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REVIEW ARTICLE
Haemobartonella felis: recent developments in
diagnosis and treatment
S Tasker1*, MR Lappin2
1
The Feline Centre, Clinical Haemobartonella felis is a pleomorphic uncultivated wall-less haemotrophic
Veterinary Science, University bacterial parasite. Phylogenetic analysis of 16S rRNA gene sequences from a
of Bristol, Langford, Bristol number of isolates of H felis has demonstrated that these bacteria are most
BS40 5DU, UK; 2CVMBS-VTH, closely related to species in the genus Mycoplasma, and Haemobartonella and
Clinical Sciences, Colorado State related organisms are currently being reclassified as Mollicutes. Diagnosis by
University, 300 W. Drake Road, cytological examination of blood smears has been problematic, but recent
Fort Collins, CO 80523, USA molecular studies have led to the development of sensitive polymerase chain
reaction (PCR) assays for diagnosis. Such studies have also resulted in the
recognition of two distinct strains of H felis, which are divided into different
groups based on phylogenetic analysis. This evolutionary divergence between
strains is accompanied by differences in pathogenecity. This review discusses
new developments in the diagnosis and treatment of H felis, focusing on the
Date accepted 1 October 2001 use of, and interpretation of, PCR assays. © 2002 ESFM and AAFP
I
n 1942 Clark described an eperythrozoon pathogenicity of this organism. Analysis of the
infection in an anaemic cat in South Africa 16S rRNA gene of several H felis isolates has led
naming the species Eperythrozoon felis. Flint & to the discovery of its evolutionary relatedness
Moss (1953) later described a similar organism to members of the Mollicutes rather than the
causing an infectious anaemia in cats in the USA. Rickettsiales (Johansson et al 1999, Neimark &
In 1955, Flint & McKelvie suggested that this Kocan 1997, Rikihisa et al 1997) and reclassifica-
organism be named Haemobartonella felis. tion of the organism has been recommended. In
Haemobartonella felis is now recognised world- situ hybridisation studies (Berent et al 2000) have
wide (Anderson & Charleston 1967, Bedford physically linked H felis DNA sequences to areas
1970, Bobade & Akinyemi 1981, Clark 1942, of known cellular pathology on feline erythro-
Espada et al 1991, Flagstad & Larsen 1969, cytes. Similarly the presence of H felis DNA
Hatakka 1972, Maede et al 1974, Manusu 1961, coincides with experimental infection (Berent
Mrljak et al 1995, Prieur 1960, Seamer & Douglas et al 1998) and the amount of DNA is correlated
1959, Théry 1966) although studies describing with the number of organisms present in the
the prevalence of infections in cats in different blood (Cooper et al 1999). These molecular find-
parts of the world have been sparse. Despite it ings have proven that H felis is the cause of feline
being a major cause of anaemia in cats there is infectious anaemia. Recent molecular work also
still a paucity of information available regarding documents the existence of different strains
its epidemiology and the disease it causes. One (Berent et al 1998, Foley et al 1998, Messick et al
of the major factors limiting the investiga- 1998, Rikihisa et al 1997) that may ultimately
tion of this organism is that it has not yet been prove to be different Haemobartonella species.
successfully cultivated outside the host. Since H felis cannot be cultured, diagnosis of
However, recent molecular studies have infection until recently was primarily based on
advanced our understanding of the nature and cytological identification of organisms on the
surface of red blood cells. However, there are
*Corresponding author E-mail: s.tasker@bristol.ac.uk various factors resulting in false positive and
Fig 2. Wright-Giemsa stained blood smear (original magnification ×400) showing H felis bodies on approximately 65% of
erythrocytes. Ring forms of H felis are visible (large arrows). Larger and more densely staining Howell–Jolly bodies can be
seen (small arrows) for comparision.
Recent developments in Haemobartonella felis 5
0.03
E coli
E wenyonii
329
E erythrodidelphis
588
H felis
Birmingham
1000 1000
H felis
California
E suis
999
H muris
H felis
Oklahoma
496
993
H felis
501 Illinois
1000
H felis
Ohio-Florida
1000
H canis
M fastidiosum
1000
M cavipharyngis
M felis
Fig 4. Phylogenetic tree comparing the available Haemobartonella felis sequences and the related organisms Eperythrozoon
wenyonii, Eperythrozoon erythrodidelphis, Eperythrozoon suis, Haemobartonella muris, Haemobartonella canis, Mycoplasma
fastidiosum, Mycoplasma cavipharyngis and Mycoplasma felis. Escherichia coli is shown for reference. The numbers at each node
indicate the number of times the groups to the right of the node occurred among 1000 trees. The bar represents the mean
number of differences per site.
8 S Tasker, MR Lappin
(18%) but very few cats were infected with the Splenomegaly and lymphadenopathy may
large strain precluding statistical evaluation of occur, reflecting extramedullary haematopoiesis.
an association between the large strain and anae- Icterus, due to haemolysis, is occasionally seen.
mia. Small strain infection in the UK was com- H felis infection typically causes a regenerative
mon and was not associated with the presence of anaemia with reticulocytosis, anisocytosis,
anaemia. Further studies are required to deter- macrocytosis and polychromasia. The severity of
mine whether geographical variation in the anaemia depends on the stage of infection but
prevalence of H felis infection, including the the haematocrit usually falls to less than 20%,
different strains, exists. with average values of 15–18% reported (Foley et
PCR was shown to be more sensitive than al 1998, VanSteenhouse et al 1993). Normoblasts
examination of blood smears in the detection of may also be visible and, although these can be a
H felis in several studies. As previously dis- feature of diseases which are not associated with
cussed, Westfall et al (2001) found that only regenerative anaemias, H felis was found to be
37.5% of samples were positive on cytopathology the most common cause of normoblastaemia
after experimental infection compared to 100% in a recent retrospective study (Hammer &
positivity with PCR. H felis can be detected by Wellman 1999). Non-regenerative anaemias due
PCR as early as 8 days post-infection and cats to haemobartonellosis have also been reported
remain PCR positive until antibiotic treatment is (VanSteenhouse et al 1993).
started. Cats then remain negative by PCR for
the duration of antibiotic treatment, but become
Treatment
positive again between 3 days and 5 weeks after
completion of the antibiotic course (Berent et al Haemobartonella spp are sensitive to tetracyclines
1998, Foley et al 1998). Blood samples for H felis which specifically inhibit protein synthesis in
PCR should therefore not be submitted during procaryotes. Tetracycline and oxytetracycline can
antibiotic treatment. Subclinically infected cats both cause drug-induced pyrexia (Wilkinson
remain PCR positive for at least 6 months, long 1968) in cats and require three times daily
after clinical signs of disease have resolved. dosing, which may be problematic. The preferred
Additionally, 14.5% of normal, naturally exposed tetracycline derivative used is doxycycline
cats in a US study (Jensen et al 2001) and 10% of due to fewer side effects and less frequent
healthy cats in a UK study (Tasker et al 2001b) dosing. The recommended doxycycline dose is
were positive for H felis by PCR. Thus, it is 5–10 mg/kg per os once daily. Therapy should
apparent that a positive PCR result does not be continued for 14 to 21 days depending on
equate with clinical disease, making interpret- response to treatment. As mentioned above, PCR
ation of results problematic. A positive PCR has demonstrated that although the tetracyclines
result should be interpreted in line with the are effective for the treatment of anaemia, treat-
strain identified, the haematological findings and ment does not eliminate the causal organism
clinical signs reported. (Berent et al 1998, Foley et al 1998). Enrofloxacin
has been recommended by some (Winter 1993)
for the treatment of haemobartonellosis at a dose
Clinical signs and haematology features
of 10 mg/kg per os daily for at least 14 days.
Previous reports that uncomplicated H felis Fluoroquinolones are said to have activity
infection caused few or no clinical signs (Bobade against mycoplasmal organisms but further
et al 1988, Seamer & Douglas 1959) may have study into their effectiveness against H felis is
reflected infection with an H felis small strain of warranted before a recommendation can be
low pathogenicity (Foley et al 1998). Chronically made. The macrolide azithromycin, which is
infected cats are usually clinically normal (Berent effective for the treatment of several Mycoplasma-
et al 1998). In other studies, a severe haemolytic associated syndromes in humans, was recently
anaemia occurred in all infected cats (Flint et al found to be ineffective in the treatment of haemo-
1958, Foley et al 1998), most probably due to a bartonellosis at one dose regime (15 mg/kg per
pathogenic large strain. Clinical signs seen in ill os twice daily) (Westfall et al 2001).
cats are non-specific but include those typically The anaemia induced by H felis is thought to
associated with anaemia such as pallor and be, in part, immune-mediated so glucocorticoids
lethargy, as well as anorexia, weight loss and may be indicated (VanSteenhouse et al 1993). It
depression. Intermittent pyrexia is often seen, is important that concurrent diseases such as
particularly in the acute stages of the disease. toxoplasmosis, which could be exacerbated by
Recent developments in Haemobartonella felis 9
the use of glucocorticoids, are ruled out first cally infected cats, all blood donor cats from
(Hoskins & Barta 1984). Some advocate the use areas where haemobartonellosis occurs, should
of glucocorticoids only if the anaemia is pro- be screened by PCR if possible.
nounced or acute in onset and/or autoagglutina- (5) Treatment of healthy cats is not recom-
tion is present (Carney & England 1993). The mended at this time since no drug or protocol
recommended dose of prednisolone is 2 mg/kg have been shown to clear the body of the
per day per os, alongside antibiotic therapy, with organism.
a tapering of dosage over 3 weeks. The value of (6) The currently recommended first line treat-
glucocorticoids in the treatment of H felis has ment is doxycycline at a dose of 5–10 mg/kg per
not yet been evaluated. However, cats with os once daily for 14 to 21 days depending on
experimentally induced haemobartonellosis response to treatment.
have apparently responded to tetracycline
derivatives (with or without supportive treat-
ment) without the use of glucocorticoids (Berent Conclusions
et al 1998, Foley et al 1998). In recent years molecular studies have suggested
Supportive care including whole blood trans- reclassification of H felis into the Mollicutes fam-
fusion may be required in severely anaemic cats. ily and enabled the development of diagnostic
Cats tolerate anaemia well but if the anaemia is PCR assays. The discovery of different H felis
severe (haematocrit less than 12%) or if the PCV strains which vary so greatly in pathogenicity
has dropped rapidly, a blood transfusion may be means that the interpretation of a positive PCR is
necessary. Feline blood transfusions should only not straight forward, and confirming that H felis
be performed with typed or cross-matched is the cause of clinical disease is difficult. In the
recipient and donor blood to avoid potentially future, research should focus on looking into the
fatal blood transfusion reactions. existence of additional H felis strains and how
It has not been definitely documented that effective PCR is in detecting different strains, and
H felis is transmitted by fleas but it has been determining whether geographical variation in
suggested that they are a major vector for H felis prevalence of different strains exists. The patho-
transmission. Since it is known that H felis can be genesis of such strains also needs further inves-
transmitted by inoculation of infected blood, it tigation, in particular with respect to interaction
seems wise to recommend thorough flea control with other feline diseases, and the host response
to potentially lessen the risk of a cat acquiring to H felis infection.
haemobartonellosis.
Based on studies to date, several recommenda-
tions concerning testing methods and when to Addendum
administer antibiotics with anti-Haemobartonella Since this article was submitted for publication
activity can be made. (26 February 2001), the official reclassification of
H felis within the genus Mycoplasma has been
(1) If a cat has clinical findings consistent with proposed in two reports. It is suggested that the
haemobartonellosis and H felis is detected cyto- small strains (California and Birmingham) are
logically or DNA is detected by PCR (either renamed as ‘Candidatus Mycoplasma haemo-
strain), treatment is indicated. minutum’ whilst the large strains (Ohio/
(2) If cytology is the only test available and Florida, Illinois and Oklahoma) are renamed
is negative in a cat with a high index of as ‘Candidatus Mycoplasma haemofelis’. The
suspicion for haemobartonellosis (such as Candidatus classification indicates that this is a
unexplained haemolytic anaemia), the cat should provisional status for the organism until further
be treated due to a high incidence of false phenotypic and genotypic information is
negative cytological results. available.
(3) In experimental studies, DNA can usually be Foley JE, Pedersen NC (2001) ‘Candidatus
detected by PCR prior to clinical signs of disease. Mycoplasma haemominutum’, a low-virulence
Thus, if PCR results on blood collected prior to epierythrocytic parasite of cats. International
treatment are negative, the cat probably does not Journal of Systematic and Evolutionary Microbiology
have haemobartonellosis and other differential 51, 815–817.
diagnoses should be considered. Neimark H, Johansson KE, Rikihisa Y, Tully JG
(4) Since H felis can be transmitted by blood, and (2001) Proposal to transfer some members of
cytology is commonly falsely negative in chroni- the genera Haemobartonella and Eperythrozoon to
10 S Tasker, MR Lappin
the genus Mycoplasma with descriptions of Flint JC, McKelvie DH (1955) Feline Infectious Anaemia —
‘Candidatus Mycoplasma haemofelis’, ‘Candidatus Diagnosis and Treatment. In 92nd Annual Meeting of the
American Veterinary Medical Association, pp. 240–242.
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Acknowledgements Molecular, clinical, and pathologic comparison of two
Dr CR Helps of the University of Bristol is distinct strains of Haemobartonella felis in domestic cats.
thanked for his help with the construction of the American Journal of Veterinary Research 59, 1581–1588
phylogenetic tree. ST is part funded by the Royal Hammer AS, Wellman M (1999) Leukoerythroblastosis and
normoblastemia in the cat. Journal of the American Animal
College of Veterinary Surgeons Trust Fund. Hospital Association 35, 471–473
Harvey JW, Gaskin JM (1977) Experimental feline haemo-
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