State-of-the-Art Review
Journal of Veterinary Emergency and Critical Care 20(1) 2010, pp 62–69 doi:10.1111/j.1476-4431.2009.00491.x
Feline hemotropic mycoplasmas Jane E. Sykes, BVSc, PhD, DACVIM
Abstract Objective – To describe the current understanding of the etiology, pathogenesis, diagnosis, and treatment of feline hemotropic mycoplasmosis (feline infectious anemia). Data Sources – Manuscripts published on hemotropic mycoplasmosis in cats and other animal species, based on a search of PubMed using the search terms ‘hemoplasmas,’ ‘haemoplasmas,’ ‘hemotropic,’ ‘haemotropic,’ and ‘Haemobartonella,’ as well as references published within manuscripts accessed. Human Data Synthesis – Although hemotropic bacteria such as Bartonella bacilliformis have been recognized in humans for over 100 years, it has only been in recent years that some of these have been identified as hemotropic mycoplasmas. Veterinary Data Synthesis – Three species of hemotropic mycoplasmas have been documented in cats worldwide, Mycoplasma haemofelis, ‘Candidatus Mycoplasma turicensis,’ and ‘Candidatus Mycoplasma haemominutum.’ These organisms were previously known as Haemobartonella felis, but are now known to be mycoplasmas. M. haemofelis is the most pathogenic species, and causes anemia in immunocompetent cats. Although ‘Candidatus Mycoplasma turicensis’ and ‘Candidatus Mycoplasma haemominutum’ may be more capable of causing anemia in immunosuppressed cats, their pathogenicity remains controversial. Assays based on polymerase chain reaction technology are the most sensitive and specific diagnostic tests available for these organisms, because they remain uncultivable in the laboratory setting. Blood smears are unreliable for diagnosis of hemoplasmosis because of their lack of sensitivity and specificity. Conclusions – Cats presenting to emergency/critical care specialists with hemolytic anemia should be tested using polymerase chain reaction assays for hemotropic mycoplasmas before instituting antimicrobial therapy. Positive test results for M. haemofelis suggest involvement of this organism in hemolytic anemia. Other differential diagnoses for hemolytic anemia should be considered in cats testing positive for ‘Candidatus Mycoplasma turicensis’ and ‘Candidatus Mycoplasma haemominutum,’ because the presence of these organisms is not always associated with anemia. Blood from infected cats should be handled with care because of the potential zoonotic nature of this infection. (J Vet Emerg Crit Care 2010; 20(1): 62–69) doi: 10.1111/j.1476-4431.2009.00491.x
Keywords: anemia, hemolytic, mycoplasma, polymerase chain reaction, zoonoses
Introduction Previously known as Haemobartonella and Eperythrozoon, hemotropic mycoplasmas (hemoplasmas) are small (0.3–0.8 mm), unculturable epierythrocytic bacteria that are capable of causing severe hemolytic anemia. The feline disease caused by these organisms, previously known as Haemobartonellosis, has been referred to as feline infectious anemia. Because of their previous From the Department of Medicine & Epidemiology, University of California – Davis, Davis, CA 95618. The author declares no conflicts of interest. Address correspondence and reprint requests to Dr. Jane E. Sykes, BVSc (Hons), PhD, DACVIM, Department of Medicine & Epidemiology, University of California – Davis, 2108 Tupper Hall, Davis, CA 95618, USA. Email: jesykes@ucdavis.edu
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name and their association with erythrocytes, they are often confused with Bartonella, an intraerythrocytic bacteria that causes cat scratch disease in humans. In contrast to the hemoplasmas, Bartonella spp. do not appear to cause hemolytic anemia in cats, instead causing chronic, largely asymptomatic infections. Hemoplasmas infect a wide variety of mammalian species and have a worldwide distribution. Sequence analysis of the 16S rRNA genes of Haemobartonella and Eperythrozoon spp. has shown that they belong to a group of fastidious mycoplasmas, rather than rickettsias as previously thought.1–3 Diagnosis of hemoplasma infections is currently based on visualization of coccoid bacteria associated with erythrocytes on blood smears, together with the results of specific polymerase chain reaction (PCR) assays. In recent years, several new hemoplasma species have been discovered in cats, & Veterinary Emergency and Critical Care Society 2009
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which appear to vary in their pathogenicity, responsiveness to antimicrobial drugs, and ability to form a carrier state.4–6
nisms.16–18 Their small size, absence of a cell wall, and other genomic similarities also support the classification of Haemobartonella and Eperythrozoon as mycoplasmas.19
Current Published Human Research Information and Data
The Current Published Veterinary Information
Hemotropic bacteria were first identified in humans following an epidemic of an acute febrile hemolytic illness in railroad workers that were involved in construction of the Oroya railroad project in Peru, around 1870.7 The disease became known as Oroya fever. In 1905, the Peruvian microbiologist, Alberto Leonardo Barton Thompson, detected organisms in association with erythrocytes while examining blood smears under the microscope from 14 patients with Oroya fever.8 The organisms were termed Barton’s endoglobular bodies, because Barton believed they were located within the erythrocyte. In 1913, these organisms were named Bartonella bacilliformis by the Harvard scientist Richard Strong, after he traveled to Peru to confirm Barton’s observations.7 Decades later, numerous pieces of serologic and molecular evidence led to the recognition of Bartonella henselae as the cause of cat scratch disease in humans, as well as bacilliary angiomatosis, peliosis hepatitis, endocarditis, and other diverse clinical manifestations, most commonly in the immunocompromised.9 In contrast to B. bacilliformis, B. henselae was not recognized in association with erythrocytes using light microscopy, but has recently been detected within human erythrocytes using electron microscopic techniques.10 Hemotropic organisms other than Bartonella spp have occasionally been documented in humans, including anemic patients with acquired immunodeficiency syndrome and systemic lupus erythematosus.11–14 Recently, Mycoplasma haemofelis was detected using PCR in an human immunodeficiency virus-infected human from Brazil that was co-infected with B. henselae,15 suggesting that M. haemofelis may be a zoonosis. Based on sequence analysis of the 16S rRNA gene, Haemobartonella and Eperythrozoon species fall within the pneumoniae group of mycoplasmas, which includes the human mycoplasmal pathogens Mycoplasma pneumoniae and Mycoplasma genitalium, as well as mycoplasmas of guinea pigs and horses, Mycoplasma cavipharyngis and Mycoplasma fastidiosum.1–3 M. pneumoniae is an important cause of community acquired pneumonia in people. Although mycoplasmas generally reside on mucosal surfaces of the respiratory and genital tracts, occasionally causing arthritic disease, the ability of a variety of mycoplasma species to adhere to erythrocytes has been long documented, and has been used as a model to study epithelial adherence mecha-
Etiology and epidemiology In the 1920s, organisms resembling B. bacilliformis were seen in association with erythrocytes of rodents and dogs, and these organisms were also named Bartonella.20,21 However, it became apparent that these organisms differed from B. bacilliformis in that they could not be cultured in the laboratory, and they usually caused disease in splenectomized animals. As a result, it was proposed that bartonellaceae infecting animals be given the names Haemobartonella or Eperythrozoon.22 In general, the name Eperythrozoon was given to epierythrocytic organisms that commonly exhibited ring forms and were often found free in the plasma. Epierythrocytic organisms were first identified in 1942, in an anemic cat in South Africa, and were named Eperythrozoon felis.23 Recognition of similar organisms in the United States occurred in Colorado in 1953, and these were shown to cause anemia when blood from an infected anemic cat was injected intraperitoneally into research cats.24 In 1955, the name Haemobartonella felis was suggested for the organisms that were rarely seen free in the plasma, and ring forms were uncommonly identified.25,26 The infection was recognized in cats from other US states,27,28 and subsequently was found to have a worldwide distribution.29–39 With the advent of PCR assays in the 1990s, amplification of DNA from Eperythrozoon spp and Haemobartonella spp became possible. Sequence information from amplified 16S rRNA gene DNA revealed the similarity of these organisms to mycoplasmas, and H. felis was renamed M. haemofelis (hereafter referred to as Mhf).2 The 16S rRNA gene is a conserved gene among bacteria, but contains sequences useful for bacterial identification, hence its widespread use as a target for PCR. Around the same time, a novel haemobartonella-like organism was detected in a cat in California that was co-infected with FeLV. This organism was only 0.3 mm in diameter, approximately half the size of Mhf, and considerably less pathogenic.4 Although also referred to as the small form or California variant of H. felis, the term ‘Candidatus Mycoplasma haemominutum’ (hereafter referred to as Mhm) was subsequently used to describe this organism. The ‘Candidatus’ term for newly described hemoplasmas is required because the organisms cannot be cultivated in the laboratory, and should be removed when more information is available to support their classification.
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Hemoplasma species
6.5% 0.5% 0% 0.1% 10% 1.3% 10% 1.3% 1.7%
26%
23% 16% 13% 3.3% 47% 17% 24% 10% 11.2%
38%
4.8% 0.5% 47% 0.7% 21% 5.9% 4.8% 15% 1.5% 2.8%
Mycoplasma haemofelis ‘Candidatus Mycoplasma haemominutum’ ‘Candidatus Mycoplasma turicensis’
Canada (45 stray cats)45
United States (310 cats with United possible States (263 hemoplasma sick cats)6 infection)43 Canada (742 healthy pet Japan (60 pet cats Italy (307 cats visiting undergoing mostly sick veterinary wellness cats)46 hospitals)42 testing)45 South Africa (69 cats suspected to Australia have hemoplasma (147 sick cats)41 infection)41 Switzerland (713 healthy and sick cats)40 United Kingdom (1585 samples submitted for hemoplasma testing)44
Country (Population sampled)
Three years later, a third hemoplasma was identified, ‘Candidatus Mycoplasma turicensis’ (Mtc).5 This organism was first identified in Switzerland (Latin, Turicum, Zurich) and subsequently has also been reported from the United Kingdom, Australia, South Africa, United States, Italy, Japan, and Canada.40–46 Mtc was discovered using PCR techniques, and has never been identified on blood smears. Inoculation of 2 specific pathogen-free cats with this organism resulted in mild anemia in 1 cat, and severe anemia in the other, although the cat with severe anemia was also immunosuppressed with glucocorticoids.5 Organism loads in cats infected with Mtc have typically been extremely low.40,41 Finally, PCR products with sequences identical to ‘Candidatus M. haematoparvum,’ a novel canine hemoplasma, were amplified from the blood of 2 cats in the United States,6 but this organism has not been detected using PCR in subsequent feline studies. Using cytologic evaluation of blood smears, Mhf appears as cocci to small rings and rods, sometimes forming short chains of 3–6 organisms, each organism being approximately 0.6 mm in diameter. The results of epidemiologic studies using PCR suggest that this organism is the least prevalent of the 3 feline hemoplasmas, being found in 0.5–5% of sick cats visiting veterinary hospitals (Table 1).40–46 Experimental inoculation of cats with Mhf results in moderate to severe anemia, and cats infected with Mhf sometimes demonstrate marked fluctuations in organism loads over the course of infection, with peak organism numbers correlating with dramatic declines in the HCT.4,47 Young cats may be more susceptible to infection and disease.43 Most infections with Mhm are chronic and asymptomatic. Using PCR to detect the organism, Mhm can be detected in as many as one-fifth to one-half of cats visiting veterinary hospitals for a variety of reasons, depending on the geographic location, with the prevalence of infection generally increasing with age.40–46,48 Inoculation of cats with Mhm results in only a mild, transient decrease in HCT, and the prevalence of infection in anemic cats has been the same or lower than the prevalence of infection in nonanemic cats.6,40,48,49 After infection, organism numbers gradually increase, then reach a plateau.47 There is some evidence that Mhm may play a role in disease. Cats co-infected with both FeLV and Mhm develop more significant anemia than cats infected with Mhm alone. Also, cats that are co-infected with FeLV and Mhm may be more likely to develop myeloproliferative disease compared with cats infected with FeLV alone.50 Proposed mechanisms have included immunosuppression, erythroid hyperplasia, and immune stimulation leading to
Table 1: Prevalence (%) of various hemoplasma species in different geographical locations and cat populations as determined using PCR assays
J.E. Sykes
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enhanced rate of mutation and myeloproliferative disease. Several case reports exist that describe positive test results for Mhm in conjunction with anemia in cats that are not concurrently infected with retroviruses, although the association with anemia was not proven in these studies through the use of a control population or experimental inoculation.51–53 Infection with Mhm was more prevalent in cats suspected to have hemoplasmosis (generally as a result of acute anemia) compared with cats that were ill for various reasons from a similar geographic location, suggesting a causative role for Mhm in anemia. However, this must be interpreted with caution as samples were not collected from each population over the same period of time.43 In addition, among anemic cats, infection with Mhm was associated with higher MCV values than in cats not infected with hemoplasmas, suggesting the possibility of induction of increased erythrocyte turnover by this organism. Infection with Mtc has had a similar prevalence in the cat population to Mhf, with most studies showing a prevalence of 0.5–10% in sick cats visiting veterinary hospitals (Table 1).40–46 The pathogenic potential of Mtc may be lower than that of Mhf, but greater than that of Mhm.43 Cofactors, such as co-infection or concurrent immunosuppression, may be important in development of anemia in cats infected with Mtc.41 In most recent studies, feline hemoplasma infection has been strongly associated with male sex, nonpedigree status, and access to the outdoors.6,40,41,43,48,54,55 Some studies,43,46,54,56,57 but not others,40 have shown an association between retrovirus infection and hemoplasmosis. Cats infected with Mhf in the United States were 6 times more likely to be infected with FIV than cats negative for hemoplasmas.43 Co-infections with Mhm and Mtc or Mhm and Mhf have also been recognized.6,40–44,46,48,49,55,58 The mode of transmission for the feline hemoplasmas also remains unknown. Fleas have been suggested to transmit Mhf,56,59 but infection is still prevalent in some regions where flea infestation is uncommon.49 As might be expected, fleas collected from cats contain hemoplasma DNA.45,60,61 However, attempts to use fleas to transmit feline hemoplasmas has been met with disappointing results, with only 1 of 6 inoculated cats developing transient PCR positivity in the absence of illness.59 Mhf has been detected using PCR in some Ixodes ricinus ticks from Europe62 and Mhm has been detected in unfed I. ovatus ticks from Japan.63 However, another study of almost 2000 unfed Ixodes spp ticks in Switzerland did not yield evidence of hemoplasma DNA using PCR,64 and infections have been described in suburban areas where there is minimal tick exposure.6 Geographical variation in the prevalence of hemoplasma infection in cats supports a role for ar-
thropod vectors in transmission.6,40 All 3 feline hemoplasma species can be detected commonly in wild felids, suggesting the possibility that they may act as reservoirs of infection for arthropod transmission.65 Mosquitos have been suggested to play a role in transmission,6 but a recent study of pooled field-caught mosquitos from Colorado revealed only the DNA of Mycoplasma wenyonii, a bovine hemoplasma.a Transplacental spread has also been hypothesized.66 Direct transmission through biting and fighting is emerging as a possible mode of transmission, based on the strong male sex predeliction and association with FIV infection in some studies. Hemoplasmas have also been detected in the saliva and feces of experimentally infected cats early in the course of infection, as well as in the saliva, gingival, and claw beds of naturally infected cats, although organism levels in these secretions have been low.64,67,b Furthermore, an association between hemoplasmosis and the development of cat-bite abscesses has been reported,54 although it is possible that these instances may have represented reactivation of infection following the stress of the fight or bite wound. Transmission has occurred following blood transfusion,40 and it is suggested that prospective blood donors be screened for hemoplasmas using PCR assays.68 Pathogenesis After inoculation of experimental cats with Mhf, there is a delay of 2–34 days before acute onset of clinical signs. In the acute phase, which lasts 3–4 weeks in the absence of treatment, severe anemia and bacteremia occur, which is typically when cats present to veterinarians. During this phase, sharp declines in the HCT may correlate with the appearance of large numbers of organisms in blood smears.4,66 This may be due to direct damage to the erythrocyte by the organism or through immune-mediated mechanisms, supported by the detection of cold agglutinins in infected cats.69 Anemia results primarily from extravascular hemolysis, although intravascular hemolysis has been described in some infected cats.5,53 Positive direct Coombs, increased osmotic fragility, and decreased erythocyte lifespan have also been noted in cats with hemoplasmosis.5,69–71 The number of infected erythrocytes may decline from 90% to o1% in o3 hours.66,72 Recent studies in pigs have suggested that invasion of the erythrocyte cytoplasm by Mycoplasma suis may explain organism disappearance during this phase.73 Sequestration of the organism in splenic or pulmonary macrophages is another possible explanation. In surviving cats, the immune system intervenes, with a corresponding increase in the HCT, and a disappearance of organisms from blood smears. Despite organism disappearance, posi-
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tive PCR results persist.74 It has been suggested that recovered cats may remain carriers for years, the organism evading the host immune system, with possible reactivation of disease with stress, pregnancy, intercurrent infection, or neoplasia.66,74,75 Challenging this is the fact that PCR positivity for Mhf is usually associated with the presence of anemia in client-owned cats, and attempts to reproduce disease reactivation experimentally through abscess creation, glucocorticoid or cyclophosphamide administration, and splenectomy have been disappointing.75 One study showed persistence of positive PCR results for 6 months after recovery from acute infection once antimicrobials were discontinued, and administration of methylprednisolone was associated with reappearance of organisms on blood smears.74 In contrast to hemoplasma infections of other host species, splenectomy has a variable effect on the course of feline hemoplasmosis. Recrudescence of anemia and bacteremia has been documented in some chronically infected cats, although other studies suggest splenectomy increases the number of visible organisms in blood smears without causing significant anemia.72,75 Infection of splenectomized cats with Mhm does not seem to enhance the pathogenicity of this organism.76
Clinical signs and laboratory abnormalities Depression, inappetence, and dehydration are common signs of infection with Mhf, and some cats may also present with weight loss. Anemia is manifested by weakness, mucosal pallor, tachypnea, tachycardia, and occasionally syncope or neurologic signs if acute and severe. Some owners may report that their cat eats dirt, litter, or licks cement. Other physical examination abnormalities may include cardiac murmurs, splenomegaly, and icterus. Some cats may be febrile, and moribund cats may be hypothermic. Autoagglutination may be noted in blood smears from some infected cats. The most characteristic abnormality on the CBC is regenerative anemia, with anisocytosis, reticulocytosis, polychromasia, Howell-Jolly bodies, and occasionally marked normoblastemia. Nonregenerative anemia may also be noted. In some cases this is because sufficient time for a regenerative response has not yet elapsed. In others, anemia is nonregenerative as a result of concurrent FeLV infection.77,78 Concurrent occult infection with hemoplasmas should be considered in any FeLV-positive cat with macrocytosis, even in the absence of reticulocytosis. WBC counts may be normal, elevated, or low. The serum chemistry profile may reveal elevated alanine aminotransferase, hyperbilirubinemia, and prerenal azotemia. 66
Diagnosis The differential diagnoses for cats presenting with hemoplasmosis include primary immune-mediated hemolytic anemia, other infectious causes of anemia such as feline infectious peritonitis virus and feline retrovirus infections, cytauxzoonosis, Heinz body hemolytic anemia, and inherited erythrocyte disorders such as pyruvate kinase deficiency, and the red cell fragility disorder of Abyssinian and Somali cats. Attempts to isolate feline hemotropic mycoplasmas in the laboratory have been unsuccessful. Cytologic detection of hemoplasmas has low sensitivity.47 Mhf is visible o50% of the time in acutely infected cats, because organisms may disappear for several days before reappearing on blood smears over the course of infection. Fresh smears should be examined because the organism may detach from erythrocytes in the presence of ethylene diamine triacetic acid (EDTA). Mtc has never been seen on blood smears. Mhm is generally not visible in chronically infected cats, and although smaller than Mhf, it may not always be reliably distinguished from Mhf based on size alone.79 False positive diagnoses occur when stain precipitate, basophilic stippling, and Howell-Jolly bodies are confused with organisms. Diagnostic PCR assays for hemoplasmas are based on detection of the 16S rRNA gene. These assays have been shown to be significantly more sensitive than blood smear evaluation, although they may not consistently detect the organism in asymptomatic carrier cats.4,44,47,49,74,80,81 Hemoplasma PCR assays are now commercially available in some veterinary diagnostic laboratories, including conventional PCR assays, whereby bands on a gel are interpreted as positive results, and real-time PCR assays, which rely on fluorometric detection of the PCR product, and can provide information regarding organism load. Conventional PCR assays generally do not distinguish Mtc from Mhf. Real-time PCR assays are generally species specific, and may be less prone to false positive results because of contamination. Because the pathogenic potential of each hemoplasma species differs, the laboratory must be consulted to determine the species specificity of the assay(s) offered. Dried blood smears can also be used for PCR but are less sensitive than a larger volume of liquid whole blood.82 Treatment with antimicrobial drugs may result in false negative results using PCR, so blood must be collected before initiating antimicrobial therapy. Treatment Treatment is indicated for cats with clinical signs and laboratory abnormalities consistent with hemoplasmosis. Treatment of PCR positive, asymptomatic cats is not recommended, because no treatments have yet been
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identified that eliminate the organism. Mhm does not appear to respond as well as Mhf to therapy with doxycycline or fluoroquinolones.76,83 Antimicrobial therapy cannot be used to reliably eliminate infection from potential blood donors. Spontaneous clearance of bacteremia has been reported in cats experimentally infected with Mtc.40 The treatment of choice for hemoplasmosis is doxycycline (10 mg/kg/d, PO) for a minimum of 2 weeks, and transfusion with packed red cells or whole blood where necessary. Because of the potential for esophagitis, it has been recommended that administration of doxycycline hyclate be followed by administration of a bolus of several milliliters of water.84,85 Doxycycline has not been reported to cause discoloration of the teeth in young cats or dogs, and appears to be safe for use in children.86 Enrofloxacin (5 mg/kg/d, PO) is a suitable alternative to doxycycline.87 Pradofloxacin also appears to be a suitable alternative.88 Azithromycin was not effective for treatment of feline hemoplasmosis using an experimental model.80 The use of immunosuppressive doses of glucocorticoids to suppress an associated immune-mediated hemolytic process is controversial, given that glucocorticoids may cause reactivation of latent infection, but may be necessary in cats that fail to respond to antimicrobial therapy alone, or in cases where the diagnosis is uncertain.
atic because of the high prevalence of infection in the cat population, and inoculation of splenectomized, glucocorticoid-treated cats has not been associated with anemia in our studies (unpublished data). However, it remains possible that strain variation may exist within this species, with some strains being more capable of causing anemia than others. Until more information becomes available regarding the pathogenic potential of this organism, blood testing negative for all hemoplasma species is preferred for transfusion purposes.
Recommendations for Future Studies/Change in Current Practices Future research on hemoplasmas will likely be focused on the mode(s) of transmission of these organisms, so that methods of prevention can be implemented more effectively. Further research is required to more fully understand the pathogenic potential of Mtc and Mhm. Increased understanding of the zoonotic potential of hemoplasmas is also required, and until this occurs, veterinarians should handle blood products from infected cats with care. Additional efforts to manipulate these organisms in the laboratory may lead to improved understanding of the pathogenesis of hemoplasma infections, as well as improved methods of diagnosis, treatment, and prevention.
Application to Emergency and Critical Care
Footnotes
Cats with hemoplasmosis are frequently presented to emergency/critical care hospitals as a result of moderate to severe hemolytic anemia and associated clinical signs. Before antimicrobial treatment, diagnostic tests that should be considered include fresh blood smear evaluation, slide agglutination test, CBC (including a new methylene blue stain for Heinz bodies), Coombs test, cross-match and blood typing, serological tests for FeLV and FIV, chemistry panel, as well as PCR testing for Mhf, Mtc, and Mhm. Assays to assess coagulation may also be considered. Treatment with doxycycline and erythrocyte transfusions should be instituted pending the results of PCR, which typically becomes available within 1–3 days. The results of epidemiologic studies suggest that alternate diagnoses should be considered in cats testing positive for Mtc, Mhm or cats testing negative for hemoplasmas that fail to respond to antimicrobial therapy. In addition, hemoplasmas have been shown to survive up to 1 week in stored blood products. Cats testing positive for Mhf using PCR should be excluded as blood donors. The significance of positive test results for the other 2 hemoplasma species is less clear. Excluding cats testing positive for Mhm is most problem-
a
b
Lin PC, Hawley JR, Bolling BG, et al: Prevalence of hemoplasma DNA in field-caught mosquitos in Colorado (abstr). J Vet Intern Med 2009;23:718. Lappin MR, Dingman P, Levy J, et al: Detection of hemoplasma DNA on the gingival and claw beds of naturally exposed cats (abstr). J Vet Intern Med 2008;22(3):779.
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