Feline Haemotropic Mycoplasma Infections: Giving You The Advantage

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Key Points:

  • M. haemofelis is associated with clinical anaemia
  • M. haemominutum tends to cause mild, often subclinical disease but is the most common species to infect cats.
  • The mode of transmission is unknown, however, the flea is suspected to be the major vector.
  • Haemoplasmas induce anaemia by either direct damage to the membrane of the red blood cells (RBCs) or via immune-mediated mechanisms directed at either RBC antigens or the organism itself.
  • The most common signs that cats with clinically significant haemoplasma infections display are lethargy, inappetance, mucous membrane pallor, weakness, tachypnoea and tachycardia.
  • Typically infection with haemoparasites causes a regenerative anaemia, manifested clinicopathologically by increased absolute reticulocyte count, and normal plasma protein levels.
  • PCR methodologies have generally superseded direct visualisation of the parasite on blood smears as the diagnostic test of choice.
  • Oral doxycycline +/- blood transfusion is the first line of treatment.
  • Antibiotic therapy should be continued for 6-8 weeks and owners should be warned that recurrences may occur.

What are haemotropic Mycoplasmas?

Haemotropic Mycoplasmas or "haemoplasmas" are small pleomorphic (rod, spherical or ring-shaped) bacteria that occur singly or in chains of three to six organisms on the surface of RBCs.

These bacteria lack a cell wall, which is the reason why they do not show up with Gram-staining, and also the reason why they are resistant to penicillin-based antibiotics.

Previously, these bacteria were known as Haemobartonella however sequencing of the 16S rRNA gene has led to their reclassification as mycoplasmas.1

There are four recognised haemoplasmas of cats:

  1. Mycoplasma haemofelis, (formerly known as Ohio or “large form” felis), generally associated with clinical anaemia (although incidences of subclinical infection do exist).
  2. Candidatus haemominutum (previously California or small form H. felis) tends to cause milder disease, often without overt anaemia, although a decrease in the haematocrit may occur.2 Infections tend to be clinically significant if the host is immunocompromised (e.g. FeLV co-infection, undergoing chemotherapy for lymphoma etc.). Interestingly, it has been proposed that Ca. M. haemominutum may induce neoplastic transformation of cells infected with FeLV (leading to myeloproliferative disease). This is the most common species to infect cats.
  3. Candidatus turicensis, first reported in Switzerland in 2005.3 Its pathogenicity has not been extensively studied; however, it has been shown via PCR to be present in cats with clinically significant haemolytic anaemia. Immunosuppression has been shown to increase the pathogenicity of this haemoplasma species. Studies have shown this species to be present in the UK, Australia, Brazil, Canada, Germany, Italy, Japan, South Africa and the USA.
  4. Candidatus mycoplasma haematoparvum. The prevalence and pathogenicity of this species is currently unknown.4

Candidatus” is an interim taxonomical term used for organisms that cannot be cultured. For full acceptance of a bacterial species name, the organism needs to be isolated, cultured, described and then entered into a Bacteriology Culture Collection. Obviously, these criteria cannot be met when the organism cannot be grown in the laboratory.

How do cats get haemoplasma infections?

Haemoplasma infections tend to occur much more commonly in male cats with outdoor access. Generally, cats tend to be infected with a single species, however co-infections with M. haemofelis and Ca. M. haemominutum or Ca. M. turicensis have been reported.

The mode of transmission is still somewhat of a mystery despite concerted research, and although the flea is suspected to be the major vector, infections can occur in areas where flea infestations are uncommon. Although fleas have been shown to contain haemoplasma DNA, this may simply be due to the nature of their blood diet and does not prove transmissibility. Experimental attempts to transmit the disease with fleas have not yielded definitive results. Because of the male predisposition, direct inoculation via fighting activity (akin to how FIV is transmitted) has also been proposed, although levels of the organism in saliva have been found to be low.

Transmission via contaminated blood transfusion has been documented, so it is ideal that cats been screened for these organisms prior to entering into a blood donation program.

How do they cause anaemia?

Haemoplasmas induce anaemia by either direct damage to the membrane of the red blood cells (RBCs) (e.g. intravascular haemolysis) or induction of immune-mediated mechanisms directed at either RBC antigens or the organism itself (extravascular haemolysis “Type II” or “Type III” antibody-dependent cytotoxic immune reaction), which is thought to be the major pathogenic mechanism. It is thought that macrophages within the spleen can remove the organism and release the “cured” RBC back into circulation. This may account for the rapid clearance of parasites from RBC that can occur in the space of a few hours. It is likely though, that the majority of infected RBCs are destroyed within the spleen.

What are the clinical features of haemoplasma infections?

The most common signs are lethargy and inappetance. Fever, jaundice and splenomegaly may also be features.

The signs of anaemia are typically apparent:

  • mucous membrane pallor
  • weakness
  • tachypnoea
  • tachycardia, and
  • occasionally syncope or collapse.

Some owners report pica (eating dirt or cat litter).  A haemic murmur may also be present on cardiac auscultation.

All cats with clinically significant anaemia should be suspected to have a potential haemoplasma infection, as it is one of the most common and most treatable aetiologies of this clinical problem.

How are these infections diagnosed?

Typically, infection with haemoparasites causes a regenerative anaemia, however many animals present in the acute, pre-regenerative stage. A regenerative response accompanied by a normal total plasma protein level should prompt the clinician to consider haemolysis and/or internal blood loss as the main cause of the anaemia.

Signs of regeneration are typically manifested by:

  • The presence of polychromatophilic erythrocytes (Figure 1)
  • Increased absolute reticulocyte count, and
  • Increased mean corpuscular volume (MCV) although this not always present.
Figure 1 Polychromatophilic erythrocytes are larger and more basophilic than mature RBCs. Image courtesy Dr Peter Lording.

Figure 1. Polychromatophilic erythrocytes are larger and more basophilic than mature RBCs. Image courtesy Dr Peter Lording.

If sufficient time has elapsed for the clinician to rule out pre-regenerative anaemia (typically 3-5 days), concurrent predisposing illness such as Feline leukaemia virus infection or other bone marrow disease may explain a persistent non-regenerative anaemia.

A specific diagnosis of haemoplasma infection can be difficult if one relies on visualisation of the parasite on RBCs via cytological examination of a blood smear, usually performed by a cytopathologist (Figure 2). Many false negative results occur due to the unpredictably cyclical nature of the RBC parasitism. False positive results may occur if Howell-Jolly bodies and stain precipitates are mistaken for haemoplasmas.

Figure 2. Haemoplasmas visible with New Methylene Blue stain (some are pointed out with green arrows) Image courtesy Dr Peter Lording.

Figure 2. Haemoplasmas visible with New Methylene Blue stain (some are pointed out with green arrows) Image courtesy Dr Peter Lording.

PCR methodologies have generally superseded direct visualisation and this test is now readily available in many countries.  PCR is extremely sensitive and specific if the laboratory utilises positive and negative controls. It must be remembered that the presence of haemoplasma organisms in a patient’s blood does not necessarily prove that this is the cause of the anaemia, as some normal individuals can be PCR positive. It is helpful to know which species has been detected, as subclinical infection appears to be much more common with Ca. M. haemominutum. As the results of the PCR may take several days, presumptive therapy with antimicrobials and supportive therapy such as blood transfusion and IV fluids should be given pending the results.

“Real time” PCR can actually quantitate the number of organisms/ml of blood.5 This has been a useful tool for researchers to determine the most effective antibiotics to treat the infection.6 In the clinical setting, blood for haemoplasma testing should always be collected before the commencement of treatment as cats can quickly become PCR-negative, even if the infection is not eventually eliminated.

Clumping of red cells is commonly seen on feline blood smears. If RBCs line up in a stack this is termed “rouleaux”. Quite commonly observed in the cat, rouleaux is not normally associated with a specific pathologic process, but may be more prominent when there are high levels of plasma proteins, and should be differentiated from more sinister RBC agglutination (bunches of grapes) by mixing 1 drop of blood with 1 drop of saline on a slide. If RBC clumping persists, this is more likely to be true agglutination.

This is because the parasite can be quickly cleared from the blood stream with antibiotic therapy, but the organism may be sequestered in organs such as the spleen.

The immune-mediated component of the disease may be detected via the observation of gross autoagglutination on a “saline-slide” test (see box below), or a positive Coomb’s test.

Other causes of haemolytic anaemia in cats:

  • Secondary immune-mediated (lymphoma, FIP, etc)
  • Hypophosphatemia (usually secondary to treatment for DKA or re-feeding syndrome)
  • Primary immune-mediated
  • Oxidative (Heinz body) anaemia Onion ingestion, paracetomol (acetominophen), repeated propofol administration (consecutive days)
  • Hereditary RBC defects
    • Pyruvate kinase deficiency (Abyssinian, Somali, DSH)
    • Increased erythrocyte osmotic fragility (Abyssinian, Somali)
    • Porphyria (Siamese, DSH)
  • Neonatal isoerythrolysis
  • Acute haemolytic transfusion reactions
  • Microangiopathic (fragmentation injury) anaemia (DIC - though not as commonly seen as in dogs, haemangiosarcoma)
  • Gram-negative sepsis
  • Feline Leukaemia Virus infection
  • Other infectious agents (Cytauxzoon felis [North America/Europe], Babesia species [South Africa/Middle East])

How are haemoplasma infections managed?

Antibiotic therapy is the mainstay of treatment for clinically affected cats. Treatment of asymptomatic, healthy, PCR-positive cats is not recommended.

The aim is to “tip the balance” in favour of the cat’s immune system as current therapies do not eliminate the organism.

Doxycycline* (10 mg/kg/day PO either SID or divided BID) is recommended as the first line of treatment.

Enrofloxacin (5 mg/kg PO SID) may also be effective, however controlled studies evaluating this drug using treatment courses longer than two weeks have not been published. The possible side effect of acute retinal degeneration also needs to be borne in mind, thus pradofloxacin (where available) is the preferred fluoroquinolone.

Although the optimal duration of treatment is currently not known, it is recommended that cats remain on antibiotics for 6-8 weeks.

*As doxycycline hyclate-induced oesophageal damage has been reported in cats it is generally recommended that practitioners use the monohydrate formulation (Vibravet®, Zoetis) if available, or that the cat be given a bolus of water after the dose is given.

The concurrent use of corticosteroids is controversial, and most cats will respond to doxycycline alone, although where there is evidence of marked agglutination 24-48 hours of glucocorticoid therapy may be beneficial. Supportive therapy, such as a typed blood transfusion may also be required depending on the severity of the anaemia (Figure 3). Other supportive therapy such as IV fluid should be made on a case-by-case basis depending on clinical need.

Figure 3. Whole blood transfusion in a cat infected with Mycoplasma haemofelis. Image Courtesy Dr Jody Braddock

Figure 3. Whole blood transfusion in a cat infected with Mycoplasma haemofelis. Image Courtesy Dr Jody Braddock

The decision to provide blood via transfusion should always be based on clinical need, not just the PCV value.

Clinical indications that a blood transfusion is required include:

  • Lethargy
  • Collapse
  • Tachypnoea
  • Tachycardia (though this might not be observed in some feline patients)
  • Bounding femoral pulses

Blood typing of the patient should be performed as soon as possible to facilitate the sourcing of a potential donor cat. This can be done as an in-house procedure at either the primary or referral veterinary facility using card or lateral flow kits, or done via an external laboratory.

What is the prognosis?

Cats that recover spontaneously from infection may remain chronic carriers of unknown duration (possibly lifelong). Cats treated with antibiotic therapy may also remain carriers and relapses are reported.

Author
Dr Carolyn O’Brien BVSc(Hons) MVet Clin Stud FANZCVS (Feline Medicine)
Registered Specialist in Feline Medicine
Melbourne Cat Referrals

Carolyn graduated from the University of Melbourne in 1994. She completed a residency program in Small Animal Medicine at the University of Sydney in 2003, and concurrently completed a Masters degree in Veterinary Clinical Studies in the epidemiology and treatment of fungal infections (specifically Cryptococcus) in cats and dogs.

She successfully completed the Fellowship examinations of the Australian and New Zealand College of Veterinary Scientists in Feline Medicine in 2004, and has worked in both university and private referral practice.

Carolyn is currently undertaking a PhD project investigating the ecology and epidemiology of environmental mycobacteria, specifically looking at Mycobacterium ulcerans infection in animal species, and the causative agents of feline leprosy. Carolyn is the senior tutor for the Centre for Veterinary Education’s Feline Medicine Distance Education program and also works as a specialist clinical consultant.

References

  1. Neimark, H, Johansson, KE, Rikihisa, Y, Tully, JG. Proposal to transfer some members of the genera Haemobartonella and Eperythrozoon to the genus Mycoplasma with descriptions of 'Candidatus Mycoplasma haemofelis','Candidatus Mycoplasma haemomuris','Candidatus Mycoplasma haemosuis' and'Candidatus Mycoplasma wenyonii'. International Journal of Systematic and Evolutionary Microbiology 2001; 51(3): 891-899.
  2. Foley, JE, Pedersen, NC. 'Candidatus Mycoplasma haemominutum', a low-virulence epierythrocytic parasite of cats. International journal of systematic and evolutionary microbiology 2001; 51(3): 815-817.
  3. Willi, B, Boretti, FS, Cattori, V, Tasker, S, Meli, ML, Reusch, C, Lutz, H, Hofmann-Lehmann, R. Identification, molecular characterization, and experimental transmission of a new hemoplasma isolate from a cat with hemolytic anemia in Switzerland. Journal of clinical microbiology 2005; 43(6):2581-2585.
  4. Sykes, JE, Drazenovich, NL, Ball, LM, Leutenegger, CM. Use of Conventional and Real‐Time Polymerase Chain Reaction to Determine the Epidemiology of Hemoplasma Infections in Anemic and Nonanemic Cats. Journal of veterinary internal medicine 2007; 21(4):685-693.
  5. Tasker, S, Helps, CR, Day, MJ, Gruffydd-Jones, TJ, Harbour, DA. Use of real-time PCR to detect and quantify Mycoplasma haemofelis and “Candidatus Mycoplasma haemominutum” DNA. Journal of clinical microbiology 2003; 41(1):439-441.
  6. Tasker, S, Helps, CR, Day, MJ, Harbour, DA, Gruffydd-Jones, TJ, Lappin, MR. Use of a Taqman PCR to determine the response of Mycoplasma haemofelis infection to antibiotic treatment. Journal of microbiological methods 2004; 56(1):63-71.

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