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Mycotic keratitis in a khaki Campbell duck (Anas platyrhynchos domesticus).

Abstract: A 1.5-year-old, intact female khaki Campbell duck (Anas platyrhynchos domesticus) was evaluated for lethargy and a swollen left eye (OS). Mucoid discharge, chemosis, and conjunctival hyperemia with trace aqueous flare, indicating anterior uveitis, in the anterior chamber were evident on ophthalmic examination. There was no fluorescein stain uptake by the cornea. Initial topical antibiotic therapy and systemic anti-inflammatory treatments were unsuccessful, and the lesion progressed to a diffuse, yellow-white plaque, which covered 90%95% of the cornea 4 days later. There was moderate blepharospasm, mild blepharedema, and epiphora OS. The mobility of the nictitating membrane was impaired because of the presence of the plaque over the cornea. Cytologic examination of a corneal scraping revealed fungal hyphae, and aerobic culture confirmed Aspergillus species. Treatment with topical voriconazole (1 drop OS q4h-q6h) was initiated and was switched to oral voriconazole (20 mg/kg PO ql2h) 6 days after initiating treatment. The ocular disease improved during the antifungal treatment period. Eightyfour days after initial presentation (9 days after discontinuation of treatment), there was no clinical evidence of mycotic keratitis on ophthalmic examination.

Key words: Aspergillus species, fungal keratitis, keratomycosis, ocular, bird, avian, khaki Campbell duck, Anas platyrhynchos domesticus

Clinical Report

A 1.5-year-old, intact female khaki Campbell duck (Anas platyrhynchos domesticus) was presented to the Veterinary Medical Teaching Hospital at the University of California, Davis, for evaluation of the left eye (OS). The day before admission the bird was lethargic, and the left eye was swollen. On presentation the bird was bright and responsive. It weighed 1.84 kg and was in mildly thin body condition (body condition score, 4 of 9). Results of the physical examination were largely unremarkable, with the exception of the changes in the eye. Mucoid discharge was present OS, along with mild chemosis and conjunctival hyperemia. The cornea appeared intact with no fluorescein stain uptake by the cornea in both eyes (OU). There was trace flare, indicative of anterior uveitis, in the anterior chamber OS; this made critical evaluation of the fundus with direct and indirect ophthalmoscopy difficult. The bird was prescribed meloxicam (0.5 mg/kg PO q12h) and topical neomycin/polymyxin/ bacitracin ophthalmic ointment (0.64-cm [0.25-inch] strip OS q6h).

On recheck examination, 4 days after initial presentation, the condition of the eye had markedly worsened. Mild blepharedema, moderate blepharospasm, and epiphora OS were present. The conjunctival hyperemia and chemosis had worsened from mild to moderate. A diffuse, yellow-white plaque was present over 90%-95% of the cornea, and the nictitating membrane was unable to move normally across the surface of the globe because of the presence of the plaque. No intraocular structures of the eye were able to be assessed because of the presence of the plaque (Fig 1). The right eye (OD) remained unaffected. A sample of the corneal plaque was collected with the back end of a No. 15 Bard-Parker scalpel blade (Aspen Surgical, Caledonia, MI, USA) for cytologic analysis and aerobic bacterial culture. While awaiting the culture results, the topical antibiotic selection was changed to 0.3% ofloxacin ophthalmic solution (1 drop OS q2h during the day, and once in the middle of the night; Falcon Pharmaceuticals, Fort Worth, TX, USA), and the meloxicam was continued as previously prescribed. On cytologic examination of the corneal scrape, large numbers of small, blue, round-to-ovoid, fungal conidia were embedded singly and in large aggregates in abundant mucin. Numerous septate branching hyphae coursed across the sample (Fig 2). Increased numbers of heterophils and macrophages were scattered singly and were enmeshed within fungal hyphae, and frequently contained phagocytosed conidia. Low numbers of hyperplastic epithelial cells were clustered across the sample. Cytologic interpretation was marked, mixed inflammation with fungal sepsis and epithelial hyperplasia, suggestive of Aspergillus or Penicillium species. A corneal scraping sample was inoculated onto 5% defibrinated sheep blood agar and incubated at 35[degrees]C in 5% C[O.sub.2]. No bacterial growth was observed, but 2 colonies of mold were detected after 24 hours of incubation. Morphologically, the mold was off-white to teal green with a pale undersurface. Microscopically, the isolates had hyaline septate branching fungal hyphae, hemispherical vesicles with uniserate phialides, and globose chaining conidia. Based on the morphologic appearance, the mold was identified as Aspergillus fumigatus complex. The topical antibiotic was discontinued, and topical voriconazole (1 drop OS q4h-q6h; Vfend, 200 mg/vial suspended in preservative-free saline for a final concentration of 10 mg/mL, Roerig/Pfizer, New York, NY, USA) was initiated.

[FIGURE 1 OMITTED]

The bird was rechecked 7 days after initial presentation (2 days after initiating the voriconazole). The bird's weight had decreased to 1.5 kg. The blepharospasm and epiphora OS remained unchanged; however, the conjunctival hyperemia and chemosis had decreased from moderate to mild. There was no change in the blepharedema or in the mobility of the nictitating membrane. Across the cornea OS, dense superficial and anterior stromal corneal vascularization was present and extended 2-3 mm from the limbus. The plaque had reduced dorsally leaving 80%-85% of the cornea affected, and it had consolidated from being fluffy and filamentous to a "cake frosting" appearance (Fig 3). The OD continued to be normal. In addition to the ophthalmic evaluation, blood was collected for a complete blood cell count (CBC) to evaluate for systemic inflammation. An estimated white blood cell count was calculated from a blood smear, and a differential test was performed. A mild leukocytosis was present (21.8 X [10.sup.3] cells/[micro]L; reference interval, (1) 4.5-13.0 X [10.sup.3] cells/[micro]L) characterized by a mild heterophilia with an increased H:L ratio (heterophils, 15.3 X [10.sup.3] cells/[micro]L; lymphocytes, 3.49 X [10.sup.3] cells/[micro]L; reference intervals (1): heterophils, 1.35-9.1 X [10.sup.3] cells/[micro]L; lymphocytes, 0.9-8.45 X [10.sup.3] cells/[micro]L) and a mild monocytosis (0.87 X [10.sup.3] cells/[micro]L; reference interval, (1) 0-0.39 X [10.sup.3] cells/[micro]L). Differential diagnoses for the abnormal findings on the CBC were a stress leukogram and a mild inflammatory response.

[FIGURE 2 OMITTED]

Eleven days after initial presentation, the bird presented for examination and a repeat CBC. The day before presentation, the owner noted that a layer of the plaque overlying the cornea had fallen off. The bird's weight remained stable at 1.5 kg; however, its appetite had decreased. The blepharospasm remained unchanged; however, the blepharedema, conjunctival hyperemia, and chemosis continued to improve. The eye was phthisical, as evidenced by mild wrinkling of the eyelid margins and an asymmetric corneal profile when the bird's face was viewed from the front. Light perception was intact based on dazzle reflex OU, and the patient retained the ability to maneuver around the room successfully. Across the cornea OS, fibrotic, irregular, diffuse granulation tissue and dense superficial, and anterior stromal corneal vascularization were present, extending to the axial cornea. A limited view of the anterior chamber was visible through the dorsal aspect of the cornea, but the remainder could not be assessed because of diffuse corneal fibrosis over the remaining ventral cornea. Stromal swelling in the ventrolateral paraxial cornea was present with a visible break in the epithelium, and a subsequent 2-3-mm-diameter, superficial corneal ulcer, with a pinpoint white plaque, present in the center. The corneal plaque prevented the measurement of intraocular pressure in the OS. Because of the development of a superficial corneal ulcer, the 0.3% ofloxacin ophthalmic solution was reinstated (1 drop OS q8h, separated from the voriconazole drops by 5 minutes when given at the same time). The CBC was repeated and showed a moderate leukocytosis (35 X 103 cells/pL) with an inverted H:L ratio (heterophils, 5.6 X [10.sup.3] cells/[micro]L; lymphocytes, 28.7 X [10.sup.3] cells/[micro]L), and signs of toxicity were present within the heterophils. Results of the plasma biochemical analysis were unremarkable. (1) Because of the worsening systemic inflammation and the presence of corneal vascularization, oral voriconazole (20 mg/kg PO q12h; Voriconazole tablets, Mylan Pharmaceuticals, Morgantown, WV, USA) was prescribed because it allows penetration into the cornea through the vascularization as well as providing systemic therapy. Once the treatment with oral voriconazole was started, the topical formulation was discontinued.

[FIGURE 3 OMITTED]

Twenty-four days after initial presentation (7 days after starting the systemic voriconazole), the bird's weight had increased to 1.7 kg. The bird's appetite and energy level had returned to normal. Both eyes were open and appeared comfortable, and there was no fluorescein stain uptake by the cornea OU. Systemic meloxicam and topical ofloxacin were discontinued, whereas oral voriconazole treatment was continued.

Forty-two days after initial presentation, the bird's weight remained static (1.7 kg), as did appetite and energy level. The OS continued to improve through clearing of the fibrosis at the dorsal and dorsomedial cornea. The diffuse superficial and midstromal corneal vascularization persisted in the midcornea. The examination was unchanged, except for continued improvement in the degree of fibrosis. A repeat CBC was performed, and results showed the white blood cell count had returned to within reference intervals (9.1 x [10.sup.3] cells/[micro]L), and the toxic changes within heterophils had resolved. A mild monocytosis persisted (0.64 x [10.sup.3] cells/[micro]L) as well as the inverted H:L ratio (heterophils, 0.64 x [10.sup.3] cells/ [micro]L; lymphocytes, 7.74 x [10.sup.3] cells/[micro]L). Recommendation was made to continue the oral voriconazole treatment for an additional 28 days with a recheck examination 2 weeks after discontinuation of medication.

[FIGURE 4 OMITTED]

Eighty-four days after initial presentation and 9 days after discontinuation of systemic voriconazole, the bird was reexamined. Both eyes appeared comfortable, with the OS being phthisical. Direct pupillary light responses were brisk and complete OU. The diffuse, superficial and midstromal corneal vascularization was mildly improved compared with the previous visit (Fig 4). The dyscoria OS persisted, but an anterior cortical cataract with posterior synechia was visualized. Intraocular pressures were measured in both eyes with applanation tonometry (Tonopen, Reichert Technologies. Buffalo, NY, USA) and were found to be nearly equal (OD, 12 mm Hg; OS, 13 mm Hg). Fundic examination was possible because of corneal clearing and was unremarkable OU. Blood was collected for a CBC and plasma biochemical panel to evaluate for systemic inflammation and liver toxicosis because of long-term voriconazole administration. A mild leukocytosis (22 x [10.sup.3] cells/ [micro]L) with a moderate monocytosis' (2.86 x [10.sup.3] cells/[micro]L) was present. Results of the plasma biochemical analysis had no appreciable abnormalities. (1)

The owner reported that the eye had not changed in the subsequent follow-up period. The bird was scheduled for a recheck examination 105 days after initial presentation; however, it was found dead with predatory injuries on day 101. There was insufficient tissue remaining, including the skull, for necropsy.

Discussion

Fungal keratitis is an uncommon disease in avian patients. Most reports are from gallinaceous species that have been managed in a production setting. (2-4) The only fungal organism reported previously as a cause of keratitis in ducks is Candida albicans, (5) To our knowledge, aspergillosis has not been reported as a cause of keratitis in ducks. In other species, fungal keratitis has most commonly been reported in equine and bovine species, where it is suspected that their predisposition is because of the high amounts of organic matter in their environment. (6,7)

Many different organisms have been reported to cause fungal keratitis. Similar to this case, Aspergillus species have been the causative agent of fungal keratitis in other avian reports, including A fumigatus in chickens, (2-4) as well as in a lovebird (Agapornis roseicollis). (8) Infections caused by species of Acremonium, Alternaria, Aspergillus, Candida, Cephalosporium, Curvularia, Fusarium, Pseudallescheria, and Scedosporium have been reported in dogs (9); whereas, in humans, the most common organisms include Fusarium, Candida, and Aspergillus species. (10,11)

Most cases of fungal keratitis are thought to be related to damage to the cornea, typically resulting from a traumatic event. (9,12,13) In humans, other predisposing factors are immunosuppression, previous corneal surgery, topical treatment with corticosteroids or antimicrobials, and systemic disorders. (9,11,14) In many areas, human fungal keratitis occurrence is higher in the winter months and around the harvesting season, (11) which may be related to a drier environment and an increase in airborne conidia being released. Because of the infrequency with which mycotic keratitis has been reported in avian species, no correlation can be made to season and incidence rate; however, it has been speculated that development of disease in poultry is related to factors in the environment in production settings, such as fumes and ammonia. (2-4) Fungi are considered to be opportunistic pathogens and part of the normal ocular surface flora in all species. (7) In a report of bacterial and fungal flora found in healthy eyes of birds of prey, fungal growth was found in 2.3% of sampled eyes; the low prevalence was thought to be transitory and resulting from environmental exposure. (6)

Traumatizing agents may be of plant or animal matter, and may either directly implant fungal conidia in the corneal stroma, or abrade the epithelium. (14) After a traumatic incident, the fungal organisms are able to adhere to the exposed corneal stroma and penetrate more deeply, which can lead to corneal perforation. (15) These lesions may then extend into the anterior segment but rarely progress into the posterior part of the eye. (3) In this case, the fungal keratitis likely was a result of trauma because of the acute onset and unilateral nature. The uveitis may have been caused by reflex or fungal endophthalmitis, which then led to the cataract and posterior synechia appreciated in the OS. The cause of phthisis may have been corneal perforation with subsequent inflammation and remodeling, or because of chronic uveitis.

Severe keratitis with the presence of fungal hyphae within the corneal stroma are hallmarks of disease. (14) Clinical signs are epiphora, mucopurulent discharge, blepharospasm, periorbital swelling, development of a caseous plaque of fibrinopurulent exudate under the nictitating membrane, conjunctival hyperemia, and corneal edema. Hyphate lines extending beyond the ulcer edge into the normal cornea and multifocal, granular, greywhite, "satellite" stromal infiltrates are also suggestive of fungal keratitis. (14)

The presumptive diagnosis of fungal keratitis can be made based on clinical presentation, and cytologic, microbiologic, and molecular investigations are recommended to confirm the diagnosis. (16) Corneal scrapings performed under aseptic conditions may be collected from the leading edge and base of the corneal ulcer for inoculating culture plates and preparing smears for direct microscopic examination. Once an organism has grown, antifungal susceptibility testing would ideally be performed; however, time and financial constraints may preclude this step, (11,17) as it did in this case. Polymerase chain reaction testing can be done as an additional diagnostic test; however, it may be more expensive than conventional microbiologic methods, and may be reserved for diagnosis in patients where conventional tests do not yield positive results. (14) Cytologic assessment and fungal culture were pursued in the current case after the lesion progressed to a corneal opacity with white, filamentous material, and provided a morphologic diagnosis of A fumigatus.

Medical and surgical management can be used in the treatment of fungal keratitis, with medical management preferred in small-animal patients. (9) In small-animal patients, topical ophthalmic treatment is preferred because of its benefits, including higher drug concentrations at the site of infection, no hepatic metabolism, and fewer adverse systemic side effects. (18) The most commonly prescribed antifungal medications used for topical treatment are natamycin, amphotericin B, miconazole, and voriconazole. (18)

Voriconazole is a synthetic, second-generation, triazole antifungal medication that is a derivative of fluconazole, but has a greater spectrum of activity and enhanced potency. (19) Voriconazole inhibits ergosterol synthesis by inhibiting cytochrome P450-dependent 14-[alpha] sterol demethylase, which results in plasma membrane permeability changes and inhibition of fungal growth. (7) It is considered to be fungistatic at low concentrations and fungicidal at higher concentrations. (20) In human medicine, topical application of antifungal medications is recommended hourly for several days, and which frequency is gradually reduced. (14)

Therapy should be maintained for at least 6 weeks because resolution can be slow. (14) Clinical signs that indicate improvement are a decrease in pain and the size of the lesion and infiltrate, rounding of the feathery margins of the ulcer, and hyperplastic masses or fibrous sheets in the region of the healing fungal lesion. (14) In the case described here, topical therapy was chosen initially based on cytology and culture results, which resulted in improvement of the lesions exhibited by filamentous material consolidating into a plaque and flaking off of the cornea. However, therapy was switched from topical to systemic when there was evidence of inflammatory changes on the leukogram, as well as evidence that the systemic therapy would be able to penetrate the cornea through the development of corneal vascularization. Additionally, systemic voriconazole may also help corneal infections by reaching therapeutic levels in the aqueous humor and tear film. (21) Improvement in this case was evident from clearing of the corneal fibrosis and an increase in corneal vascularization, as well as the return of a pupillary light response and ability to perform a funduscopic examination in the affected eye. Furthermore, the patient's eye became more comfortable over time as exhibited by the decrease in blepharospasm and ocular discharge.

In this case, the fungal keratitis responded appropriately to the treatment with topical and systemic antifungal therapy with improvement of the clinical signs during the follow-up period. Reasons for success may have been the rapid diagnosis, the use of diagnostic testing, and pairing the results with appropriate therapy. In humans, corneal ulcers caused by fungal organisms can be more difficult to treat than bacterial ulcers, and with worse outcomes. (22) If a diagnosis is made within a short period chances of a complete recovery are improved. (14) In this case, long-term follow-up ceased after the death of the patient.

Fungal keratitis should be considered in cases of suspected or known corneal trauma with nonhealing or rapidly changing lesions, of corneal ulceration or abscessation that does not respond to empiric antibiotic treatment, or of corneal lesions that appear to have a typical fungal infection appearance. (7) The present report highlights the importance of cytologic examination and culture in identifying corneal pathogens, as well as examination of the patient's overall systemic health to evaluate the need for systemic treatment. To our knowledge, this is the first reported case of successful treatment with topical and systemic voriconazole of a corneal infection from A fumigatus complex in a duck.

References

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(2.) Beckman BJ, Howe CW, Trampel DW, et al. Aspergillus fumigatus keratitis with intraocular invasion in 15-day-old chicks. Avian Dis. 1994;38(3):660-665.

(3.) McCowan C, Bibby S, Scott PC. Mycotic keratitis due to Scedosporium apiospermum in layer pullets. Vet Ophthalmol. 2014; 17(1):63-66.

(4.) Dalton JR, Ainsworth H. Mycotic keratoconjunctivitis in 12-day-old red-legged partridges (Alectoris rufa). Vet Rec. 2011; 168(22):590-591.

(5.) Crispin SM, Barnett KC. Ocular candidiasis in ornamental ducks. Avian Pathol. 1978;7(1):49 59.

(6.) Dupont C, Carrier M, Higgins R. Bacterial and fungal flora in healthy eyes of birds of prey. Can Vet J. 1994;35(11):699 701.

(7.) Grundon RA, O'Reilly A, Muhlnickel C, et al. Keratomycosis in a dog treated with topical 1% voriconazole solution. Vet Ophthalmol. 2010;13(5):331-335.

(8.) Carrasco L, Bautista MJ, de las Mulas JM, Jensen HE. Application of enzyme-immunohistochemistry for the diagnosis of aspergillosis, candidiasis, and zygomycosis in three lovebirds. Avian Dis. 1993;37(3):923-927.

(9.) Pucket JD, Allbaugh RA. Rankin AJ. Treatment of dematiaceous fungal keratitis in a dog. J Am Vet Med Assoc. 2012;240(9): 1104-1108.

(10.) Prajna NV, Krishnan T, Mascarenhas J, et al; Mycotic Ulcer Treatment Trial Group. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013; 131 (4):422-429.

(11.) Manikandan P, Varga J, Kocsube S, et al. Epidemiology of Aspergillus keratitis at a tertiary care eye hospital in south India and antifungal susceptibilities of the causative agents. Mycoses. 2013;56(1):26-33.

(12.) Thomas PA. Current perspectives on ophthalmic mycoses. Clin Microbiol Rev. 2003; 16(4):730-797.

(13.) Wright GW, Frank JF. Ocular lesions in chickens caused by ammonia fumes. Can J Comp Med Vet Sci. 1957;21(7):225-227.

(14.) Thomas PA, Kaliamurthy J. Mycotic keratitis: epidemiology, diagnosis and management. Clin Microbiol Infect. 2013;19(3):210-220.

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(16.) Leek AK, Thomas PA, Hagan M, et al. Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal keratitis. Br J Ophthalmol. 2002;86(11): 1211-1215.

(17.) Andrew SE. Corneal fungal disease in small animals. Clin Tech Small Anim Pract. 2003; 18(3): 186-192.

(18.) Al-Badriyeh D, Neoh CF, Stewart K, Kong DC. Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis. Clin Ophthalmol. 2010;4:391-405.

(19.) Sabo JA, Abdel-Rahman SM. Voriconazole: a new triazole antifungal. Ann Pharmacother. 2000;34(9): 1032-1043.

(20.) Hariprasad SM, Mieler WF, Lin TK, et al. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol. 2008;92(7):871-878.

(21.) Clode AB, Davis JL, Salmon J, et al. Evaluation of concentration of voriconazole in aqueous humor after topical and oral administration in horses. Am J Vet Res. 2006;67(2):296-301.

(22.) Wong TY, Ng TP, Fong KS, Tan DT. Risk factors and clinical outcomes between fungal and bacterial keratitis: a comparative study. CLAO J. 1997;23(4):275-281.

Miranda J. Sadar, DVM, David Sanchez-Migallon Guzman, LV, MS, Dipl ECZM (Avian), Dipl ACZM, Andrew G. Burton, BVSc, Barbara A. Byrne, DVM, PhD, Dipl ACVIM, Dipl ACVM, K. Tomo Wiggans, DVM, Meng, and Steven R. Hollingsworth, DVM, Dipl ACVO

From the William R. Pritchard Veterinary Medical Teaching Hospital (Sadar, Burton, Wiggans), the Department of Medicine and Epidemiology (Guzman), the Department of Pathology, Microbiology, and Immunology (Byrne), and the Department of Surgical and Radiological Sciences (Hollingsworth), School of Veterinary Medicine, 1 Shields Ave, University of California. Davis, CA 95616, USA.
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Author:Sadar, Miranda J.; Guzman, David Sanchez-Migallon; Burton, Andrew G.; Byrne, Barbara A.; Wiggans, K.
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Geographic Code:1USA
Date:Dec 1, 2014
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