Could this be lepto? Part 1

Leptospirosis is a widespread bacterial zoonosis that is estimated to cause significant illness in over one million people throughout the world every year.1 Infection is routinely identified in dogs and is a leading cause of acute kidney injury (AKI) in this species in many parts of the U.S.2,3 Leptospira are thin, motile spirochetes (Figure 1); numerous species (≈20), both pathogenic and saprophytic, have been described. Classification of these organisms is complex, as the various species contain numerous serogroups, each of which contain immunologically related serovars. Infection and clinical disease in dogs are associated with at least nine serogroups, with varying geographical prevalence. Cats appear to be inherently resistant to leptospirosis, and clinical disease is rarely reported.4 However, recent evidence suggests cats may be a significant source of environmental contamination.5 Figure 1: Digitally-colorized, scanning electron microscopic image of numerous corkscrew-shaped, Leptospira sp. bacteria atop a 0.1µm polycarbonate filter. Image: Public Health Image Library CDC. Pathogenic leptospires are maintained in the environment by wild or domesticated reservoir hosts. The dog is the primary host for L. canicola; the rat for L. icterohaemorrhagiae; and the cow for L. pomona and L. hardjo. The number of organisms excreted by a reservoir host is impressive; just one ml of urine from a rat can contain six million viable leptospires.6 Infection can occur by direct contact of infected urine with intact mucous membranes; the organism may also enter via damaged skin. Indirect transmission probably accounts for the majority of cases, as leptospires can survive for many months in surface water, and over 40 days in contaminated soil. The organisms cannot, however, tolerate freezing temperatures and ultraviolet (UV) light.1 The incubation period is generally short, probably less than a week, but it depends on the particular strain and the host response. Clinical disease reflects a widespread vasculitis; this means numerous body systems may be affected and specific findings can vary considerably from patient to patient. Clinical presentation Although many of us traditionally associate leptospirosis with young, large-breed dogs living in rural environments, clinical disease is routinely reported in small dogs from urban homes.7 The possibility of leptospirosis should never be discounted simply on the basis of signalment and environmental circumstances. We should also think of leptospirosis as causing a spectrum of clinical compromise, ranging from a subclinical infection picked up during investigation of chronic kidney disease, to an acute and rapidly fatal condition. This variation may be due to the infecting serovar and/or host response, although there are only modest correlations between clinical signs and specific serovars.8 Signs in overtly affected dogs are somewhat nonspecific; most owners simply report the pet is not feeling well, with a reluctance to move (secondary to generalized myalgia), and anorexia.1,9,10 Vomiting is also common. Observant clients may notice polyuria, with or without concurrent polydipsia. Other signs reported include ocular changes and respiratory compromise due to pulmonary hemorrhage. Bleeding tendencies may cause petechiation, hematemesis, hematuria, or epistaxis. On physical examination, most dogs with acute leptospirosis are depressed and variably dehydrated. Fever is common but is not noted in all cases. Renal pain may be appreciated. Ophthalmic examination may reveal uveitis or retinal hemorrhage. Although pulmonary involvement is uncommon in the U.S., tachypnea and pulmonary crackles may be noted. Diagnostic findings Results of routine laboratory testing are variable and may need to be scrutinized carefully to identify key “clues” pointing towards leptospirosis. However, as most dogs have renal involvement, the possibility of leptospirosis should be considered in every dog with evidence of an AKI. Complete blood count. Neutrophilia is common, but a left shift is not routinely reported (seen in 100,000/µL.1,9,10 Serum biochemical profile. Azotemia is common but is not always present, and its severity may be impacted by hydration status. Normal blood urea nitrogen (BUN) and creatinine concentrations do not exclude the possibility of leptospirosis, particularly if the patient has inadequately concentrated urine or other findings suggesting renal dysfunction (see below). Hepatic involvement is also common, but may not be noted until a few days after initial presentation in dogs with AKI. Hepatic involvement without renal injury has also been reported.1,9,10 It is important to note a primarily cholestatic pattern is expected, rather than one suggesting hepatocellular injury; activities of alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) are often significantly higher than those for alanine and aspartate aminotransferase (ALT and AST, respectively). Serum bilirubin may be above the reference range and patients may be overtly icteric; this finding has been associated with a poorer prognosis. Hyperammonemia can occur in dogs with substantial hepatic involvement. Electrolytes. Hypo- or -hyperkalemia may be noted. Hyperkalemia should always raise the concern for markedly decreased urine production. However, as renal potassium loss can be substantial in the early phases of leptospirosis, patients with oliguria or anuria may present with a normal serum potassium concentration. Serum sodium and chloride concentrations are often low; phosphorus is often elevated, particularly in azotemic animals. Urinalysis. Affected dogs are usually isosthenuric; some dogs are actually hyposthenuric due to an impaired response to antidiuretic hormone.1,9,10 Glucosuria, proteinuria, and hematuria are common, along with pyuria and casts. Leptospires are not visible on routine urine sediment examinations and can only be recognized using dark field microscopy. As a patient with standard bacterial pyelonephritis and associated AKI can look very much like a dog with leptospirosis, a urine sample should be submitted for routine quantified culture and sensitivity even if leptospirosis seems highly likely. Coagulation times. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are variably prolonged, primarily due to a consumptive process. Substantial hepatic compromise will also affect clotting times. Results of thromboelastography are variable, with normal, hyper- and hypo-coagulable states reported. Dogs with evidence of hypocoagulability and a hemorrhagic diathesis are less likely to survive.11 Figure 2: Mediastinum and pulmonary structures from a dog with leptospirosis. Note the petechial and ecchymotic hemorrhages throughout the lung tissue. Image: Public Health Image Library CDC. Thoracic radiographs. Dogs with leptospirosis may develop a condition called leptospiral pulmonary hemorrhage syndrome (LPHS). Affected dogs will have a variable interstitial or alveolar radiographic pattern, particularly in the caudal dorsal lung fields.1,9,12 This condition is characterized by widespread intra-alveolar hemorrhage and is thought to reflect the host response to infection rather than direct damage from the organism itself (Figure 2). In one report from Europe, 35 out of 50 dogs with leptospirosis had radiographic pulmonary changes; 31 had overt respiratory distress and >65 percent of these dogs were eventually euthanized.12 This condition is uncommon in the U.S. Abdominal ultrasonography. Findings on transabdominal ultrasonography may include renomegaly, perinephric fluid, and increased cortical echogenicity.1,9 These findings are not specific for leptospirosis but do help to exclude other causes AKI such as ethylene glycol, pyelonephritis or urinary tract obstruction. (Figures 3 and 4.) Figure 3: Transabdominal ultrasonographic image of the left kidney of a dog with leptospirosis. The kidney is hyperechoic, with a reduced corticomedullary distinction and radiating striations in the inner cortical tissue. Image courtesy Diagnostic Imaging Service at Texas A&M Veterinary Medical Teaching Hospital. Figure 4: Transabdominal ultrasonographic image of the left kidney of a dog with leptospirosis. Note the fat surrounding the kidney is hyperechoic. Image courtesy Diagnostic Imaging Service at Texas A&M Veterinary Medical Teaching Hospital. Establishing a diagnosis Serology. Establishing a diagnosis of leptospirosis traditionally depended on proving seroconversion; this is defined as a four-fold increase in antibody titers over a two- to four-week period or an absolute titer ≥ 1:1600. Titers for leptospirosis are determined using the microscopic agglutination test (MAT) (Figure 5); this is widely available through reference laboratories and is fairly inexpensive. It is, however, somewhat subjective and cross contamination of materials can impact results. For this reason, it is ideal to send both the acute and convalescent samples to the laboratory at the same time, so the results can be interpreted with more confidence.13 Figure 5: Photomicrograph of a leptospiral microscopic agglutination test; live organisms are mixed with the patient’s serum and the slide is viewed using dark field microscopy technique. Note the presence of numerous, brightly stained, Leptospira sp. bacteria. Agglutination of organisms indicates the presence of antibodies. Image: Public Health Image Library CDC. Titers measured in the acute phase of the illness may be negative, although a result of 1:800 for any serovar is supportive of infection.1 It is noteworthy, however, that this result was reported in a large percentage of dogs two to four months post vaccination.14 Caveats to reliance on acute titers to rule out leptospirosis in or out include: 1) Seropositivity does not indicate active disease and may reflect prior exposure or vaccination. 2) Acutely infected dogs are often seronegative.15 It has also been suggested that prompt treatment for leptospirosis may blunt seroconversion, meaning we cannot ultimately prove the diagnosis. In house testing options are also available: the Witness Lepto test (Zoetis) and the Snap Lepto Test (IDEXX Laboratories). The Witness test detects IgM antibody specific to multiple Leptospira antigens derived from filtered whole cell extracts of serovars Grippotyphosa and Bratislava. This test performed well in a recent study and was positive in all 32 experimentally infected dogs by day 10.16 In contrast, the Snap Lepto test was positive in <10 percent at that time. Sensitivity for this test has been reported to be <80 percent for dogs with MAT titers below 1:3200.17 Polymerase chain reaction. Polymerase chain reaction (PCR) tests rely upon the detection of genetic material from the targeted organism(s). This approach permits the identification of acute infection prior to the production of antibodies and is not impacted by prior vaccination.18 Leptospire numbers are usually highest in blood for the first seven to 0 days post infection, after which time the organisms settle in the renal tubules; at this time, urine becomes the superior test material.19 Unfortunately, it is impossible to determine the date of infection in a clinical setting, so most experts recommend testing both urine and blood. These samples must not be pooled as this may limit test sensitivity. Ideally, PCR should be performed on samples collected before antimicrobials are given, as multiple doses will kill the organism and limit detection of its genetic material. EDTA samples can be stored for up to a week at 39.2 F/4 C prior to testing; similar information for urine samples is not available, but freezing has been shown to decrease PCR sensitivity. Diagnostic performances of commercially available PCR tests may vary; consequently, results should be interpreted cautiously and supported whenever possible by serological testing. In particular, a negative PCR result should not be used to discount the possibility of leptospirosis. Next week look for Part 2, which delves into details about treatment options, prognosis, follow-up tips, public health issues, and more on this vital topic. Audrey Cook, BVM&S, MRCVS, MSc Vet Ed, Dip ACVIM (SAIM), Dip ECVIM (CA), Dip ABVP (feline practice) is professor of Small Animal Internal Medicine at Texas A&M University. She is chief of the Internal Medicine Section, and currently divides her time between the Internal Medicine Service and the Interventional Radiology and Endoscopy Service. References Abela-Ridder B, Sikkema R, Hartskeerl RA. Estimating the burden of human leptospirosis. Int J Antimicrob Ag. 2010;36:S5-S7. Sykes JE, Hartmann K, Lunn KF, et al. 2010 ACVIM small animal consensus statement on leptospirosis: diagnosis, epidemiology, treatment, and prevention. J Vet Intern Med 2011;25:1-13. White AM, Zambrana-Torrelio C, Allen T, et al. Hotspots of canine leptospirosis in the United States of America. Vet J.2017;222:29-35. Murillo A, Goris M, Ahmed A, Cuenca R, Pastor J. Leptospirosis in cats: Current literature review to guide diagnosis and management. J Fel Med Surg. 2020;22(3):216-228. Dorsch R, Ojeda J, Salgado M, et al. Cats shedding pathogenic Leptospira spp.—An underestimated zoonotic risk?. PloS One. 2020;15(10):e0239991. Costa F, Wunder Jr EA, De Oliveira D, Bisht V, Rodrigues G, Reis MG, Ko AI, Begon M, Childs JE. Patterns in Leptospira shedding in Norway rats (Rattus norvegicus) from Brazilian slum communities at high risk of disease transmission. PLoS Neglect Trop D. 2015;9(6):e0003819. Ward MP, Guptill LF, Wu CC. Evaluation of environmental risk factors for leptospirosis in dogs: 36 cases (1997–2002). J Am Vet Med Assoc. 2004 Jul 1;225(1):72-77. Goldstein RE, Lin RC, Langston CE, et al. Influence of infecting serogroup on clinical features of leptospirosis in dogs. J Vet Int Med. 2006;20(3):489-494. Langston CE, Heuter KJ. Leptospirosis: A re-emerging zoonotic disease. Vet Clin N Am-Small. 2003;33(4):791-807. Tangeman LE, Littman MP. Clinicopathologic and atypical features of naturally occurring leptospirosis in dogs: 51 cases (2000–2010). J Am Vet Med Assoc. 2013;243(9):1316-1322. Barthélemy A, Magnin M, Pouzot‐Nevoret C, Bonnet‐Garin JM, Hugonnard M, Goy‐Thollot I. Hemorrhagic, hemostatic, and thromboelastometric disorders in 35 dogs with a clinical diagnosis of leptospirosis: a prospective study. J Vet Intern Med.2017;31(1):69-80. Kohn B, Steinicke K, Arndt G, Gruber AD, et al. Pulmonary abnormalities in dogs with leptospirosis. J Vet Intern Med. 2010;24(6):1277-1282. Reagan KL, Sykes JE. Diagnosis of canine leptospirosis. Vet Clin N Am-Small. 2019;49(4):719-731. Martin LER, Wiggans KT, Wennogle SA, et al. Vaccine associated Leptospira antibodies in client-owned dogs. J Vet Int Med. 2014;28(3):789-792. Fraune CK, Schweighauser A, Francey T. Evaluation of the diagnostic value of serologic microagglutination testing and a polymerase chain reaction assay for diagnosis of acute leptospirosis in dogs in a referral center. J Am Vet Med Assoc. 2013;242(10):1373-1380. Lizer J, Velineni S, Weber A, et al. Evaluation of 3 serological tests for early detection of leptospira‐specific antibodies in experimentally infected dogs. J Vet Int Med. 2018;32:201-207. Curtis KM, Foster PC, Smith PSet al. Performance of a recombinant LipL32 based rapid in-clinic ELISA (SNAP® Lepto) for the detection of antibodies against Leptospira in dogs. International Journal of Applied Research in Veterinary Medicine. 2015;13(3). Midence JN, Leutenegger CM, Chandler AM, et al. Effects of recent Leptospira vaccination on whole blood teal‐time PCR testing in healthy client‐owned dogs. J Vet Intern Med. 2012;26(1)149-152. Harkin KR, Roshto YM, Sullivan JT. Clinical application of a polymerase chain reaction assay for diagnosis of leptospirosis in dogs. J Am Vet Med Assoc. 2003;222:1224-1229.

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Could this be lepto? Part 1

Recognizing and treating leptospirosis

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