Feline infectious anemia in Cats (Felis) | Vetlexicon
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Feline infectious anemia

ISSN 2398-2950


Synonym(s): anaemia, haemotrophic

Introduction

  • Cause: hemotropic bacteria known as hemoplasmas (Mycoplasma haemofelisCandidatus Mycoplasma haemominutum, 'Candidatus Mycoplasma turicensis'). The protozoal parasite (Babesia felis) causes similar disease in some parts of the world (eg South Africa).
  • Signs: changes consistent with immune-mediated hemolytic anemia (eg lethargy, inappetence, depression, pallor, tachycardia, tachypnea) and inflammation (fever).
  • Diagnosis: hematology plus PCR confirmation of organisms (ideal) or demonstration of intracellular parasites on blood smear (less ideal).
  • Treatment: antimicrobials - doxycycline or fluoroquinolones (eg marbofloxacin, pradofloxacin).
  • Prognosis: good unless immunosuppressed.
    Print off the owner factsheet on Feline Infectious Anemia (FIA) Feline Infectious Anemia (FIA) to give to your client.

Background

  • Hemoplasmas (the generic name for the hemotropic mycoplasmas) were re-classified into the genus Mycoplasma from order Rickettsiales genera Haemobartonella and Eperythrozoon based on DNA sequence data. In cats, the more pathogenic large form of Haemobartonella felis (also known as Ohio / Florida / Illinois / Oklahoma variant) was reclassified as M. haemofelis, and the less pathogenic small form of Haemobartonella felis (also known as California / Birmingham variant) was reclassified as ‘Candidatus M. haemominutum’.
  • They are uncultivatable, wall-less (hence Gram-stain negative), obligate parasites of the mammalian red blood cell (RBC). During acute infection they can result in direct or indirect damage to RBC leading to anemia. Presence of a chronic hemoplasma carrier state (particularly with ‘Candidatus M. haemominutum’) has limited association of risk factors with clinical signs of anemia.

Presenting signs

  • Lethargy / weakness / depression / collapse.
  • Inappetence / anorexia.
  • Pallor +/- jaundice.
  • Tachycardia, tachypnea.
  • Fever.
  • Dehydration.

Acute presentation

  • Variable; collapse with subnormal temperature in the most severe cases.

Geographic incidence

  • Worldwide.

Pathogenesis

Etiology

Transmission

  • Common natural route of transmission undetermined.
  • Horizontal transmission through aggressive interactions (bites) suspected, but experimental studies using subcutaneous inoculation of saliva or blood from infected cats showed limited success at transmitting infection.
  • Cat fleas, Ctenocephalides felis Ctenocephalides felis, are suspected play a role, at least in some cases, but experimental studies have not provided strong support that this is a common route.
  • Ticks are thought to provide a common route of hemoplasmas transmission in dogs, and feline hemoplasmas have been detected in ticks; however, experimental studies into the role of ticks in the transmission of hemoplasmas in cats have not been performed.
  • Blood transfusion Blood transfusion of infected blood is an iatrogenic route of transmission.
  • Vertical transmission suggested in early reports, and for other host species.

Predisposing factors

General

  • There is conflicting evidence on the importance of these factors.
  • May affect cats with some degree of immune compromise:
    • Stress (pregnancy, neoplasia, concurrent infection).
    • Immunosuppression, eg FeLV, FIV,  immunosuppressive drugs.
    • Splenectomy (clinically less important than in dog).
    • May be primary pathogen in some cases.

Pathophysiology

  • Infection with wall-less (Gram stain-negative) bacteria of different pathogenicities:
    • M. haemofelis is most pathogenic.
    • Candidatus M. haemominutum’ rarely causes clinical disease in the absence of comorbidities.
    • Candidatus M. turicensis’ appears to be of intermediate pathogenicity, but generally clinical disease is uncommon.
  • Hemoplasmas parasitize the surface of RBC → shorter RBC lifespan (hemolysis or splenic sequestration) → anemia:
    • RBC membrane damaged at site of hemoplasma binding.
    • Bystander damage.
  • Antibodies against the RBCs may be induced leading to immune-mediated hemolysis as evidenced by auto-agglutination or a positive Coombs test result (but these are detectable after the onset of anemia).
  • Clearance of parasite can occur in the spleen without loss of red cell, allowing cells to return to the circulation. This may explain the rapid recovery from clinical signs and increase the PCV following treatment, sometimes without evidence of reticulocytosis.
  • Acute M. haemofelis infection can result in cyclical changes in hematocrit in some cats.

Timecourse

  • In experimental studies hemoplasmas can be detected from 2 days post-inoculation with anemia typically occurring from two weeks post-inoculation (but can be much shorter at 5 days).
  • Animals may be chronically infected (carrier state).
  • Relapse of infection (as evidenced by increased hemoplasma numbers and decreased hematocrit) may occur in times of stress or treatment with immunosuppressive agents (eg methylprednisolone acetate), but this typically does not result in clinical signs.

Diagnosis

Presenting problems

  • Anemia.
  • Pyrexia which may be intermittent.

Client history

  • Lethargy / weakness / depression / collapse.
  • Inappetence / anorexia / weight loss.

Clinical signs

  • Weakness / depression / collapse.
  • Weight loss.
  • Pallor occasionally with mild jaundice.
  • Tachycardia, tachypnea, heart murmur (due to anemia).
  • Fever, or subnormal temperature in acute collapse.
  • Dehydration.
  • Splenomegaly.

Diagnostic investigation

Clinical signs are not pathognomonic for FIA. Anemia should be confirmed and characterized (regenerative vs. non-regenerative; presence / absence of auto-antibodies). Presence of hemoplasmas should be confirmed, and infecting agent speciated. Presence of co-morbidities (eg retroviral infection; neoplasia) should be investigated.

Hematology

Serology

  • Hemoplasmas serological assays are only currently available for research / experimental cases Serology.
  • Assessment of FeLV FeLV test and FIV FIV test status is useful.

Serum biochemistry

Urinalysis

  • Rarely hemoglobinuria.

Confirmation of diagnosis

  • Demonstrate presence of anemia, alongside presence of hemoplasma infection (particularly M. haemofelis), and positive response to appropriate antibiotics.

Confirmation of hemoplasma infection

  • Polymerase chain reaction PCR (Polymerase chain reaction):
    • More sensitive than direct visualization of the organism on blood smears.
    • Can detect organisms one day post-inoculation.
    • Some assays are quantitative ‘real-time’ PCRs (useful for monitoring response to treatment).
    • Infecting hemoplasma species and co-infections can be determined.
    • Can get negative result if cat is on antibacterial treatment at time of sampling.
    • Negative PCR result during treatment does not indicate cure, ie some cats will be PCR-positive after antibiotics are withdrawn.
    • Around 10% of healthy cats are PCR positive for ‘Candidatus M. haemominutum’. A positive PCR result only confirms presence of the organism and causality of clinical signs present.
  • Direct visualization of the organism on blood smears:
    • Small cocci or (rarely) ring forms on the surface of RBCs .
    • Dark purple-colored hemoplasmas are seen against the blue-colored RBC on Giemsa (Staining techniques: Giemsa) or Toluidine Blue stained thin blood smear.
    • Orange-red colored hemoplasmas on acridine orange stained thin blood smear when viewed by fluorescent microscopy.
    • False positives may occur, particularly if inexperienced, decreasing specificity.
      • Artifact - stain debris.
      • Mis-identification of RBC changes - Howell Jolly bodies .
    • False negatives are common, making sensitivity poor:
      • Blood smears should be made from fresh blood or from EDTA blood within an hour of sampling.
      • Parasites appear in blood intermittently and can be cleared in a few hours of starting treatment.
      • High concentrations of EDTA or prolonged exposure (>12 hours) to concentrations of EDTA found in standard blood tubes will cause release of organisms from the RBC surfaces.
      • Candidatus M. turicensis’ organism numbers are so low they are not seen using light microscopy, even during peak parasitemia.

Gross autopsy findings

  • Tissue pale and/or jaundiced.

Histopathology findings

  • Reactive hyperplasia of lymphoid tissue.
  • Hepatocellular cholestasis.
  • Splenic hemosiderin deposits.

Differential diagnosis

Treatment

Standard treatment

Supportive care

  • Fluid therapy to correct fluid deficits (Fluid therapy: overview).
  • Blood transfusion (Anemia: transfusion indications) if clinically required - usually when PCV <0.10 l/l, but can be needed at higher PCV if onset of anemia was rapid.
  • Prednisolone (Prednisolone) 2 mg/kg PO SID (tapering course) may be indicated but is controversial:
    • Most cats with FIA clinically improve with antibiotics and supportive care (eg fluids, blood) even when severely affected.
    • Reserve for severely affected cats, particularly those with an immune-mediated component (eg auto-agglutination or Coombs’ positive).
    • May limit further investigation of co-morbidities, eg neoplasia.

Specific therapy for FIA

  • Antibiotics are typically administered for 2-4 weeks.
  • Doxycycline (Doxycycline) 10 mg/kg PO SID (+/- as divided dose BID):
    • Risk of esophagitis and esophageal stricture if incomplete swallowing.
    • Follow with food or 5 ml water to promote complete swallowing.
    • Doxycycline monohydrate paste is less acidic cf. doxycycline hyclate tablets, potentially reducing the risk of esophageal damage.
  • Oxytetracycline is not recommended due to superior properties of doxycycline (ie it requires less frequent administration and can be given with food).
  • Fluoroquinolones:
    • Marbofloxacin (Marbofloxacin) 2 mg/kg PO SID.
    • Pradofloxacin (Pradofloxacin) 5 mg/kg PO SID.
    • Enrofloxacin (Enrofloxacin) should not be used where doxycycline or other fluoroquinolones are available due to the risk of irreversible retinal damage and blindness. Dose should not exceed 5 mg/kg SID.
Antibiotic resistance has been suspected in other species with hemoplasma infections. Consider switch of antibiotic class if M. haemofelis organism numbers do not decrease on treatment.
  • Clearance protocol for M. haemofelis:
    • Doxycycline (5 mg/kg PO BID for 4 weeks) → quantitative PCR (performed in triplicate to increase sensitivity, on multiple sampling occasions).
    • If organisms still detectable → marbofloxacin (2 mg/kg PO SID for 2 weeks).
Neither drug is licensed for the treatment of hemoplasmas and the courses are relatively long.

Monitoring

  • Hematology/PCV for resolution or recurrence of anemia.
  • Quantitative PCR to monitor for clearance of the organisms. 
  • Checking in-contact cats for the parasite is unlikely to be helpful as a routine (ie in most cases treatment would not be indicated if clinically normal).
  • Blood donors:
    • Should be checked for hemoplasma infection by PCR during initial screening, and periodically thereafter.
    • Any cats that are currently or historically have been infected with hemoplasmas should not be used as blood donors.

Prevention

Outcomes

Prognosis

  • Good, depending on presence of co-morbidities.
  • Many cats remain infected life-long (carriers) but may be clinically normal; long-term consequences of this are unknown.
  • Infection with one hemoplasma does not confer protection against future infection with a different species of hemoplasma; however, it does appear to confer protection against re-challenge with the same species of hemoplasma.

Expected response to treatment

  • Increasing PCV.
  • Improving demeanor.
  • Response to antibiotics is suspected to vary between species:
    • Most antibiotic treatment studies have focused on M. haemofelis.
    • Only transient reductions in organism numbers for ‘Candidatus M. haemominutum’ were seen following marbofloxacin administration in one study.
    • In a small number of cats, doxycycline was most effective at clearing infection with ‘Candidatus M. turicensis’.
  • Clearance of infection:
    • May occur spontaneously some months after clinical signs have resolved, more likely for M. haemofelis than ‘Candidatus M. haemominutum’.
  • Antibiotic combination protocols may be considered to clear infection in cats infected with M. haemofelis.

Zoonotic implications

  • Zoonotic M. haemofelis infection has been described in an immunocompromised man (HIV-positive; concurrent Bartonella henselae infection):
    • Source of infection was suspected to have been one of the M. haemofelis-infected cats in the household.
    • Scratches and bites reported but route of transmission remains unknown.
  • Minimize risk of potential transmission, particularly with known immunocompromised clients / vets:
    • Avoid aggressive interactions.
    • Arthropod prophylaxis sensible, although arthropod-vectored transmission unproven.

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Novacco M, Sugiarto S, Willi B et al (2018) Consecutive antibiotic treatment with doxycycline and marbofloxacin clears bacteremia in Mycoplasma haemofelis-infected cats. Vet Microbiol 217, 112-20 PubMed.
  • Tasker S, Hofmann-Lehmann R, Belák S et al (2018) Haemoplasmosis in cats: European guidelines from the ABCD on prevention and management. J Feline Med Surg 20 (3), 256-61 PubMed.
  • Baumann J, Novacco M, Willi B et al (2015) Lack of cross-protection against Mycoplasma haemofelis infection and signs of enhancement in “Candidatus Mycoplasma turicensis”-recovered cats. Vet Res 46, 104 PubMed.
  • Hicks C A, Willi B, Riond B et al (2015) Protective Immunity against Infection with Mycoplasma haemofelis. Clin Vaccine Immunol 22 (1), 108-118 PubMed.
  • Dowers K L, Tasker S, Radecki SV et al (2009) Use of pradofloxacin to treat experimentally induced Mycoplasma haemofelis infection in cats. Am J Vet Res 70 (1), 105-111 PubMed.
  • Museux K, Boretti F S, Willi B et al (2009) In vivo transmission studies of 'Candidatus Mycoplasma turicensis' in the domestic cat. Vet Res 40 (5), 45 PubMed.
  • Dean R S, Helps C R, Gruffydd-Jones T J et al (2008) Use of real-time PCR to detect Mycoplasma haemofelis and Candidatus Mycoplasma haemominutum in the saliva and salivary glands of haemoplasma-infected cats. J Feline Med Surg 10 (4), 413-417 PubMed.
  • Peters I R, Helps C R, Willi B et al (2008) The prevalence of three species of feline haemoplasmas in samples submitted to a diagnostics service as determined by three novel real-time duplex PCR assays. Vet Microbiol 126 (1-3), 142-150 PubMed.
  • dos Santos A P, dos Santos R P, Biondo A W et al (2008) Hemoplasma infection in HIV-positive patient, Brazil. Emerg Infect Dis 14 (12), 1922-1924 PubMed.
  • Tasker S, Caney S M, Day M J et al (2006) Effect of chronic FIV infection and efficacy of marbofloxacin treatment on Mycoplasma haemominutum infection. Microbes and Infection 117 (2-4), 169-79 PubMed.
  • Woods J E, Wisnewski N, Lappin M R (2006) Attempted transmission of 'Candidatus Mycoplasma haemominutum' and Mycoplasma haemofelis by feeding cats infected Ctenocephalides felis. Am J Vet Res 67 (3), 494-497 PubMed.
  • Willi B, Boretti F S, Cattori V et al (2005) Identification, molecular characterisation and experimental transmission of a new haemoplasma isolate from a cat with haemolytic anemia in Switzerland. J Clin Microbiol 43 (6), 2581-2585 PubMed.
  • Foley J E, & Pedersen N C (2001) Candidatus Mycoplasma haemominutum, a low-virulence epierythrocytic parasite of cats. Int J Syst Evol Microbiol​ 51 (Pt 3), 815-817 PubMed.