Bone Marrow Hypoplasia Associated With Fenbendazole Administration in a Dog

Introduction

Fenbendazole is a benzimidazole anthelminthic widely used in veterinary medicine to treat various parasitic infections in domestic animals. The popularity and widespread use of this compound are based on its efficacy and wide margin of safety.¹² The benzimidazoles act by binding to parasite tubulin, effectively inhibiting cellular division and polymerization of microtubules, thereby altering cellular metabolism.²³ Differences in affinity between parasitic and mammalian tubulin, as well as differences in the pharmacokinetics of benzimidazoles between parasites and mammals, are responsible for the relatively high therapeutic index for this class of drugs.

Bone marrow toxicity has been reported with benzimidazole anthelminthics in various species. Albendazole has caused bone marrow toxicity in people, as well as in the dog and cat.^4–6 Albendazole may be more toxic to the bone marrow than other commonly prescribed benzimidazoles because of differences in pharmacokinetics. Albendazole is absorbed from the gastrointestinal tract to a greater degree than other benzimidazoles.³

Bone marrow toxicity has been less frequently described in conjunction with fenbendazole administration. A recent report described bone marrow hypoplasia associated with fenbendazole administration in painted storks.⁷ Proposed mechanisms for the toxicity included increased affinity of benzimidazoles for avian tubulin and high dosing or frequency of administration. Additional reports have described similar toxicities associated with fenbendazole and albendazole in other avian species.⁸⁹ In the dog, a single case report described bone marrow toxicity associated with fenbendazole. In that report, a bluetick coonhound developed aplastic anemia after concurrent administration of fenbendazole and trimethoprim-sulfadiazine.¹⁰ In that single case, the anemia was deemed more likely the result of trimethoprim-sulfadiazine administration (with its attendant well-described toxicities) than the result of fenbendazole administration.^10–13 The purpose of this report is to describe a case of fenbendazole-associated pancytopenia in a dog.

Case Report

A 1.5-year-old, castrated male Doberman pinscher was referred to the University of Missouri-Columbia Veterinary Teaching Hospital (UMC-VMTH) for evaluation of coughing and bilateral mucopurulent nasal discharge of 7 months’ duration. The dog was first observed to cough after participation in an obedience training class. The character of the cough was initially productive, but it had been nonproductive for the last 2 months and had gradually increased in frequency. Clinical signs were unresponsive to a variety of antibiotics (e.g., cephalexin, doxycycline, azithromycin) and cough suppressants (e.g., butorphanol) administered at appropriate dosages. Vaccinations were administered 1 month prior to referral, and ivermectin^a was administered monthly as a heartworm preventative.

Physical examination revealed a bright, mentally alert, normothermic dog with normal hydration. Body weight was 46.5 kg, and body condition score was 6/9. Mild, bilateral mucopurulent nasal discharge was present, and a dry cough was elicited upon palpation of the cervical trachea. Respiratory rate was 24 breaths per minute, and pulmonary auscultation was unremarkable. Heart rate was 84 beats per minute (bpm), with normal auscultation and pulse quality. The remainder of the physical examination was unremarkable.

Diagnostic evaluation included a complete blood cell count (CBC), serum biochemical profile, urinalysis, fecal flotation and sedimentation examinations, thoracic radiographs, and canine heartworm antigen testing (via enzyme-linked immunosorbent assay [ELISA]). The CBC abnormalities included basophilia and eosinophilia [see Table, Day 0]. Serum biochemical abnormalities included an alanine aminotransferase (ALT) of 238 U/L (reference range, 21 to 122 U/L) and an alkaline phosphatase (ALP) of 123 U/L (reference range, 22 to 116 U/L). Urinalysis was unremarkable, with a specific gravity of 1.059. Fecal flotation and Baermann sedimentation were negative for parasite ova or larvae. Canine heartworm ELISA antigen testing was negative. Thoracic radiographs revealed a moderate to marked, diffuse bronchointerstitial pattern involving all lung lobes.

Considering the dog’s age and presentation, differential diagnoses included occult lungworm infection, eosinophilic bronchitis, and allergic bronchitis. The nasal discharge was thought to be secondary to chronic pulmonary disease and coughing. Further plans included empirical treatment for occult lungworm infection, followed by general anesthesia and bronchoscopy if symptoms did not resolve. Fenbendazole^b (50 mg/kg per os [PO] q 12 hours for 14 days, with food) was prescribed, and the dog was discharged from the hospital.¹⁴ Four days after initiation of therapy, the owners reported a dramatic decrease in the frequency of coughing and the quantity of nasal discharge.

On day 11 of therapy, the dog began shivering and became lethargic and anorexic. Fenbendazole treatment was discontinued by the owners. No improvement was noted, and the dog was presented to a local emergency clinic the next day. Physical examination abnormalities included a rectal temperature of 106°F. An intramuscular injection of enrofloxacin^c (unknown dose) was administered, and the dog was sent home. Several hours later, the owners presented the dog to the UMC-VMTH for further evaluation.

On presentation to VMTH (day 12 after initiation of fenbendazole), the dog was severely depressed, lethargic, febrile (105.1°F), and tachycardic (120 bpm). Nasal discharge and cough were not detected. Diagnostic testing included a CBC, serum biochemical profile, serial blood cultures, and thoracic and abdominal radiographs. The CBC demonstrated leukopenia, lymphopenia, eosinopenia, and thrombocytopenia [see Table, Day 12]. The serum biochemical profile revealed elevated ALT (142 U/L; reference range, 21 to 122 U/L) and ALP (251 U/L; reference range, 22 to 116 U/L), low blood urea nitrogen (6 mg/dL; reference range, 8 to 28 mg/dL), hyponatremia (138 mmol/L; reference range, 140 to 150 mmol/L), and hypokalemia (3.5 mmol/L; reference range, 3.8 to 4.9 mmol/L). On thoracic radiographs the previously described interstitial pulmonary pattern had resolved. Abdominal radiographs and a urinalysis obtained via aseptic urethral catheterization were unremarkable.

The dog was admitted to the hospital, and treatment was initiated with intravenous (IV) fluids^d (60 mL/kg per day). After obtaining three blood cultures at hourly intervals, ampicillin^e (22 mg/kg IV q 8 hours) was initiated. The dog was isolated in a glass-enclosed run with separate air exchange in the intensive care unit, and all individuals treating the dog wore examination gloves and gowns.

On day 13 (day 2 of hospitalization), fever, lethargy, depression, and anorexia persisted. Mucoid nasal discharge and a grade III/VI left and right systolic murmur were also noted. Subsequent diagnostic testing included a CBC, prothrombin time (PT) and activated partial thromboplastin time (aPTT), Ehrlichia canis (E. canis) antibody titers, antinuclear antibody titers (ANA), and a bone marrow aspirate and core biopsy. Both bone marrow samples were obtained from the right proximal humerus under propofol^f anesthesia. The CBC revealed persistent leukopenia, anemia, thrombocytopenia, neutropenia, lymphopenia, and eosinopenia [see Table, Day 13]. The only notable morphological finding was reactive-appearing lymphocytes. Results of PT and aPTT were within reference ranges (PT, 5.4 to 7.4 seconds; aPTT, 11.9 to 18.5 seconds). Marrow aspirate cytopathology revealed no identifiable bone marrow particles and was cytopathologically consistent with hemodilution. Histopathological examination of the core biopsy revealed marked hypocellularity [see Figure]. Erythroid and myeloid lines were both present, but there were slightly more erythroid precursors. Megakaryocytes were present in small numbers. Histopathological diagnosis was bone marrow hypoplasia of undetermined etiology.

Enrofloxacin (5 mg/kg IV q 12 hours) was initiated, and IV fluid therapy and ampicillin were continued. On day 14, the dog remained febrile (range, 104.7° to 106.2°F), depressed, and anorectic, with a persistent nasal discharge and systolic heart murmur. Marked lameness and discomfort were detected in the right humerus, attributed to the bone marrow biopsy. Superficial dermal pustules were observed on the rostral muzzle, and scant melena was also noted. Enrofloxacin and ampicillin were discontinued because of lack of response, and imipenem/cilastatin^g (5 mg/kg IV q 6 hours) was initiated.

Within 24 hours on imipenem/cilastatin, the fever resolved. The dog’s attitude was greatly improved, and appetite and activity significantly increased by day 16. Thereafter, rectal temperature remained normal for the duration of hospitalization. A repeat CBC on day 16 revealed little appreciable change in hematopoietic cell counts, but mild anisocytosis and reactive lymphocytes were noted. Results of E. canis titers, ANA testing, and blood cultures were negative. Fluid therapy was discontinued. The dog showed consistent clinical improvement over the next few days, with resolution of nasal discharge and facial pustules and improvement of the right forelimb lameness. Serial CBCs on days 17, 18, and 19 showed continued improvement in cell counts [see Table]. The morphological changes also improved on each subsequent CBC and included mild neutrophil toxicity, giant platelets, reactive lymphocytes, and mild anisocytosis. On day 19, the dog was discharged on amoxicillin (20 mg/kg PO q 12 hours for 5 days) and enrofloxacin (5 mg/kg PO q 12 hours for 5 days). On day 26, the dog was acting well, physical examination by the referring veterinarian was unremarkable, and a CBC was within reference ranges. On day 83, the CBC remained unremarkable.

Discussion

Pancytopenia is a reduction in the circulating numbers of white blood cells, red blood cells, and platelets. Several conditions have been associated with the development of pancytopenia, including exposure to toxins and drugs.¹⁵¹⁶ Differential diagnoses for pancytopenia include infectious diseases (e.g., Ehrlichiosis, parvovirus infection), bone marrow necrosis (e.g., endotoxin, toxins), myelofibrosis, myelophthisis, hemophagocytic syndrome, malignant histiocytosis, hypersplenism, myelodysplasia, radiation damage, drug-associated pancytopenia (e.g., estrogen, chemotherapeutic agents, phenylbutazone, meclofenamic acid, trimethoprim/sulfadiazine, quinidine, thiacetarsamide, captopril, albendazole, cephalosporin), and idiopathic causes.¹⁶ Infectious causes of pancytopenia were considered unlikely in this case in the absence of clinical evidence of gastrointestinal viral enteritis and negative E. canis titer results. Acute ehrlichial infections may cause pancytopenia prior to the development of antibodies, but the bone marrow is characteristically hypercellular rather than hypocellular.¹⁷ Clinicopathological evidence in this dog did not support bone marrow necrosis, myelofibrosis, myelophthisis, hemophagocytic syndrome, malignant histiocytosis, hypersplenism, or myelodysplasia, and there had been no exposure to radiation.

The clinical course in the case reported here is suggestive of a drug-induced pancytopenia. The pancytopenia in this case occurred within 11 days of initiating fenbendazole, and it gradually resolved 15 days after discontinuation of therapy.

Destruction of progenitor and proliferating cells in the marrow causes characteristic changes in the peripheral blood and generally induces clinical signs within 2 to 3 weeks after exposure to a given compound.¹⁸¹⁹ There was no historical exposure to known toxins, and endogenous production of myelosuppressive toxins (i.e., estrogen) was ruled out because spontaneous recovery occurred with only supportive treatment. Fenbendazole was the only drug administered within 40 days of onset of the pancytopenia.

Following exposure to a myelotoxic drug, alterations occur first (often 5 to 6 days postexposure) in the number of circulating segmented neutrophils, because the circulating half-life of neutrophils is shorter than any other cell type. A decrease in circulating platelet numbers often occurs 8 to 10 days postexposure, followed by a decrease in red blood cells.¹⁹ On presentation at day 12 of therapy, a CBC performed on this dog showed neutropenia and thrombocytopenia but a normal packed cell volume (PCV). These results were consistent with an acute drug reaction; however, the anemia did worsen over days 12 to 13. Because there was no evidence of dehydration, hemolysis, or overt bleeding, the authors speculated that occult gastrointestinal tract bleeding, perhaps related to thrombocytopenia, contributed to the progressive anemia. Further support for this speculation was the parallel drop in the plasma total solids and the observation of scant melena 2 days after the decrease in PCV.

Bone marrow recovery usually occurs 10 to 14 days after removal of a myelotoxic agent, from stem-cell repopulation of progenitor and proliferating cells.¹⁹ In this dog, improvement in the thrombocytopenia and neutropenia was evident 5 days after discontinuation of fenbendazole, and the CBC was normal 15 days after discontinuation of the drug. Based on this recovery, the authors concluded that fenbendazole was the most likely cause of the pancytopenia and the resultant clinical signs.

Results of diagnostic tests and clinical signs at initial presentation were considered to be consistent with lung-worm infection. Because of the geographic location of this dog, the onset of coughing after exposure to other dogs, the radiographic interstitial pattern, and peripheral eosinophilia and basophilia, a therapeutic trial with fenbendazole was attempted prior to more invasive diagnostic tests (e.g., transtracheal wash, bronchoscopy, bronchoalveolar lavage). The cough and nasal discharge resolved within 3 days of initiation of fenbendazole. Occult lungworm infection was considered likely, despite negative fecal flotation and sedimentation, because of the duration of cough and failure of the previous treatments administered. Fecal flotation and sedimentation tests depend upon visualizing ova or larvae, and negative tests are possible with intermittent shedding of ova.^20–22 Thoracic radiographs taken on day 12 of fenbendazole therapy were improved.

Fenbendazole is recommended for treatment of Crenosoma vulpis and Paragonimus kellicotti at oral doses ranging from 50 to 100 mg/kg per day, divided q 12 hours.¹⁴²³²⁴ The dosage administered to the dog in this report was near the upper limits of this recommended range. Toxicity studies in dogs have found no adverse effect when fenbendazole was administered daily for 30 days at 250 mg/kg and for 90 days at 125 mg/kg.³ In fact, lethal doses of fenbendazole could not be attained in mice and rats when the limits of maximal possible drug administration were reached (10,000 mg/kg).³ Despite a wide margin of safety, adverse drug events associated with fenbendazole have been recorded. Events reported to the Food and Drug Administration (FDA) from 1987 through 2000 included vomiting (45% of all reports), depression/lethargy (30% of all reports), anorexia (19% of all reports), and death (14% of all reports).²⁵ All reports were anecdotal, and causation or accuracy was not verified in most cases. It is possible that some of the adverse events in dogs reported to the FDA may have been associated with fenbendazole-induced pancytopenia.

The dog in this report was a Doberman pinscher, a breed known to have a drug hypersensitivity to sulfadiazine.¹¹ Sulfadiazine hypersensitivity in Doberman pinschers is most consistent with an immune-complex disease (i.e., type III hypersensitivity reaction) and usually involves polyarthropathy rather than marrow disease.¹¹ The dog described in this report showed no signs of immune-complex disease. The pancytopenia experienced by this dog may have been an idiosyncratic reaction unique to this individual, especially given the paucity of reports of bone marrow toxicity associated with fendbendazole in the veterinary literature and the drug reporting registries. In contrast to a dose-related side effect, idiosyncratic reactions are defined as unpredictable reactions that occur in a small percentage of the population and have no relationship to administered dosages. In many cases, idiosyncratic reactions have an underlying genetic basis.²⁶

Conclusion

Pancytopenia occurred following administration of fenbendazole in this dog and may have resulted from bone marrow toxicosis associated with an idiosyncratic reaction to the drug. The clinical course of the disease, lack of exposure to other drugs or toxins, and failure to identify other causes of pancytopenia all suggested that the condition was induced by fenbendazole administration. In this dog, pancytopenia was reversible, following withdrawal of fenbendazole and administration of supportive therapy with fluids and bacteriocidal antibiotics. Similar to other benzimidazole anthelmintics, veterinarians should be aware of the possibility of bone marrow toxicity associated with the use of fenbendazole in dogs.