac disease. Voriconazole doses ranged from 10 to 21 mg/kg (median, 16 mg/kg), with most cases prescribed as every-12-hour frequency (12/14). Three of 14 (21%) cases died or were euthanized within 24 days of diagnosis. One case was euthanized at 311 days, and 6 cases were lost to follow-up. Four of 14 (29%) cases lived > 12 months from diagnosis. Two of these cases cleared clinical infection after receiving voriconazole at 17 to 18 mg/kg (q 12 h). No adverse effects attributable to voriconazole were reported.

CLINICAL RELEVANCE

Voriconazole can be safely used for the treatment of suspected fungal respiratory infection in psittacines. However, the prognosis for resolution is guarded, and prolonged treatment and repeated diagnostic imaging are necessary in many cases.

Introduction

Fungal infections of the lower respiratory tract, usually caused by Aspergillus spp, are frequently seen in psittacine patients, with certain species, such as African grey parrots, being more commonly affected.1 Aspergillosis can develop when a bird is exposed to an overwhelming spore challenge or when the bird is immune compromised by underlying disease or poor husbandry.1 Diagnostic imaging is usually employed to evaluate birds with clinical signs consistent with lower respiratory tract disease. Radiography is often a first-line diagnostic due to its availability in first-opinion practice, cost-effectiveness, and rapid results. However, radiographic interpretation can be limited by the location and extent of disease and generally requires sedation to be achieved. Computed tomography also requires sedation and is less accessible and more expensive than radiography, but this modality has a greater sensitivity and specificity concerning the diagnosis of lower respiratory disease in birds, in particular diseases affecting the lungs. Both imaging techniques may identify evidence of infectious disease, but findings are not pathognomonic, and infection with Aspergillus spp cannot be confirmed with imaging alone.2 Endoscopic evaluation allows for visual confirmation of infectious lesions and the opportunity to obtain cytology and fungal culture samples to establish an etiological diagnosis. This procedure is invasive and requires general anesthesia, which is of higher risk in patients with advanced disease.2,3

Treatment of aspergillosis in psittacines has been reported to include oral and/or intravascular antifungals as well as topical antifungals in the form of nebulization or, less commonly, topical application during laparoscopy.1,3 Certain oral antifungals, such as itraconazole, have been reported to be poorly tolerated in certain common psittacine species, such as African grey parrots.1,4 Voriconazole is currently considered the most effective oral antifungal medication in humans and is recommended as the primary therapy.5 A pharmacokinetic study6 of voriconazole in Timneh African grey parrots (Psittacus erithacus timneh) evaluated 18-mg/kg doses (q 12 h) in a multidose study and determined a 12- to 18-mg/kg twice-daily starting dose. A similar multidose study in Hispaniolan Amazon parrots (Amazona ventralis) evaluated 18-mg/kg doses (q 8 h), and both studies6,7 determined that plasma concentrations decreased after multiple doses potentially indicating induced metabolism of the drug. The only adverse effect reported in these6,7 studies was polyuria. While pharmacokinetic studies for antifungals are available for psittacines, no efficacy data are available for any antifungal drug in psittacines. In birds of prey, efficacy data on the use of voriconazole show it is highly effective in the treatment of aspergillosis.8 Antifungal therapy is usually prolonged, and relapses of the infection can occur once antifungal treatment is discontinued.1

The objectives of this retrospective study were to retrospectively evaluate the use of voriconazole in psittacine species for the treatment and outcome of suspected or confirmed fungal infections of the respiratory tract.

Methods

Medical records were reviewed for the period of January 1, 2012, to September 1, 2023, for the prescription of voriconazole in psittacine birds seen at the University of Wisconsin-Madison School of Veterinary Medicine. Patients were eligible for inclusion if a CT scan was performed, interpretation by a board-certified radiologist was consistent with an infectious process of the respiratory tract, with fungal organisms as a prioritized differential, and the patient was discharged with a voriconazole prescription. Data extracted from the medical record included age, sex, clinical signs at presentation, physical examination findings, CBC and plasma biochemistry profile performed at diagnosis and during the treatment period, medication prescriptions, diagnostic imaging reports, and endoscopy and necropsy results. All cases listed as surviving were contacted by phone to obtain follow-up from the owner or primary care veterinarian records.

Results

Signalment

Fourteen psittacine patients met the inclusion criteria and received voriconazole for suspected aspergillosis diagnosed on CT. Eight patients were African grey parrots (7 Psittacus erithacus erithacus and 1 Psittacus erithacus timneh) with an age range of 18 to 38 years (median, 25.5 years), 3 cockatiels (Nymphicus hollandicus) with an age range of 13 to 20 years (median, 17 years), 2 Amazon parrots (Amazona spp) aged 14 and 20 years, and 1 pionus parrot (Pionus sp) aged 12 years. Seven of 14 patients were female, 1 of 14 was of unknown sex, and 6 of 14 were male (Table 1).

Table 1

Signalment, presenting complaint, and physical examination findings of 14 psittacines treated with voriconazole for suspected or confirmed fungal infection of the respiratory tract.

Case Species Sex Age Presenting complaint Duration of signs Physical exam findings
1 African grey (Timneh) Female 23 Acute dyspnea, wet cough/sneeze 12–24 h Harsh lung sounds, air sac crackles, dyspnea
2 African grey (Congo) Unknown 30 Hyporexia, lethargy 3–4 d No abnormalities on auscultation, feather loss
3 African grey (Congo) Female 18 Lethargy 1 mo Grade II/VI murmur, no respiratory abnormalities
4 African grey (Congo) Male 38 Voice change 1 wk Wheezing on auscultation, dyspnea
5 African grey (Congo) Male 18 Cough 2 wk Wheezing and click on auscultation
6 African grey (Congo) Male 37 Cough/sneeze 3–4 d Harsh lung sounds, grade III/VI heart murmur
7 African grey (Congo) Female 26 Voice change 3–4 wk Harsh lung/air sac sounds, dyspnea, dehydration
8 African grey (Congo) Male 25 Dyspnea Unrecorded Wheezing on auscultation, dyspnea
9 Amazon Female 20 Sneeze, dyspnea 1 d Wheezing on auscultation, dyspnea, dehydration
10 Amazon Male 14 Dyspnea, mucoid nasal discharge 2 y Harsh lung sounds, air sac crackles, dyspnea
11 Pionus Female 12 Pruritic dermatitis 5 y Harsh lung sounds, air sac crackles, dermatitis
12 Cockatiel Female 18 Voice change, lethargy 2 wk Harsh lung sounds, stertor, dyspnea
13 Cockatiel Female 20 Dyspnea 2 d Dyspnea, feather loss, no abnormalities on auscultation
14 Cockatiel Male 13 Dyspnea, sneeze, voice change 2 mo Lung and air sac crackles, dyspnea

History and clinical findings

Seven of 14 patients were evaluated or treated by a primary veterinarian before being referred for further evaluation, and 7 of 14 patients were seen primarily through the teaching hospital. Presenting complaints included dyspnea (7/14), coughing/sneezing (6/14), voice change (4/14), lethargy (3/14), hyporexia (1/14), mucoid nasal discharge (1/14), and pruritic dermatitis (1/14). Duration of signs before presentation ranged from 1 day to 5 years, with 6 of 14 patients having signs for 1 week or less, 4 of 14 having signs from 1 week to 1 month, and 3 of 14 having signs > 1 month, with 1 patient’s duration of signs unrecorded. Case 11, a pionus parrot with the longest duration of signs, had pruritic dermatitis intermittently for 5 years, and evidence of respiratory disease was found incidentally on physical examination (Table 1).

Physical examination findings included abnormal respiratory auscultation (11/14), dyspnea (9/14), heart murmur (2/14), dehydration (2/14), feather loss (2/14), and dermatitis (1/14; Table 1). Patients were found to be mildly underconditioned (4/14), normal body condition (6/14), or overconditioned (4/14), with no patients being severely underconditioned (< 2/5 body condition score).

An initial CBC was performed in 9 of 14 cases, with leukocytosis present in 5 of 9 cases compared to species-specific reference ranges (6 X 103 to 13 X 103/µL in Psittacus spp, 5 X 103 to 11 x 103/µL in N hollandicus).9 The leukocytosis was characterized as moderate to marked heterophilia with some cases accompanied by mild monocytosis. Case 10, an Amazon parrot, had leukopenia at 2.4 X 103/µL WBCs compared to Amazona spp (reference range, 6 X 103 to 17 X 103/µL).9 Case 5, a Congo African grey, had moderate anemia with a PCV of 34% (45% to 53% in Psittacus spp)9 with a normal total WBC count (Table 2).

Table 2

Initial diagnostic test results and comorbidities of 14 psittacines treated with voriconazole for suspected or confirmed fungal infection of the respiratory tract.

Case Initial bloodwork CT Comorbidities
1 No CBC; uric acid, 10.8 µg/dL Bilateral pneumonia and air sacculitis Hematochezia, hepatic lipidosis, mild atherosclerosis, bilateral renomegaly
2 TWBC, 59,700 Right pulmonary granuloma Feather picking
3 Within normal limits Bilateral pneumonia and air sacculitis Atherosclerosis, cardiomegaly
4 TWBC, 33,400; AST, 909 U/L Left pneumonia and syringeal granuloma
5 PCV, 34%; TWBC, 12,000 Right pneumonia Nephrolithiasis
6 Not performed Left pneumonia and left air sac granuloma with air sacculitis Atherosclerosis, heart murmur, hepatic lipidosis
7 TWBC, 26,600 Bilateral pneumonia and air sacculitis with right bronchial plugging Reproductive cyst/mass
8 TWBC, 15,700 Bilateral pulmonary and air sac granulomas
9 TWBC, 8,300 Severe bilateral pneumonia, air sacculitis, tracheitis, and granuloma formation Previous treatment 1 y to 6 mo prior with itraconazole/terbinafine
10 TWBC, 2,400 Left air sac granuloma, bilateral air sacculitis and bronchitis, and left bronchial plugging Previous intermittent 2 y treatment with enrofloxacin and fluconazole
11 Not performed Right air sac granuloma Pruritic dermatitis
12 TWBC, 15.1K; AST, 547 Bilateral pneumonia
13 No CBC; AST, 539; bile acids, 75 Tracheal granuloma Arthritis, historic elevated bile acids, chronic rhinitis
14 TWBC, 8,200; AST, 1,270, bile acids, 183 Right pneumonia and air sacculitis Testicular neoplasm with liver metastasis

TWBC = Total WBC count.

Initial plasma biochemistry (Vetscan Avian Reptilian Profile Plus; Zoetis) was performed in 12 of 14 cases and compared to species-specific reference ranges. Mild elevations in creatine kinase were attributed to handling or injections and were not included in the results. Elevated AST was present in 4 of 12 cases in 1 Congo African grey and all 3 cockatiel cases compared to species-specific reference ranges (109 to 305 U/L in Psittacus spp, 160 to 383 U/L in N hollandicus).9 Case 14, a cockatiel diagnosed with metastatic testicular neoplasm within the liver, had an elevated bile acids at 183 µmol/L, while case 13, another cockatiel, had high normal bile acids of 75 µmol/L with historic elevated bile acids (< 95 µmol/L in avian species).10 Case 1, a Timneh African grey, had elevated uric acid at 10.8 mg/dL (2.7 to 8.8 mg/dL in Psittacus spp).9

Initial CT findings consistent with aspergillosis included pneumonia (10/14), air sac disease (9/14), pulmonary granuloma (3/14), bronchial obstruction (2/14), syringeal granuloma (1/14), tracheitis (1/14), and tracheal granuloma (1/14). Nine of 14 cases had 2 or more of these findings, with 8 of these cases having concurrent pulmonary and air sac disease. Seven of 14 cases had bilateral disease, with 7 of 14 cases having unilateral or tracheal disease (Table 2).

Aspergillosis was confirmed antemortem in only case 4, a Congo African grey parrot that underwent tracheoscopy for sampling of a tracheal granuloma. Fungal culture grew Aspergillus fumigatus, and the patient received intratracheal administration of amphotericin B after tracheoscopy. This was the only case in which endoscopy was performed.

Treatment

Eight of 14 cases were treated as outpatients, and 6 of 14 cases were hospitalized for diagnostics or supportive care ranging from 1 to 6 days (Table 3). Voriconazole was prescribed at a dose range of 10 to 21 mg/kg (median, 16 mg/kg), with 12 of 14 cases prescribed as every-12-hour frequency. One case was prescribed with a frequency of every 8 hours and 1 case with a frequency of every 8 to 12 hours. Additional treatments varied between cases. Twelve of 14 cases received antibiotic therapy, including enrofloxacin, azithromycin, amoxicillin, and clavulanic acid, or trimethoprim-sulfamethoxazole. Six of 14 cases received nebulization therapy including amphotericin B, gentamicin, terbutaline, acetylcysteine, saline, or meropenem. Six of 14 cases were treated with meloxicam. Three of 14 cases received terbinafine as a secondary antifungal agent. Case 1, the Timneh African grey parrot, received terbinafine at 15 mg/kg (q 12 h) together with voriconazole at the time of the initial diagnosis. Case 9, an Amazon parrot, had previously received terbinafine and itraconazole for suspected aspergillosis and received 23 mg/kg of terbinafine (q 24 h) when voriconazole was started for recurrent disease. Case 10, the other Amazon parrot, started 31 mg/kg of terbinafine (q 24 h) when progression of disease was noted on CT after 3 months off voriconazole and voriconazole was restarted lifelong (Table 3).

Table 3

Treatment information, follow-up diagnostics, and outcome of 14 psittacines treated with voriconazole for suspected or confirmed fungal infection of the respiratory tract.

Case Hospitalization Voriconazole dose (frequency) Voriconazole duration Additional medications Follow-up diagnostics Outcome
1 3 d 12 mg/kg (q 12 h) 20 d continuous TMS, omeprazole, terbinafine, amphotericin B nebulization N/A Died 20 d after diagnosis
2 1 d 10 mg/kg (q 12 h) 70 d continuous Enrofloxacin CBC: TWBC, 9,800; CT: resolved pulmonary granuloma Disease reoccurrence 40 months after treatment
3 Outpatient 12 mg/kg (q 12 h) 60 d continuous Azithromycin No CBC/biochemistry; CT: improvement of pneumonia on right, otherwise static Lost to follow-up after voriconazole discontinued
4 6 d 18 mg/kg (q 12 h) 1 y continuous Intratracheal amphotericin B post-tracheoscopy, azithromycin, amphotericin B nebulization, gentamicin nebulization N/A Alive 50 mo after treatment
5 Outpatient 15 mg/kg (q 12 h) Lost to follow-up Meloxicam, amoxicillin–clavulanic acid N/A Lost to follow-up
6 Outpatient 17 mg/kg (q 12 h) 120 d intermittent Amoxicillin–clavulanic acid CBC: TWBC, 12,200; CT: resolved pneumonia, static left air sac granuloma and air sacculitis Alive 45 mo after treatment
7 4 d 17 mg/kg (q 12 h) 9 d continuous Enrofloxacin, meloxicam, amphotericin B nebulization, terbutaline nebulization, acetylcysteine nebulization, deslorelin implant N/A Died 9 d after diagnosis
8 Outpatient 17 mg/kg (q 12 h) 305 d (lifelong) intermittent Meloxicam, gentamicin nebulization, azithromycin CBC: TWBC, 21,300; CT: static pulmonary and air sac granulomas Euthanized 10 months after diagnosis; necropsy performed
9 1 d 10 mg/kg (q 8–12 h) 24 d continuous Azithromycin, terbinafine diagnosis of recurrent disease N/A Euthanized 24 d after
10 Outpatient 20 mg/kg (q 8 h) Lifelong intermittent Saline nebulization, enrofloxacin, terbinafine CBC: TWBC, 8,100; CT: static left air sac granuloma, bilateral air sacculitis and bronchitis, and left bronchial plugging Alive 608 d after voriconazole started
11 Outpatient 18 mg/kg (q 12 h) Lost to follow-up Meloxicam, TMS N/A Lost to follow-up
12 Outpatient 21 mg/kg (q 12 h) Lost to follow-up N/A N/A Lost to follow-up
13 2 d 15 mg/kg (q 12 h) 74 d continuous Enrofloxacin, meropenem nebulization, ursodiol, silymarin, amphotericin B nebulization, meloxicam No CBC/biochemistry; CT: improved tracheal granuloma Lost to follow-up after 74 d recheck
14 Outpatient 14 mg/kg (q 12 h) Lost to follow-up Meloxicam, silymarin, leuprolide Lost to follow-up N/A

N/A = Not available. TMS = Trimethoprim/sulfamethoxazole.

Adverse effects attributable to voriconazole were not reported in any of the cases. Hyporexia was reported in only 1 of 14 cases and developed after multiple months of receiving treatment. The duration of voriconazole treatment was variable by case and outcome. Duration could not be determined in 4 cases due to loss of follow-up. Seven of 10 cases received continuous voriconazole treatment; 3 of 10 cases received intermittent treatment due to progression of disease or recurrent clinical signs after discontinuation of voriconazole or client noncompliance. Patients that died or were euthanized within the first 30 days of treatment were not included in calculating treatment duration. The remaining 7 cases with available follow-up to estimate treatment duration included 2 cases that continued on lifelong treatment with voriconazole. The 5 cases that discontinued voriconazole administration had a duration of treatment ranging from 60 to 365 days (median, 74 days).

Outcomes

Follow-up diagnostics were performed in 6 of 14 cases, with all 6 undergoing repeat CT scans (Table 3). Four of 6 cases showed partial improvement or resolution of disease. Pulmonary disease consisting of pneumonia, pulmonary granuloma, or bronchitis showed improvement or resolution in 3 of the 5 cases with disease in this location. Disease within the air sacs consisting of air sacculitis or air sac granuloma showed improvement or resolution in 0 of the 4 cases with disease involvement in this location, and lesions remained static. Two cases showed improvement of pulmonary lesions, but static air sac disease. Case 13, a cockatiel with only a tracheal granuloma, showed improvement on repeat CT.

Complete blood count and plasma biochemistry were performed during treatment in 4 of the 6 cases with follow up diagnostics. Three of 4 cases had a normal total WBC count during treatment with voriconazole, with 1 of 3 having a leukocytosis before treatment, 1 of 3 having a leukopenia prior to treatment, and 1 of 3 not having a CBC performed prior to treatment. Case 8 maintained a leukocytosis of 21.3 X 103/µL following 6 months of voriconazole treatment compared to 15.7 x 103/µL prior to treatment. There were no clinically relevant abnormalities on plasma biochemistry in 4 of 4 cases, including normal liver values of AST and bile acids. Of note, none of the cases with elevated uric acid, AST, or bile acids on initial samples had follow-up bloodwork performed.

Four of 14 cases were lost to follow-up after the initial diagnosis and treatment with voriconazole. Three of 14 cases died or were euthanized within 24 days of diagnosis, all of which presented with dyspnea and evidence of respiratory disease on auscultation. Two of these 3 cases had been prescribed terbinafine at the time of diagnosis. Two of 14 cases were lost to follow-up after repeat CT at 60 and 74 days of treatment showed improvement and voriconazole was either discontinued or prescribed for an additional set time. One of 14 cases (case 8) was euthanized 311 days after diagnosis due to inappetence and difficulty medicating. This 25-year-old Congo African grey parrot was maintained on lifelong voriconazole at 17 mg/kg (q 12 h) due to the return of respiratory signs with a previous 6-day gap in treatment and static pulmonary and air sac granulomas on CT. Gross necropsy identified disseminated fungal plaques with no growth on culture, and histopathology confirmed fungal hyphae. Medication compliance is suspected to be a factor based upon discharge instructions.

Four of 14 cases survived > 1 year after diagnosis and remain alive, with 2 of these cases having cleared disease without reoccurrence (Table 3). At the time of diagnosis cases 4 and 6 were 38- and 37-year-old Congo African grey parrots; they have lived 50 and 45 months since completing voriconazole treatment of 1 year continuously at 18 mg/kg (q 12 h) and 120 days intermittently at 17 mg/kg (q 12 h) respectively. Case 10 is a 14-year-old Amazon parrot that has lived 20 months since diagnosis and remains on voriconazole at 20 mg/kg (q 8 h) and terbinafine lifelong after progression of disease on CT was noted with 3 months off medication. Case 2 is a 30-year-old Congo African grey parrot that completed 70 days of continuous voriconazole treatment at 10 mg/kg (q 12 h) for a pulmonary nodule that was considered resolved on repeat CT (Figure 1). The patient remained clinically free of disease for 40 months before a new air sac granuloma was diagnosed on a repeat CT prompted by lethargy. Voriconazole treatment was reinitiated in this patient with improvement noted, and the patient is under continued care.

Figure 1
Figure 1

Cross-sectional CT images of a 30-year-old Congo African grey parrot (case 2). A—Large right-sided pulmonary mass suspected to represent a fungal granuloma. B—The same bird after 70 days of continuous treatment with voriconazole, showing resolution of the previously diagnosed pulmonary granuloma and formation of a pulmonary bulla.

Citation: Journal of the American Veterinary Medical Association 2024; 10.2460/javma.24.01.0018

Discussion

Triazoles are a group of antifungal medications including itraconazole, fluconazole, and voriconazole that can be given orally with potential adverse effects of alterations in liver function and gastrointestinal signs.4 African grey parrots are reportedly more sensitive to itraconazole, frequently presenting with anorexia and depression.4 Fluconazole is water soluble and has the potential to be administered in drinking water,4 but has no mold activity and is considered ineffective against aspergillosis.5 Additionally, both itraconazole and fluconazole take longer to reach steady-state concentrations than voriconazole. Voriconazole is being utilized at increasing frequency for avian aspergillosis4 and is currently the treatment of choice for human cases of aspergillosis.5

The pharmacokinetic studies6,7 of voriconazole in psittacines found no evidence of hepatitis, and all Timneh African grey parrots but only 1 Hispaniolan Amazon parrot developed polyuria. No adverse effects attributable to voriconazole administration were identified in this retrospective study, and those patients that had biochemistry performed during treatment had normal liver values. Case 8 reported hyporexia prior to euthanasia, but this occurred 10 months after diagnosis and initiation of voriconazole and is unlikely to be related to drug administration. Regular monitoring of liver values while receiving voriconazole is recommended, as hepatic toxicosis has been reported with voriconazole use in both human and avian patients.4,7,8

Both pharmacokinetic studies also identified decreased plasma concentrations after multiple-dose administration of voriconazole, indicating the potential for induced metabolism.6,7 Dose simulation showed that every-3-to-5-hour dosing would be required to maintain appropriate plasma concentrations in Hispaniolan Amazon parrots.7 This frequency of dosing would be impractical for prolonged outpatient treatment, and most cases in this study were prescribed an every-12-hour frequency. Although increased frequency such as every-8-hour dosing may be needed to increase time of plasma concentrations above MIC, this must be balanced with client and patient compliance. Only case 10 was prescribed voriconazole with every-8-hour dosing, at 20 mg/kg, and has been continued on both voriconazole and terbinafine lifelong with static CT findings of left air sac granuloma, bilateral air sacculitis, and left bronchial obstruction. Clinical signs returned when the patient was trialed off medication, and the higher dose and frequency appear unable to fully clear the infection. In avian species, it is recommended to maintain plasma concentrations above 0.4 µg/mL, which was not achieved with 18 mg/kg of voriconazole (q 8 h) in Hispaniolan Amazon parrots.7 Multidose pharmacokinetic studies at higher dosages may help determine whether appropriate plasma concentrations could be maintained with reasonable dosing frequency for outpatient treatment. Monitoring for therapeutic drug levels may be beneficial to determining appropriate doses by individual for long-term use of voriconazole.

Terbinafine was prescribed in a total of 3 cases. Case 1 had elevated uric acid and hematochezia identified during initial hospitalization for diagnosis and died 20 days after diagnosis. Case 9 had received terbinafine with itraconazole for suspected aspergillosis previously and was euthanized 24 days after diagnosis of recurrent disease. Case 10 remains on voriconazole and terbinafine as described previously. Terbinafine may be more likely to be prescribed in cases that appear more severe to the treating clinician. The efficacy of terbinafine use in conjunction with voriconazole requires further research.

There was a notable difference in CT response to treatment between pulmonary or tracheal lesions and lesions within the air sac. Of the 6 cases with repeated CT scan performed, 4 of these had air sacculitis or distinct granuloma formation. These lesions remained static on imaging in all 4 cases, including case 6, which is alive 45 months after completing voriconazole treatment and remains clinically free of disease. One potential cause for the difference in response is decreased vasculature within the air sac system compared to the pulmonary system, which may decrease efficacy of voriconazole treatment or the ability to resolve lesions. It is possible the lesions are inactive but remain present on CT imaging as chronic changes. Case 8 was the only case with necropsy performed, which occurred after nearly continuous treatment with 17 mg/kg of voriconazole (q 12 h) for 10 months. Disseminated granulomas were identified on necropsy with fungal hyphae confirmed on histopathology. There was no fungal growth on culture. The lack of response to treatment in this case could be due to decreased medication compliance, voriconazole resistance, or chronic granulomatous lesions without active infection.

A study8 on the efficacy of voriconazole use in 20 falcons (Falco spp) achieved complete clinical resolution in 14 and partial response in 5, and only 1 bird died. There are many potential variables for the difference in response between that study and our retrospective study such as species-specific differences. Additionally, the falcons were much younger, aspergillosis was confirmed in every case, oral medication was administered by gavage, and 12 of the cases underwent surgical debridement of granulomatous lesions and air sac flushing with voriconazole.8 As endoscopy was performed in only 1 case of our retrospective study, alternative or underlying disease such as neoplasia could not be ruled out. Consistent grading criteria could not be used without endoscopy, and more progressive respiratory disease may have been present in the captive psittacines prior to presentation when compared to hunting falcons undergoing training. This difference in response may indicate endoscopic examination, and surgical debridement and topical treatment should be pursued in patients considered adequate anesthetic candidates.

Continued monitoring for clinical signs of disease recurrence after treatment completion is important. Case 2 developed an air sac granuloma 40 months after previous treatment completion for a pulmonary granuloma. It is unknown whether the disease was not fully cleared during initial treatment or the patient was reinfected, but voriconazole appeared effective during follow-up treatment. Cases 8 and 10 were both prescribed lifelong voriconazole due to the progression of disease on CT imaging or the return of clinical signs when medications were discontinued. In humans, aspergillosis generally occurs due to immunosuppression, and antifungal prophylaxis may be continued for the duration of immunosuppression. If breakthrough infection occurs while the patient is on antifungal treatment, surgical debridement or switching classes of antifungal agents is recommended.5 Addition of secondary antifungal agents or surgical debridement could be considered in avian cases without adequate resolution.

Limitations of this study include the retrospective nature of data collection with variability in case management, drug dosages and frequency, multidrug therapies, chronicity and severity of disease, and client interpretation of compliance and medication durations. The overall small sample size and loss of follow-up limit the ability to reach strong conclusions, and the small sample size by species prevents the identification of species-specific differences. Aspergillosis was confirmed in only 1 case that underwent endoscopy, and fungal infection was confirmed in 1 other case by necropsy. The remaining cases were suspected to have aspergillosis based on consistent CT findings; however, these CT findings could also indicate bacterial disease, neoplasia, or chronic inactive lesions. The resolution of pulmonary lesions in several cases is supportive of fungal infection, although most patients received antibiotics concurrently for potential bacterial infection. It is possible that not all cases included in this study had aspergillosis or that they had another significant underlying disease, but as this disease remains high on the differential list and many clients are unwilling or unable to pursue endoscopic confirmation, it is reasonable for clinicians to treat for aspergillosis based upon diagnostic imaging in cases with clinical suspicion.

Acknowledgments

The authors thank Ms. Gabi Conidi for her assistance in data collection and follow-up phone calls.

Disclosures

Dr. Mans is a member of the JAVMA Scientific Review Board, but was not involved in the editorial evaluation of or decision to accept this article for publication.

No AI-assisted technologies were used in the generation of this manuscript.

Funding

The authors have nothing to disclose.

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