Eperythrocytic parasites previously known as Haemobartonella and Eperythrozoon and formerly classified as rickettsial organisms are now understood to be more closely related to the order Mycoplasmatales. This affiliation is based on their lack of a cell wall, use of the codon UGA to encode tryptophan, and 16S rRNA gene sequences. Although the reassignment of Eperythrozoon and Haemobartonella to the genus Mycoplasma is still under debate, referral to this genus has been embraced, and they are commonly referred to as hemotropic mycoplasmas or hemoplasmas. Several of these previously described red cell parasites, now also having supporting genetic data, have been renamed Mycoplasma, whereas newly described hemoplasmas are given the designation "Candidatus." The hemoplasmas infect a wide variety of vertebrates throughout the world, including several reports of human infection. They share similar characteristics and morphologic features such as rod, coccoid, and ring-shaped structures found individually or in chains on the red cell and gram-negative staining because of the lack of a cell wall; none of the hemoplasmas have been cultured outside their hosts. It is well established that the hemoplasmas attach to the surface of the red cell but may under certain conditions penetrate this host cell.
Several hemoplasmas are of veterinary importance (see Table: Hemoplasmas of Veterinary Importance). These organisms vary in their ability to cause clinically significant hemolytic anemia, but infected animals may remain carriers despite antibiotic therapy. Parasitemia may reemerge if the animal is stressed or immunocompromised. Once an initial infection is controlled, either naturally or after antibiotic treatment, protective immunity develops against repeat M haemofelis infection; how long this immunity will last and whether this applies to other hemoplasma infections is unknown.
Hemoplasmas of Veterinary Importance
Hemoplasmas may be transmitted by transfer of infected blood (blood transfusion or use of contaminated needles, surgical instruments, herd or flock management equipment) or via arthropod vectors such as lice, flies, ticks, and mosquitoes. Vertical transmission from mother to offspring has been reported in cats, swine, and camelids. Direct transmission associated with fighting is suspected in cats and supported by studies reporting presence of hemoplasma DNA in saliva, on gingiva, and on claw beds of infected cats.
Hemoplasmas are capable of causing a hemolytic anemia, but the severity varies greatly. In general, asymptomatic infections tend to occur in healthy adult animals, and more severe acute anemias are associated with splenectomy, immunocompromise, concurrent diseases (such as feline leukemia virus or feline immunodeficiency virus in cats), or coinfection with multiple hemoplasma species. The main exception is M haemofelis, which causes acute hemolytic anemia in healthy cats. The anemia may be severe and occasionally fatal. Typical clinical signs include lethargy, anorexia, and fever, with splenomegaly and icterus occurring less often.
M haemocanis causes acute hemolysis in dogs that are splenectomized, but infections are usually asymptomatic in healthy dogs. M suis causes hemolytic anemia accompanied by icterus in neonatal pigs, feeder pigs, and pregnant sows. Chronic infection is associated with poor growth rates, decreased conception rates, reproductive failure, and decreased milk production. M wenyonii infection in cattle is usually asymptomatic, but a syndrome of mammary gland and hindlimb edema, decreased milk production, fever, and lymphadenopathy has been described in young, nonanemic, primiparous heifers. Infection in young bulls has been reported to cause scrotal and hindlimb edema. M ovis infection in sheep and goats is often asymptomatic, but hemolytic anemia can occur in young animals, especially those with heavy intestinal worm burdens. Chronic infection may result in poor weight gain, exercise intolerance, decreased wool production, and mild anemia. Hemoplasma infection in camelids can cause a severe hemolytic anemia in young crias. The prevalence of chronic infection in sheep, pigs, and kennel-raised dogs is high, and outbreaks of acute disease have been reported in animals during research studies. Whether the infection is chronic or acute, it may affect experimental results and lead to misinterpretation of data.
The hemolysis caused by hemoplasma infections is typically extravascular and results in a regenerative anemia. Erythrocyte agglutination may be present, and Coombs’ test results are often positive in cats infected with M haemofelis. Splenectomized dogs with acute hemolysis due to M haemocanis may have agglutination, spherocytosis, and a positive Coombs’ test. Hypoglycemia secondary to glucose consumption by the bacteria has been reported in heavily parasitized pigs, sheep, llamas, and calves; however, rapid bacterial glycolysis in vitro may also cause artifactually decreased blood glucose concentrations.
Historically, diagnosis has been made based on detection of organisms on routine Wright-stained blood smears, on which they appear as small (0.5–3 μm), basophilic, round, rod, or ring-shaped structures present on erythrocytes individually or in chains, or sometimes seen free in the background. However, parasitemia in chronic infections can be cyclic, and organisms can disappear from circulation in as little as 2 hr. In addition, hemoplasmas dissociate from erythrocytes and die after a variable amount of time in EDTA, hampering detection of organisms in aged samples. Recent development of sensitive PCR assays capable of discriminating between various hemoplasmas has greatly enhanced diagnosis of these parasites and has led to identification of several new Mycoplasma species.
For acute infections, tetracyclines (doxycycline, oxytetracycline) have been the mainstay of treatment; enrofloxacin and marbofloxacin have also been effective against M haemofelis. Glucocorticoids may be useful to decrease erythrophagocytosis in cases of severe hemolysis; some animals may require blood transfusion. Treated animals remain carriers and may experience periodic clinical relapses. Blood donors should be screened using PCR-based DNA assays to prevent transmission to transfusion recipients. Iatrogenic transmission can be avoided by using properly sterilized needles and equipment. Control of arthropod vectors is recommended, as is minimizing stress in herd and flock situations.
Hemoplasma infections are usually species specific, except for M ovis, which infects both sheep and goats, and "Candidatus M haemolamae," which infects both llamas and alpacas. There are reports of human eperythrozoonosis from Inner Mongolia, China, but supporting evidence is not compelling. However, there have been rare reports of hemoplasma infections in immunocompromised people in which molecular methods were used for confirmation. One report documented an HIV-positive human patient coinfected with Bartonella henselae and a hemoplasma genetically similar to M haemofelis. This individual owned five cats and had multiple scratch and bite wounds. All five cats were PCR positive for Bartonella spp and two were positive for M haemofelis, suggesting the possibility of zoonotic transmission. The coinfection of a veterinarian in Texas with B henselae and M ovis also has been reported.
In cats, hemotropic mycoplasmosis can produce a disease called feline infectious anemia (FIA), previously known as hemobartonellosis. Most cases are in outdoor, male cats. M haemofelis (previously the Ohio strain, or large form, of Haemobartonella felis) is the most pathogenic organism causing FIA, and it can cause hemolytic anemia in immunocompetent cats. "Candidatus M haemominutum" (previously the California strain, or small form, of H felis) is the most common hemoplasma in cat populations worldwide, but it has not been clearly associated with disease in immunocompetent cats. "Candidatus M turicensis" has never been seen on blood smears, and its pathogenicity is not well understood. Both Candidatus species may be capable of inducing anemia in cats with underlying immunosuppressive disease, such as feline leukemia virus infection.
In the case of M haemofelis infection, an incubation period of 2–30 days is followed by anemia, with some cats developing cyclical changes in PCV that coincide with the appearance of large numbers of organisms on blood smears. In untreated cats, this acute phase lasts for 3–4 wk, after which some cats may remain chronically infected despite normal or near normal PCV values. It has been suggested that recrudescence of anemia may occur when these chronically infected cats are subject to debilitating disease, stress, or immunosuppressive therapies.
Any anemic cat, especially an anemia showing evidence of regeneration (polychromasia and/or reticulocytosis), may be suspected of having FIA. The severity of clinical signs correlates with the rapidity of onset of anemia. Clinical findings include weakness, pallor of the mucous membranes, tachypnea, tachycardia, and occasionally collapse. Acutely ill cats may be febrile, and moribund cats may be hypothermic. Other physical examination abnormalities may include cardiac murmurs, splenomegaly, and icterus. In chronic or slowly developing cases, there may be normal or subnormal body temperature, weakness, depression, and weight loss or emaciation.
Expected laboratory abnormalities include a moderate to marked regenerative anemia, increased numbers of nucleated RBCs, polychromasia, anisocytosis, Howell-Jolly bodies, and an increased reticulocyte count. Coombs’ tests can become positive 7–14 days after organisms appear in the blood and remain positive throughout the acute phase, reverting to negative in chronically infected carrier cats.
Laboratory confirmation has traditionally been based on identification of organisms in the peripheral blood using light microscopy, although M haemofelis is visible <50% of the time in acutely infected cats. Some laboratories offer PCR assays that are considerably more sensitive and specific than blood-smear evaluation. Detection of M haemofelis via PCR is more significant than detection of other hemoplasma species ("Candidatus M turicensis" and "Candidatus M haemominutum") , which are not as strongly associated with anemia.
Without treatment, one third of acutely ill cats may die. Treatment involves both supportive therapies, such as oxygen and blood transfusions, and specific therapy with doxycycline (10 mg/kg/day, PO, for a minimum of 2 wk). Because of the potential for esophagitis and esophageal strictures, administration of doxycycline hyclate preparations should be followed by administration of a bolus of several milliliters of water. Enrofloxacin (5 mg/kg/day, PO) is a suitable alternative to doxycycline. Treatment of PCR-positive, healthy cats is currently not recommended, because no regimen has yet been identified that completely eliminates the organism. The use of immunosuppressive dosages of glucocorticoids to suppress immune-mediated RBC injury is controversial but may be used in cats that do not respond to antimicrobial therapy alone, or when primary immune-mediated hemolytic anemia is a possible cause.