Previously,3 we reported on suspected toxicity of albendazole in several species of birds (keas, southern speckled pigeons, pink spotted fruit doves). In this report we present additional evidence of benzimidazole toxicity in birds, this time with fenbendazole (Panacur®, Hoechst Roussel Agri-Vet Comp, Somerville, NJ), affecting solitary lories (Phigys solitarius), rock doves (Columba livia, also known as Birmingham roller pigeons), bare-faced ground doves (Metriopelia ceciliae ceciliae), and Southern picui doves (Columbina picui picui). In all cases a 100 mg/ml suspension of fenbendazole was used.
A group of seven solitary lories (four males, three females, ages 6 months to 1 year-9 months) were treated with fenbendazole (50 mg on food SID, 10 days) for capillariasis, based on examination of a pooled fecal sample. Two days following the cessation of treatment, one bird presented with lethargy. CBC revealed profound leukopenia (no white blood cells seen on smear). Despite supportive care, the bird died a few hours later. The next day another bird died before any blood could be obtained. Subsequently, the remaining five birds were examined (day 3 post fenbendazole). Complete blood counts revealed profound leukopenia in all five birds. The total number of white blood cells seen on the smears ranged from 17-38, with the majority of cells being lymphocytes. No heterophils were detected. Mild anemia was also present in four of the five birds (PCV = 28–30%). Total protein and albumin levels were decreased (total protein <2.0–3.0 g/dl; albumin 1.2–1.6 g/dl). Individual birds had mild elevations of CPK or LDH. Treatment consisted of supportive care (subcutaneous fluids, forced feeding, housing in incubator) and prophylactic antibiotic and antifungal therapy (enrofloxacin 15 mg/kg IM, BID, Baytril®, Bayer Corp., Agriculture Division, Animal Health, Shawnee Mission, KS, USA; itraconazole 10 mg/kg PO, SID, Sporanox®, Janssen Pharmaceutica Inc., Titusville, NJ, USA). A third bird died on day 6 post fenbendazole treatment. The remaining four birds survived, and by day 10–12, the white blood cell counts were beginning to recover (total count 2200–10,000/µl; 35–63% heterophils, 29–57% lymphocytes, 2–8% monocytes). Necropsy of the three dead birds revealed severe bone marrow hypoplasia, primarily of the myeloid series, and peracute bacteremias (gram-positive cocci). Ulceration of the crop and/or esophagus, with overgrowth of gram-positive cocci, was seen in two birds, while the third had necrosis of the trachea and crop with similar overgrowth of gram-positive cocci. In one bird, there was mild multifocal dilation of small intestinal crypts with attenuation and individual cell necrosis of crypt epithelial cells.
A similar scenario was experienced with a group of ten rock doves (eight males, three females; adults, exact ages unknown). Following diagnosis of capillariasis from examination of fecal samples, the rock doves were gavaged with fenbendazole (50 mg/kg PO, SID, 5 days). The first day following completion of therapy, one bird was found dead. The second day post treatment, seven birds died and by the end of the fourth day, all 10 birds were dead. Complete blood counts performed on four of the birds revealed profound leukopenia (white blood cells too few to estimate total count), characterized primarily by heteropenia. Packed cell volumes ranged from 51–62%. Other consistent findings included mild elevations of uric acid, AST and CPK. Necropsy on all 10 rock doves showed similar lesions. Bone marrow hypoplasia was severe, with myeloid cell lines the most affected. Damage to mucosal epithelial cells was evident in the intestine (where there was dilation and necrosis of crypts), and in the squamous mucosa of the esophagus, crop, and cloaca. At the latter sites, epithelial cell hypertrophy was accompanied by karyomegaly and multinucleation, resulting in a disordered appearance of the epithelium. Other lesions included skeletal muscle degeneration and necrosis (four birds), renal tubular epithelial cell necrosis with mild regeneration (four birds) and acute rod bacteremia (six birds). All of the above changes were acute to subacute. Many birds also had more chronic lesions (non-suppurative enteritis with coccidia, proventricular nematodiasis, migrating nematode larvae, mild portal hepatitis) that were considered subclinical.
The last incident of presumed fenbendazole toxicosis concerned two picui doves and two bare-faced ground doves. Following death of an exhibit mate from ascariasis, these doves were treated with fenbendazole (50 mg/kg PO, SID, 5 days). The second day following completion of the treatment, one of the bare-faced ground doves presented to the hospital with lethargy. The bird died following blood sampling. Only 96 white blood cells (almost all lymphocytes) were seen on the blood smear. PCV was 8%. Necropsy revealed normal bone marrow cellularity but the population of cells was primarily immature (left shift). Intestinal crypt necrosis and epithelial cell hypertrophy were similar to that seen in the rock doves. The bird also had mild leukocytozoonosis and other incidental lesions. Examination of the three other birds revealed similar lethargy, with profound leukopenia (total numbers of cells on smears was 5–18). AST was elevated (592–1076 U/L). Prophylactic treatment with doxycycline (50 mg/kg PO, SID) and itraconazole (10 mg/kg PO, SID) was instituted. When rechecked about 1 week later, white blood cell counts had recovered (8000–14,200/µl) and the birds were released from the hospital soon thereafter.
In summary, the most characteristic finding in all cases was profound leukopenia, with nearly absolute heteropenia. Other common, but variable, clinical findings included hypoproteinemia, hypo-albuminemia, elevated liver and muscle enzymes, uricemia, and weight loss. Characteristic postmortem lesions included bone marrow suppression (especially myeloid), epithelial cell necrosis and regeneration (especially of rapidly dividing cells), and acute bacteremia. Death in most cases was likely due to overwhelming bacterial infection, secondary to the severe immunosuppression. Virus isolation was attempted from liver of one rock dove and was negative. Although a possible viral etiology cannot be totally ruled out, lesions highly suggestive of viral infection were not seen. These clinical and postmortem observations are similar to those seen in the previously presented cases of suspected albendazole toxicity in birds.3 In addition, comparable bone marrow toxicity has been described with albendazole administration in mammals.4 Based on the histories and similarities in clinical and necropsy findings between all of these cases, we strongly suspect benzimidazole toxicity as the common link. Benzimidazoles are frequently used anthelmintics with a wide range of antiparasitic action, high degree of efficacy and a good margin of safety.2 The dosages used in these cases are within the recommendations for avian species1 and have been used without apparent ill effect in many species of birds at our institutions. Chemical analysis of one of the lots of fenbendazole used was within acceptable tolerance range. Thus, it may be that there are species-specific susceptibilities to toxicosis, especially within the Columbiformes. Alternatively, there may be as yet undiscovered co-factors in these cases that may have predisposed to toxicity.
1. Ritchie BW, Harrison GB. Formulary. In: Ritchie BW, Harrison GJ, Harrison LR, eds. Avian Medicine: Principles and Application. Lake Worth, FL: Wingers Publishing, Inc.; 1994:457–478.
2. Roberson EL. Antinematodal drugs. In: Booth NH, McDonald LE, eds. Veterinary Pharmacology and Therapeutics, 6th ed. Ames, IA: Iowa State University Press; 1988:882–927.
3. Stalis IH, Rideout BA, Allen JL, Sutherland-Smith M. Possible albendazole toxicity in birds. In: Proceedings of the Joint Conference of the AAZV/WDA/AAWV. 1995:216–217.
4. Stokol T, Randolph JF, Nachbar S, Rodi C, Barr SC. Development of bone marrow toxicosis after albendazole administration in a dog and cat. J Am Vet Med Assoc. 1997;210(12):1753–1756.