What are Feline Haemoplasmas?

The bacterium previously known as Haemobartonella felis has now been renamed Mycoplasma haemofelis (Mhf) due to its new classification as a mycoplasmal organism. Mhf and related erythrocytic mycoplasmal organisms are collectively known as 'haemoplasmas'. Additional feline haemoplasma species have been described; 'Candidatus Mycoplasma haemominutum' (CMhm), first described in 1998, and 'Candidatus Mycoplasma turicensis' (CMt), first described last year in Switzerland (Willi, et al 2006, Willi, et al 2005).

Prevalence of Feline Haemoplasmas

In worldwide prevalence studies CMhm is the most abundant haemoplasma with CMt and Mhf being less common, although some countries do have a high prevalence of CMt. Studies have found infection rates of 10-32.1% for CMhm, 1.4-6.4% for Mhf and 1.3-26% for CMt.

Pathogenesis of Feline Haemoplasmosis

Experimental CMhm infection rarely results in significant clinical signs and anaemia is not usually induced, although a fall in erythrocyte parameters can occur. Anaemia may result in retrovirus infected cats, although reports are variable. In studies in naturally infected cats, an association between anaemia and CMhm infection is not usually found although one study in Australian cats did find that CMhm positive cats had significantly lower haematocrit values than CMhm negative cats, although their retrovirus status was not determined. CMhm-associated anaemia has also been reported in a cat undergoing chemotherapy for lymphoma. It is possible that different CMhm isolates have varying pathogenicity but CMhm should not be regarded as being apathogenic. Interestingly a recent study found a significant association between CMhm infection and renal insufficiency (Willi, et al 2006). This association may have arisen because older cats are both more likely to be infected with CMhm and have renal insufficiency rather than it being a causal relationship.

Mhf often results in a severe haemolytic anaemia although the anaemia can be mild. Prevalence studies in naturally infected cats have only variably demonstrated associations between anaemia and Mhf infection. This variation is likely to be partly due to the different populations of cats sampled in the studies and whether Mhf infected cats were acutely or chronically infected. It has been hypothesised that acute infection with Mhf can result in severe haemolytic anaemia but that chronically infected cats often lack clinical signs and show no evidence of anaemia (Willi, et al 2006).

CMt was first discovered in a Swiss cat with a history of severe intravascular haemolytic anaemia (Willi, et al 2005) and experimental transmission of the CMt isolate to two SPF cats resulted in anaemia in both cats. Many CMt infected cats are also infected with CMhm (Willi, et al 2006). A significant number of CMt infected cats have been found to have concurrent diseases such as neoplasia or FIV infection, suggesting that co-factors and immunosuppression may be important in the pathogenesis of disease with this agent.

Haemoplasmas induce anaemia by haemolysis and sequestration. Positive Coombs' tests and autoagglutination have been reported in acute haemoplasmosis cases indicating the presence of erythrocyte-bound antibodies. We, and others, have demonstrated the development of cold reacting (IgM) antibodies in haemoplasma infected cats during anaemic periods, and these antibodies have disappeared following resolution of the haemoplasma-induced anaemia with antibiotic treatment, without the need for glucocorticoid treatment.

Although most haemolysis is said to be extravascular in nature (in the spleen, liver, lungs and bone marrow), intravascular haemolysis has also been reported. Splenic macrophages can also remove haemoplasmas from the surface of the erythrocytes ('pitting'), returning unparasitised cells back into the circulation. This may explain the rapid increase in PCV, without reticulocytosis, seen in some cats.

Carrier Cats

Cats which recover from infection may remain chronically infected with haemoplasmas. Long-term carrier status appears to be common following CMhm infection, although suspected clearance of infection has also been reported, with and without antibiotic treatment (Willi, et al 2006). Mhf infected cats often spontaneously clear infection from peripheral blood after infection without antibiotic treatment, and such clearance has also been reported with CMt infection. Variation exists in the long-term host-organism interaction. In carrier cats reactivation of infection can occur and may result in clinical disease (Foley, et al 1998), although this is probably quite rare.

Clinical Signs

The clinical signs seen with haemoplasma infection depend upon a number of factors such as the species involved, stage of infection, whether the haemoplasma infection is primary or secondary to another disease process or stress, and the degree and speed of development of the anaemia. Common clinical signs seen in ill cats include anorexia, lethargy, dehydration, weight loss and depression. Intermittent pyrexia is often seen, particularly in the acute stages of disease, as well as splenomegaly which may reflect extramedullary haematopoiesis. Icterus is uncommon.

Haematological Features

Pathogenic haemoplasma infection typically causes a regenerative macrocytic hypochromic anaemia. Significant reticulocytosis is not always present. Normoblasts may be present. As mentioned above, positive Coombs' tests and autoagglutination may also occur.

Diagnosis

Diagnosis of haemoplasmosis used to rely on demonstration of organisms on blood smears but this method is known to have poor sensitivity and specificity and is no longer recommended. The polymerase chain reaction (PCR) assay is now the diagnostic method of choice for haemoplasma infection, being specific and sensitive if designed and applied properly. PCR can amplify small amounts of DNA so that previously undetectable amounts become detectable. The sensitivity and specificity of PCR assays should be made available by laboratories offering them commercially, so that their reliability can be evaluated by the veterinarian. Laboratories undertaking PCR should use appropriate positive and negative controls to monitor for contamination or problems with the PCR assay.

Conventional non-quantitative PCRs can detect and distinguish feline haemoplasmas but real-time quantitative PCRs can additionally quantify haemoplasma DNA in blood samples (Tasker, et al 2003). The Universities of Bristol, UK and Zurich, Switzerland, have real-time PCR assays available to detect and quantify all three feline haemoplasmas in blood samples. Quantification of the amount of haemoplasma DNA may help determine the significance of the infection and monitor response to treatment. Cats can become negative by PCR during effective antibiotic treatment (but it may take a number of days/weeks for the haemoplasma levels to fall below detection limits) but may become positive again when antibiotic treatment is stopped (Tasker 2002). Blood samples for haemoplasma PCR should not be collected during antibiotic treatment, although a strongly positive result will indicate that the therapy is not being optimally effective. PCR can detect chronically infected and asymptomatic cats such that a positive PCR result does not always correlate with the presence of clinical haemoplasmosis.

Epidemiology

Recent studies looking at risk factors have generally found that older male cats, with outdoor access are more likely to be haemoplasma infected. The increased incidence in male cats, together with reports that cat bite abscesses and outdoor roaming are risk factors, is suggestive that horizontal transmission may occur via fighting, and CMhm and CMt have both been amplified from the saliva of infected cats (Dean, et al 2005, Willi, et al 2006).

The influence of retroviral status is not fully understood. A study of US feral cats found that FeLV infection was associated with an increased risk of co-infection with CMhm but not Mhf, whereas FIV infection was associated with an increased risk of co-infection with CMhm and Mhf (Luria, et al 2004). However a Swiss study failed to show any association between retrovirus and haemoplasma infection. These differing results may be due to differences in the populations of cats sampled (for example feral versus client owned) and it still seems prudent to recommend FeLV and FIV testing in any cat found to be haemoplasma infected.

The cat flea Ctenocephalides felis has been incriminated in the transmission of haemoplasma species in cats, and work has demonstrated transient transmission of Mhf to a cat via the haematophagous activity of Ct. felis (Woods, et al 2005).

Treatment

Doxycycline (10 mg/kg/day PO) is probably most commonly used to treat haemoplasma infection but short courses (up to 21 days) have not consistently eliminated infection. Longer treatment courses (4-6 weeks) may be required for clearance. Doxycycline appears to have activity against all three feline haemoplasmas although controlled studies have only been performed for Mhf. Oesophageal strictures secondary to oral doxycycline treatment have been reported so it is recommended that oral doxycycline dosing be followed by the administration of water by syringe, or food, to encourage passage of the drug into the stomach. Enrofloxacin treatment is also effective against Mhf disease but clearance of infection, as indicated by repeated negative PCR results, does not always result. Diffuse retinal degeneration and acute blindness have been reported following enrofloxacin treatment in cats and doses higher than the 5 mg/kg/day dose recommended by the manufacturers should not be used. Imidocarb dipropionate has been efficacious in some field cases but a controlled study failed to show any significant effect of imidocarb on either clinical signs or haematological values in experimentally infected cats. A four week course of marbofloxacin, in recent studies at the University of Bristol, did reduce Mhf copy numbers and treat clinical disease, however, consistent elimination of infection was not demonstrated. Interestingly CMhm did not show as favourable a response to marbofloxacin treatment as Mhf. Future studies should evaluate treatment regimes for each of the feline haemplasma species.

The anaemia induced by haemoplasma infection is in part immune-mediated and corticosteroids have been recommended as adjunct therapy (VanSteenhouse, et al 1993) although their value in treatment is not proven. In our experience clinically ill cats, including those that are Coombs' positive, respond to antibiotic treatment alone (Tasker 2002). Supportive care may be required, including correction of dehydration with fluid therapy and blood transfusion if the anaemia is very severe.

References

1.  Dean, R., Helps, C.R., Gruffydd-Jones, T.J. & Tasker, S. (2005) Use of real-time PCR to detect Mycoplasma haemofelis and 'Candidatus Mycoplasma haemomi nutum' in the saliva and salivary glands of haemoplasma-infected cats. In: 48th Annual British Small Animal Veterinary Association Congress. British Small Animal Veterinary Association, Birmingham, UK.

2.  Foley, J.E., Harrus, S., Poland, A., Chomel, B. & Pedersen, N.C. (1998) Molecular, clinical, and pathologic comparison of two distinct strains of Haemobartonella felis in domestic cats. American Journal of Veterinary Research, 59, 1581-1588.

3.  Luria, B.J., Levy, J.K., Lappin, M.R., Breitschwerdt, E.B., Legendre, A.M., Hernandez, J.A., Gorman, S.P. & Lee, I.T. (2004) Prevalence of infectious diseases in feral cats in Northern Florida. Journal of Feline Medicine and Surgery, 6, 287-296.

4.  Tasker, S. (2002) Feline haemoplasmas--detection, infection, dynamics and distribution. In: PhD Thesis. University of Bristol, Bristol, UK.

5.  Tasker, S., Helps, C.R., Day, M.J., Gruffydd-Jones, T.J. & Harbour, D.A. (2003) Use of Real-Time PCR to detect and quantify Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' DNA. Journal of Clinical Microbiology, 41, 439-441.

6.  VanSteenhouse, J.L., Millard, J.R. & Taboada, J. (1993) Feline haemobartonellosis. Compendium of Continuing Education for the Practising Veterinarian, 15, 535-545.

7.  Willi, B., Boretti, F.S., Baumgartner, C., Tasker, S., Wenger, B., Cattori, V., Meli, M.L., Reusch, C.E., Lutz, H. & Hofmann-Lehmann, R. (2006) Prevalence, risk factor analysis, and follow-up of infections caused by three feline hemoplasma species in cats in Switzerland. Journal of Clinical Microbiology, 44, 961-969.

8.  Willi, B., Boretti, F.S., Cattori, V., Tasker, S., Meli, M.L., Reusch, C., Lutz, H. & Hofmann-Lehmann, R. (2005) Identification, molecular characterisation and experimental transmission of a new hemoplasma isolate from a cat with hemolytic anaemia in Switzerland. Journal of Clinical Microbiology, 43, 2581-2585.

9.  Woods, J.E., Brewer, M.M., Hawley, J.R., Wisnewski, N. & Lappin, M.R. (2005) Evaluation of experimental transmission of 'Candidatus Mycoplasma haemominutum' and Mycoplasma haemofelis by Ctenocephalides felis to cats. American Journal of Veterinary Research, 66, 1008-1012.