• FIV and Hemobartonella

  • 1. Introduction

  • 2. Diagnosis

  • 3. Connection to FIV

  • 4. Treatment

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  • 1. Introduction

  • Hemobartonella felis has recently been reclassified as three distinct parasitic organisms: Mycoplasma haemofelis, Mycoplasma haemominatum, and (as first reported in a 2006 Swiss study) Mycoplasma turicensis [1]. All three are strange organisms (bacteria lacking a cell wall) that attach to the surface of red blood cells rather than infect the cells themselves. M. turicensis and M. haemominatum usually produce minimal disease. A 2003 study found a decided fall in hematocrit (red cell volume) correlating directly with rises in the M. haemofelis copy number, whereas the values of the cats infected with M. haemominatum remained within the reference range [3]. However, whereas M. haemominatum is usually not associated with clinical disease, it does, according to several sources [20], cause anemia in cats carrying pre-existing FIV or FeLV infection, and anecdotal reports suggest a suboptimal response to standard therapy. Estimates of the prevalence of these mycoplasmas within feline populations vary. A recent U.S. study of 310 cats with regenerative anemia found “overall prevalences of Mhm, Mhf, and Mtc [mixed] infection were 23.2% (72/310), 4.8% (15/310), and 6.5% (20/310), respectively” [3]. An internal study performed at Idexx Laboratories, screening samples from 303 cats with a hematocrit less than 25%, found 39 samples (13%), positive for M. haemofelis . “Feline hemoplasmas were detected in a total of 88 samples (or 29%); 13 samples had coinfections with two strains, and seven samples had coinfections with all three strains” [4].

  • M. haemofelis can produce a life-threatening "hemolytic" anemia by provoking an autoimmune attack on the parasitized cells. Various mechanisms have been suggested to explain its pathogenicity, and it is possible that several are involved. Antibody coating that marks cells for destruction is known to take place. One proposal is that phagocytic scavengers called macrophages destroy the cells in the spleen, liver, and bone marrow. It has also been proposed that parasitized red cells sequestered in small blood vessels lose their normal shape, which allows exposure to foreign antigens that incite a hemolytic response. Yet another suggestion is that the red blood cell may be an innocent bystander of complement fixation [5]. The complement system is part of the nonspecific immune response that parallels and can be recruited to aid (“complement”) the antibody response of the specific immune system.

  • Cats infected with M. haemofelis go through four phases of disease -- an asymptomatic phase following initial infection (2-21 days), an acute phase during which clinical signs occur (2-4 months), a recovery phase with mild anemia and minimal clinical signs, and a carrier phase that may last for years [6]. Many cats become lifelong carriers. Symptoms of acute infection include fever of variable magnitude, lethargy, and depression. Onset of symptoms is sometimes slow and progressive, sometimes rapid and usually accompanied by jaundice. Cats at risk for the infection are disproportionately outdoor males since the primary modes of transmission appear to be bloodsucking insects and bites associated with fighting [1]. This, of course, is the same group at risk for FIV. The infection can also be passed from mother to offspring. Younger cats tend to suffer more severe anemia, possibly due to immunological immaturity [2]

  • 2. Diagnosis

  • Diagnosis has historically been difficult because the organisms cannot be cultured due to the lack of a cell wall. Routine bloodwork can be suggestive, but is not conclusive. A complete blood count (see the page “FIV and the CBC”) can assess the extent of the anemia and provide clues to the cause. Reticulocytes are immature red blood cells that are released from the bone marrow when certain regenerative anemias are present, regenerative meaning that the bone marrow retains a capacity to manufacture red cells. A high count of reticulocytes (immature red blood cells) is common with hemobartonella because of the lysis of red cells going on, but may be inapparent at onset of infection before the bone marrow has had adequate time to begin to respond (4 to 7 days) or may be masked by concurrent illnesses that suppress bone marrow. It is particularly important to get a count of aggregate (early immature) reticulocytes for any cat presenting with an unexplained anemia to establish whether or not it is regenerative. However, many CBCs do not report on reticulocytes, so the count must be requested separately. Red cell indices may show a low MCHC [8] (mean cell hemoglobin content) and/or elevated MCV [4] (mean cell volume), the latter because immature cells are larger than mature ones. In the early, acute phase of infection, white cell counts may be normal or mildly elevated, with mild neutrophilia or monocytosis (elevations). Serum chemistries are often unremarkable and may contain features expected with red cell destruction: mild elevations of the liver enzymes ALT and AST, and elevated bilirubin (released into the circulation when red cells are destroyed), which can show in eyes and gums as yellowish jaundice if sufficiently pronounced [6].

  • Specialized testing is called for to nail down a diagnosis of hemobartonellosis. The Coombs Test, a blood test for presence of auto-antibodies, will usually establish whether an immune-mediated process is taking place. In a recent study, only cats infected with M haemofelis (of the three hemobartonella organisms) registered positive Coombs tests [2]. Examination of blood smears by microscopy has been the traditional standard for diagnosis. In fact, CBCs will often carry notations on whether blood parasites were observed by the pathologist, along with notations on unusual red cell types–Howell-Jolly bodies, spherocytes, anisocytosis, polychromasia, and hypochromasia–all of which are characteristic of this type of infection [3][5][7]. The different species of mycoplasmas can be distinguished by microscopy. However, as already noted, cats infected with hemotropic mycoplasmosis alternate phases when parasites are or are not present in the bloodstream in significant numbers. Therefore, a negative test may not be conclusive. Daily sampling may be necessary before organisms can be found. One study found, “Definitive cytological evidence of infection was seen only on blood smears collected between days 25 and 29 from the M. haemofelis-infected cat” [3]. According to Idexx, “the number of infected cells fluctuates quickly (in some cases declining from 90% to less than 1% in under 3 hours) and infection can easily be missed. False positive results are also possible because feline hemotropic mycoplasmas can be difficult to differentiate from precipitated stain, other drying or fixation artifacts, poorly staining Howell-Jolly bodies, basophilic stippling, iron-positive inclusions, Cytauxzoon felis organisms and small Babesia organisms” [4].

  • Fortunately, PCR technology, which looks for binding of pathogen DNA with a known test DNA, can verify even trace amounts of mycoplasma DNA in blood samples. PCR not only detects the presence of M haemofelis, but quantifies the result, allowing monitoring of response to treatment [3]. An in-house study by Idexx found that of 303 samples evaluated by routine microscopic examination, 10 contained M. haemofelis. “All 10 of these samples were positive for M. haemofelis by IDEXX RealPCR. In addition, 29 additional samples, for a total of 39 samples or 13%, were positive for M. haemofelis by IDEXX RealPCR. . . . PCR is up to 10 times more sensitive than microscopic evaluation and will have a significant impact on the diagnosis of feline hemotropic mycoplasmosis” [4].

  • 3. Connection to FIV

  • The relation of M. haemofelis to FIV has been a subject of some disagreement; an association with FeLV is more broadly recognized. A 2006 Swiss study found that retroviral infections generally (including FeLV and FIV) did not increase the prevalence of infection, and noted that retroviral infection was similarly prevalent in healthy and ill cats found positive for these mycoplasmas [1]. Another 2006 article published in Veterinary Microbiology found no meaningful difference in the blood chemistries of FIV+ and FIV- cats deliberately infected with M. haemofelis [14]. The Marvistavet site associates M. haemofelis only with FeLV and claims (without source citation) that FIV does not enhance the severity of hemotropic mycoplasma infection [13].

  • The preponderance of opinion, however, points to an association. HIV, it should be noted, has a strong association with the human-infecting counterpart of M haemofelis. Antech lists an association with FIV infection [8]. A 2004 review calls it a pathogen in conjunction with retroviruses, FIV as well as FeLV, a connection stated again in a 2007 German study [9]. Another review for the 27th WSAVA Congress states that concurrent infection with FeLV, FIP, and FIV will worsen the anemic state [10]. Recent studies in the U.S., Brazil [11], New Zealand [12], and Portugal [12a] have all found a marked statistical correlation of mycoplasma infection and FIV. A 2012 study concludes that "Chronic FIV infection appears to modify the acute phase response to feline haemotropic mycoplasmas" [20, Korman].

  • The 2004 review notes that "an acute and life-threatening exacerbation of hemolytic anemia in carrier animals may be activated by concurrent disease, stress, and immunosuppression" [9]. This reactivation threat has a familiar ring (See the “FIV and Toxoplasmosis” page). Human AIDS patients have been shown to be at special risk for various problems as a result of infection with a human variety of this type of organism. M. haemofelis as a reactivated infection in cats with FIV has never been studied.

  • 4. Treatment

  • M. haemofelis is treated with glucocorticoids and antibiotics, though the former is somewhat controversial. If infection is suspected but diagnosis is uncertain or pending, prophylactic treatment is prudent if symptoms are severe. In a recent studies, both Marbofloxicin (2 mg/kg PO q24 h) [14] and Enrofloxacin (5 mg/kg POd q24) [15] showed significant activity against M. haemofelis. In an earlier trial, azithromycin did not [16]. Doxycycline has been regarded as the antibiotic of choice. “Doxycycline has less side effects than other tetracyclines in cats and so is preferred. Doxycycline should be given at 10 mg/kg, PO, every 24 hours for at least 14 days. If administered for 28 days, more cats appear to stay persistently PCR negative” [17]. Imidocarb dipropionate (5 mg/kg, IM, every 2 weeks for at least 2 injections) has been used successfully when other drugs have failed [18]. “If autoagglutination [clumping of red cells due to antibody cross-linking] is evident, prednisolone is usually prescribed at 1 mg/kg, PO, every 12 hours for the first 7 days or until autoagglutination is no longer evident. Tetracyclines utilized to date appear to lessen parasitemia and clinical signs of disease but probably do not clear the organism from the body. In one study, experimentally infected cats treated with doxycycline have apparent clinical response but the organism could still be detected by PCR when the cats were given methylprednisolone acetate” [17]. In a new (2009) head-to-head study with doxycycline, a new quinolone antibiotic, Pradofloxacin, “ had anti-M hemofelis effects similar to those of doxycycline. In addition, pradofloxacin may be more effective at long-term M hemofelis organism clearance than doxycycline” [19]. Blood transfusion can be given if clinically indicated.

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  • References

  • [1] Barbara Willi, Felicitas S. Boretti, Claudia Baumgartner, Séverine Tasker, Bettina Wenger, Valentino Cattori, Marina L. Meli, Claudia E. Reusch, Hans Lutz, and Regina Hofmann-Lehmann. Prevalence, Risk Factor Analysis, and Follow-Up of Infections Caused by Three Feline Hemoplasma Species in Cats in Switzerland. Journal of Clinical Microbiology, March 2006, p. 961-969, Vol. 44, No. 3.
  • http://jcm.asm.org/cgi/content/full/44/3/961

  • [2] Tasker S, Peters IR, Papasouliotis K, Cue SM, Willi B, Hofmann-Lehmann R, Gruffydd-Jones TJ, Knowles TG, Day MJ,a and Helpsa CR. Description of outcomes of experimental infection with feline haemoplasmas: Copy numbers, haematology, Coombs' testing and blood glucose concentrations. Vet Microbiol. 2009 November 18; 139(3-4): 323-332.
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771275/?tool=pubmed

  • [3] 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. Jour Clin Microbiology Jan. 2003, p. 439–441 Vol. 41, No. 1.
  • http://jcm.asm.org/cgi/reprint/41/1/439.pdf

  • [4] IDEXX RealPCR™ Feline Hemotropic Mycoplasma (FHM) Test (formerly Haemobartonella), from IDEXX Reference Laboratories. Diagnostic Update IDEXX Reference Laboratories • June 2007.
  • http://www.idexx.com/pubwebresources/pdf/en_us/smallanimal/reference-laboratories/diagnostic-updates/realpcr-fhm-test.pdf

  • [5] Galvan S. Feline Hemothrophic Mycoplasmosis, A case of Mycoplasma haemofelis in a domestic short hair. Cornell University College of Veterinary Medicine. October 27, 2004.
  • http://dspace.library.cornell.edu:8080/bitstream/1813/13669/2/Galvan_Stephanie_paper_2004.pdf

  • [6] Plotnick A. Feline Infectious Anemia (Hemobartonellosis).
  • http://www.petplace.com/cats/feline-infectious-anemia-hemobartonellosis/page1.aspx

  • [7] Ukaszewska, J., Popiel, J., Zawadzki W, Medycyna Weterynaryjna. Mycoplasma haemofelis (Hemobartonella felis) - cause of anaemia in cats.
  • http://www.cababstractsplus.org/abstracts/Abstract.aspx?AcNo=20043205746

  • [8] Antech Diagnostics. News, July 2003.
  • http://www.antechdiagnostics.com/clients/antechnews/2003/jul03_01.htm.

  • [9] Just F, Pfister K. Frequency of haemoplasma infections of the domestic cat in Germany [Article in German.] Berl Munch Tierarztl Wochenschr. 2007 May-Jun;120(5-6):197-201.
  • http://www.ncbi.nlm.nih.gov/pubmed/17555038

  • [10] Remo Lobetti. Infectious Causes of Anaemia. 27th WSAVA Congress.
  • http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2002&PID=2594

  • [11] Macieira DB, de Menezes RD, Damico CB, Almosny NR, McLane HL, Daggy JK, Messick JB. Prevalence and risk factors for hemoplasmas in domestic cats naturally infected with feline immunodeficiency virus and/or feline leukemia virus in Rio de Janeiro - Brazil. J Feline Med Surg. Sep 29, 2007, 372-79.
  • http://www.ncbi.nlm.nih.gov/pubmed/17905624

  • [12] Jenkins KS, Dittmer KE, Marshall JC, Tasker S.J Feline. Prevalence and risk factor analysis of feline haemoplasma infection in New Zealand domestic cats using a real-time PCR assay. Med Surg. 2013 May 10. [Epub ahead of print]
  • http://www.ncbi.nlm.nih.gov/pubmed/23666110

  • [12a] Duarte A, Marques V, Correia JH, Neto I, Braz BS, Rodrigues C, Martins T, Rosado R, Ferreira JP, Santos-Reis M, Tavares L. Molecular detection of haemotropic Mycoplasma species in urban and rural cats from Portugal. J Feline Med Surg. 2014 Sep 16.[Epub ahead of print]
  • http://www.ncbi.nlm.nih.gov/pubmed/25228167

  • [13] http://www.marvistavet.com/html/body_feline_infectious_anemia.html.

  • [14] Tasker S, Caney SM, Day MJ, Dean RS, Helps CR, Knowles TG, Lait PJ, Pinches MD, Gruffydd-Jones TJ. Effect of chronic FIV infection, and efficacy of marbofloxacin treatment, on Mycoplasma haemofelis infection. Vet Microbiol, 2006 Jul 27, np.
  • http://www.unboundmedicine.com/medline/ebm/record/16876338/abstract/
  • Effect_of_chronic_FIV_infection_and_efficacy_of_marbofloxacin_treatment_on_Mycoplasma_haemofelis_infection

  • [15] 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. J Microbiol Methods. 2004 Jan;56(1):63-71.
  • http://www.ncbi.nlm.nih.gov/pubmed/14706751

  • [16] Westfall DS, Jensen WA, Reagan WJ, Radecki SV, Lappin MR. Inoculation of two genotypes of Hemobartonella felis (California and Ohio variants) to induce infection in cats and the response to treatment with azithromycin. Am J Vet Res. 2001 May;62(5):687-91.
  • http://www.ncbi.nlm.nih.gov/pubmed/11341386

  • [17] Michael R. Lappin. Haemobartonellosis. 29th WSAVA Congress.
  • http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA2004&PID=8682&O=Generic

  • [18] Lappin MR, Foster A, Geitner K, et al. Imidocarb diproprionate for the treatment of recurrent haemobartonellosis in cats. J Vet Int Med 2002;16:364.
  • http://www.veterinarytherapeutics.com/Media/PublicationsArticle/VTX_03_02_144.pdf

  • [19] Dowers KL, Tasker S, Radecki SV, Lappin MR. Use of pradofloxacin to treat experimentally induced Mycoplasma hemofelis infection in cats. Am J Vet Res. 2009 Jan;70(1):105-11.
  • http://www.ncbi.nlm.nih.gov/pubmed/19119955

  • [20] Korman RM, Cerón JJ, Knowles TG, Barker EN, Eckersall PD, Tasker S. Acute phase response to Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' infection in FIV-infected and non-FIV-infected cats. The Veterinary Journal 2012; 193(2) 433-438.
  • http://www.ncbi.nlm.nih.gov/pubmed/22763129
  • George JW, Rideout BA, Griffey SM, Pedersen NC. Effect of preexisting FeLV infection or FeLV and feline immunodeficiency virus coinfection on pathogenicity of the small variant of Haemobartonella felis in cats. American Journal of Veterinary Research 2002;63(8) 1172-1178.
  • http://www.ncbi.nlm.nih.gov/pubmed/12171173

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