Leptospirosis in a Dog with Uveitis and Presumed Cholecystitis

Introduction

Leptospirosis is caused by spirochetes of the species Leptospira interrogans sensu lato.¹ The most common serovars resulting in disease in dogs in North America include icterohemorrhagicae, canicola, grippotyphosa, hardjo, pomona, bratislava, and autumnalis.^2–4 Due to widespread use of a bivalent vaccine, the prevalence of disease from the former two serovars has decreased significantly.¹ In one study, male dogs were at greater risk than females, dogs in the 4–7 and 7–10 yr age groups were at greater risk than dogs <1 yr of age, and herding dogs, working dogs, and mixed breed dogs were at greater risk than companion dogs.⁵

Clinical signs of canine leptospirosis depend on many factors, including age and immunity of the host, environmental factors affecting the organism, and virulence of the infecting serovar.¹ Clinical manifestations of leptospirosis can include renal disease, hepatic disease, vasculitis, and myositis. Renal failure due to serovars not contained in the bivalent vaccine has become the predominate clinical syndrome, with hepatic failure occurring less commonly, although increased liver enzyme activity is common.^1,4,6 The predominate hepatic lesions include acute hepatitis, intrahepatic cholestasis, chronic active hepatitis, and hepatic fibrosis.^3,7–9 Vasculitis is seen in acute infections, which would suggest that uveitis would be a common finding. However, there are few case reports of uveitis due to leptospirosis in dogs in the literature.^10,11

The purpose of this case report is to describe a case of leptospirosis in a dog with uveitis and presumed cholecystitis, including ultrasonographic and clinicopathological findings and outcome.

Case Report

A 7 yr old castrated male Australian shepherd dog weighing 25.2 kg (55.6 lb) was examined for acute change in iris color, lethargy, and anorexia. The dog had not received routine vaccinations in the past 3 yr and had never been vaccinated for leptosporosis. The dog had free access to a large acreage farm and regularly accompanied the owner on horse trail rides. The day before presentation, the owner noted the dog had mildly decreased activity level and appetite. On admission, the dog was lethargic and tachypneic (35 breaths/min), with a normal body temperature (102.4°F; 39.1°C). Mucous membranes and the normally blue regions of both irises were icteric (Figure 1A). Aqueous flare was noted in both eyes (OU), and intraocular pressures measured with applanation tonometry^a were 27 mm Hg in the left eye (OS) and 20 mm Hg in the right eye (OD; reference interval, 19.2±5.9 mm Hg).¹² A grade II/VI left apical systolic murmur was ausculted with a normal rhythm (heart rate 90 beats/min) and pulses. Abdominal palpation was unremarkable. Dehydration was estimated at 5–7%.

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Mild mature neutrophilia (9, 450/μL; reference interval 2,455–9,170/μL), moderate lymphopenia (315/μL; reference interval 913–3,281/μL), and severe thrombocytopenia (60,000/μL; reference interval 180,000–487,000/μL) were noted on complete blood count (CBC). Biochemical analysis revealed azotemia, increased liver enzyme activities, and increased bilirubin concentration (Table 1). Urinalysis revealed a specific gravity of 1.025, 3+ bilirubinuria, and trace glucosuria. On abdominal ultrasound, the gall bladder wall was thickened and hyperechoic (Figure 2A). The gall bladder and bile ducts did not appear distended and the liver appeared normal. A small volume of perirenal effusion was noted around the left kidney. Point-of-care testing^b was negative for Dirofilaria immitis, Anaplasma phagocytophilium, Borrelia burgdorferi, and Ehrlichia canis. Initial serum antibody titers for leptospirosis using the microscopic agglutination test (MAT)^c were negative (Table 2).

TABLE 1 Clinicopathological Data for a Dog with Leptospirosis

AlkP, alkaline phosphatase; ALT, alanine transaminase; BUN, blood urea nitrogen; —, information not obtained at that time point.

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TABLE 2 Microagglutination Titer^c Results for a Dog with Leptospirosis

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Differential diagnoses that were initially considered included systemic infectious diseases such as leptospirosis or Ricketsia ricketsii based on the concurrent presence of acute renal failure, icterus , increased liver enzyme activities, uveitis, and thrombocytopenia. Differential diagnoses for the gall bladder wall thickening included hepatitis, cholangiohepatitis, or cholecystitis secondary to an infectious or inflammatory disease. Differential diagnoses for the heart murmur included a physiologic flow murmur, mitral valve endocardiosis or, less likely, mitral valve endocarditis. The trace glucosuria with normoglycemia was suggestive of proximal renal tubular disease associated with the acute renal failure.

Initial management consisted of IV 0.9% sodium chloride^d at 105 mL/hr and doxycycline^e (8 mg/kg per os [PO] q 12 hr) for possible leptospirosis or R ricketsii infection. Timolol/dorzolamide^f (one drop OU q 8 hr) and prednisolone acetate^g (one drop OU q 4 hr) were prescribed for increased intraocular pressure and anterior uveitis, respectively. Although the pressure in the OD was within the reference interval, it was considered abnormal in the presence of uveitis. On day 2, the azotemia worsened, but there was a mild decrease in liver enzyme activities and bilirubin concentration (Table 1). The dog began vomiting and therapy with metoclopramide^h (0.2 mg/kg subcutaneously [SQ] q 8 hr) and cimetidineⁱ (5 mg/kg SQ q 8 hr) was administered. Oral doxycycline therapy was discontinued, and ampicillin^j (10 mg/kg IV q 8 hr) and enrofloxacin^k (3 mg/kg IV q 24 hr) were administered to treat for the suspected infectious causes. By the evening of the second day, the dog's body weight increased to 26.8 kg, and heart rate increased to 120 beats/min from 78 beats/min 4 hr previous. Serous nasal discharge and mild peripheral edema were noted, consistent with volume overload or vasculitis. Urine production during the preceding 24 hr was estimated to be <200 mL, consistent with oliguric renal failure.

Intravenous fluid therapy was stopped, and a single dose of furosemide^l (2 mg/kg IV) was administered. Within 4 hr, urine production increased to 7.5 ml/kg/hr, heart rate decreased to 85 beats/min, and weight decreased to 26.4 kg. Fluid therapy was reinitiated at a maintenance rate of 52 mL/hr to prevent rapid dehydration associated with the conversion to a polyuric state. By the next morning (day 3), body weight decreased to 26.2 kg, with resolution of the peripheral edema and serous nasal discharge.

Biochemical analysis showed further worsening of the azotemia and severe increase in bilirubin concentration. Repeat CBC revealed persistent mature neutrophilia (14,940/μL) and lymphopenia (498/μL), with improvement in the thrombocytopenia (130,500/μL). Fluid therapy was changed to 0.45% sodium chloride with 5% dextrose^m at 100 mL/hr, and weight continued to decrease to 25.7 kg. Due to continued vomiting, maropitantⁿ (1 mg/kg SQ q 24 hr) was administered in place of metoclopramide, and no vomiting was noted afterward. Timolol/dorzolamide therapy was stopped due to low intraocular pressures (5 mm Hg OS; 4 mm Hg OD). An echocardiogram revealed chamber dimensions to be at the upper limit of the reference interval, but subjectively mild biatrial and biventricular chamber enlargement was noted. Mild mitral valve regurgitation was noted with normal valvular structures. These findings were consistent with the previously suspected volume overload but required no specific therapy.

On day 4, weight continued to decline and stabilized at 24.1 kg with increases in fluid rate to 275 mL/hr. The azotemia was markedly improved. On abdominal ultrasound, there was persistent thickening and hyperechogenecity of the gall bladder wall, but it was decreased in thickness compared with initial evaluation (Figure 2B). On day 5, the dog began eating, and free choice water was offered. Body weight was stable at 23.9 kg. On day 6, fluid therapy was tapered to 150 mL/hr, and body weight decreased to 23.5 kg. The dog continued to eat well. Ampicillin and enrofloxacin were discontinued, and treatment with doxycycline (8 mg/kg PO q 12 hr) was reinitiated.

On day 7, fluids were tapered to 50 mL/hr and body weight remained stable at 23.3 kg. Maropitant was discontinued, and cimetidine^o was changed to an oral route (8.5 mg/kg q 8 hr). The dog was eating and drinking well. On day 8, fluid therapy was discontinued. Repeat biochemistry revealed near resolution of the azotemia and marked improvement in bilirubin concentration. In addition, the previously noted iridal color change was nearly resolved (Figure 1B). The dog was discharged with instructions for the owner to continue doxycycline and prednisolone acetate (one drop OU q 12 hr) until recheck in 2 wk.

On day 21 from initial presentation the dog was re-evaluated. The owner reported the dog was normal at home. Body weight had increased to 24.8 kg and the previously noted heart murmur was the only physical examination abnormality. Biochemistry revealed resolution of the azotemia and marked improvement in liver enzyme activities and bilirubin concentration. Urine specific gravity was 1.045. Convalescent serum antibody titers revealed increases against leptosporosis serovars pomona, autumnalis, bratislava, and grippotyphosa (Table 2), consistent with acute infection. Doxycycline was continued for another week and prednisolone acetate was discontinued.

The dog was re-evaluated on day 54 after initial evaluation, and body weight was 26.5 kg. Biochemistry revealed only a slight increase in alkaline phosphatase activity (Table 1). Abdominal ultrasound revealed no ultrasonographic abnormalities of the gall bladder. Serum antibody titers for leptospirosis serovars were repeated and showed continued increases against serovar autumnalis, with a mild decrease in titer against serovar pomona. The initial magnitude and decreasing titers to bratislava and grippotyphosa were considered consistent with cross reactivity rather than an indication of these serovars as the cause of infection.

Discussion

Leptospirosis is a re-emerging zoonotic disease. The development and widespread use of a bivalent vaccination in dogs has resulted in the predominate clinical syndrome being acute renal disease rather than hepatic failure. Despite this, increased liver enzyme activities remain a common finding. Pathologic lesions associated with the liver include acute and chronic hepatitis, as well as intrahepatic cholestasis.^3,7–9 Ultrasonographic evaluation of the gall bladder was recently described in dogs in India, with leptospirosis titers of ≥100 on a MAT.¹³ Forty-one of 51 dogs were reported to have a thickened gall bladder wall, although specific measurements of the wall or its echogenecity were not noted. In addition, it was uncertain whether a definitive diagnosis of leptospirosis was obtained or which serovars were involved, whether clinical signs were present, whether treatment was administered, or what the final outcome was.

The dog in this report initially presented for icterus, anorexia, and lethargy. Due to the concurrent findings of acute renal failure, increased liver enzyme activities, thrombocytopenia, and uveitis, leptospirosis was considered the most likely cause. The initial titers were negative, and the dog had no history of vaccination for leptospirosis. Convalescent titers at day 21 revealed an increase in titers for both autumnalis and pomona to 1:800, consistent with a diagnosis of leptospirosis, whereas increased titers to other serovars likely represented cross reactivity. Further titers at day 54 showed a mild decline in titer to pomona and a consistent titer to autumnalis. This would suggest autumnalis was the responsible serovar with cross reactivity to pomona, but a definitive conclusion could not be established based on these results.¹⁴

Abdominal ultrasound revealed a markedly hyperechoic and moderately thickened gall bladder wall without gall bladder or biliary duct distension. These findings were similar to those previously reported for acute acalculous cholecystitis (AAC) in dogs.^15,16 Unfortunately, due to the lack of gall bladder distension, cholecystocentesis could not be performed to document cholecystitis and exclude ascending bacterial infection. Therefore, the diagnosis of AAC remained presumptive in this dog. The dog responded well to medical therapy for leptospirosis with complete resolution of the clinicopathological and ultrasonographic abnormalities, suggesting the AAC might have been caused by the leptospirosis. However, the response to antibiotic therapy might have been due to an ascending cholecystitis or cholangiohepatitis from a non-Leptospira sp. bacteria.

In people, AAC caused by leptospirosis has been rarely reported, with only 20 cases in the medical literature.^17–25 Clinical findings included fever, myalgia, icterus, abdominal pain, and increased liver enzyme activities. Gall bladder ultrasonographic findings included gall bladder distension, thickening and hyperechogenecity of the gall bladder wall, and pericholecystic fluid.^17,18,21,24 Of the 20 cases, only 11 reported the serovar involved, with autumnalis being most common (7 of 11), similar to the suspected serovar in the present case.^{17–20,23,25} Treatment in most patients included surgical intervention, such as tube cholecystostomy or cholecystectomy, but some patients recovered with medical therapy alone, including antibiotics and supportive care.^17–25

A change in iridal color was a main presenting complaint for the dog in this report. Presumably, this change was secondary to uveitis, resulting in breakdown of the blood ocular barrier with subsequent deposition of bilirubin in the nonpigmented, or blue, regions of the iris.²⁶ Because of the presence of vasculitis in leptospirosis cases, uveitis would be expected to be a common finding. However, it was not reported as a clinical finding in large studies of experimental or naturally acquired infection in dogs,^{4,6,8,27–31} but was reported in a few case reports.^{4,6,8,10,11,27–31} Interestingly, uveitis was the initial presenting problem in two of the reported dogs and the ocular signs were the only finding in one.

The dog in this report was initially treated with oral doxycycline to treat both leptospirosis and R ricketsii. Because of the development of vomiting, oral medications were discontinued, and parenteral administration of ampicillin for leptospirosis and enrofloxacin for R ricketsii was started. Once oral alimentation was possible, the dog was restarted on oral doxycycline because penicillins will terminate the leptospiremia, but they do not eliminate the carrier state.³ The dog made a complete recovery with resolution of all physical examination, clinicopathological, and ultrasonographic abnormalities.

Conclusion

Leptospirosis might represent a rare cause of uveitis in dogs, but could be underdiagnosed in patients for which uveitis is the only clinical finding. Cholecystitis might represent another clinical manifestation of disease in dogs as seen in humans. Due to the zoonotic potential of this infection, clinicians should consider leptospirosis a differential diagnosis in patients with uveitis or acute cholecystitis so appropriate testing, therapy, and precautions can be used.