INTRODUCTION

The 2 major differentials for elevated body temperature (> 102.5 F) are fever (pyrexia) and hyperthermia. Hyperthermia results from increased muscle activity, increased environmental temperature, or increased metabolic rate (i.e., hyperthyroidism). Fever develops when the thermoregulatory set point in the hypothalamus is increased, resulting in increased body temperature from physiologic mechanisms inducing endogenous heat production or heat conservation.¹ If the cause of fever is not apparent for > 2 weeks, the case is classified as having fever of unknown origin.

Fever results when leukocytes, particularly mononuclear cells and neutrophils, are activated. Leukocytes are generally stimulated by contact with bacterial, viral, fungal, and parasitic agents, neoplasia, tissue necrosis (extensive trauma and pancreatitis included), and primary immune-mediated diseases like immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, and systemic lupus erythematosus. Activated leukocytes release a variety of soluble factors like interleukin 1 and tumor necrosis factor, which enter the central nervous system and change the thermoregulatory set point.² The thermoregulatory set point may also be altered by intracranial disease including trauma and neoplasia, or drugs like tetracyclines. Shivering and vasoconstriction are 2 of the most important physiologic responses to a thermoregulatory set point change that result in generation and conservation of heat, respectively.

Fever < 105 F may be beneficial for the management of infectious diseases due to potentiation of phagocytosis, interferon release, and lymphocyte transformation. During chronic inflammatory conditions resulting in fever, activated mononuclear cells also sequester serum iron, decreasing bacterial replication. Body temperatures > 106 F can be detrimental due to effects on cellular metabolism. Disseminated intravascular coagulation can result from extreme increase in body temperature. Compared to dogs, cats are less likely to develop the detrimental effects of fever.

There have been multiple recent discoveries in feline infectious diseases associated with fever. Notable advances in the diagnosis and treatment of Haemobartonella felis (Mycoplasma) infections, feline ehrlichiosis, bartonellosis and toxoplasmosis have been made.

Haemobartonellosis. Haemobartonella felis is now classified as a mycoplasma. The small variant of the organism has been designated the California strain (Hfsm) and the large form has been designated the Ohio strain (Hflg). The proposed name for Hflg is Mycoplasma haemofelis. The proposed name for Hfsm is Mycoplasma haemominutum. In at least two studies, the Hflg strain was apparently more pathogenic than the Hfsm strain; all Hflg inoculated cats became clinical ill whereas Hfsm inoculated cats were subclinically infected. Coinfected, naturally exposed cats have been detected; coinfection is clinically more severe than infection by either organism alone. United Kingdom isolates are similar genetically to those of the United States.

Haemobartonella felis has been transmitted experimentally by IV, IP, and oral inoculation of blood. It is unknown whether blood-sucking arthropods like fleas and ticks can transmit the disease. Clinically ill queens can infect kittens; whether transmission occurs in utero, during parturition, or from nursing has not been determined. Transmission by biting has been hypothesized. Red blood cell destruction is due primarily to immune-mediated events; direct injury to red blood cells induced by the organism is minimal. Positive Coomb's tests are common.

In naturally exposed cats, clinical disease occurs in immunocompetent or immunosuppressed cats. Clinical signs of disease depend on the degree of anemia, the stage of infection, and the immune status of infected cats. Signs from anemia are most common and include pale mucous membranes, depression, inappetence, weakness, and occasionally, icterus and splenomegaly. Fever occurs in some acutely infected cats and may be intermittent in chronically infected cats. Weight loss is common in chronically infected cats; these cats can be subclinically infected and then have recurrence of clinical disease following periods of stress. In cats experimentally inoculated with the Hflg strain, significant clinical signs were consistent with developing anemia and were most apparent approximately 3 weeks post-inoculation.

The anemia associated with haemobartonellosis is generally macrocytic, normochromic but may be macrocytic, hypochromic if coinfections leading to chronic inflammation exist. Chronic non-regenerative anemia is unusual in haemobartonellosis. Neutrophilia and monocytosis have been reported in some H felis infected cats. Diagnosis is based on demonstration of the organism on the surface of erythrocytes on examination of a thin blood film or polymerase chain reaction (PCR). Organism numbers fluctuate and so blood film examination can be falsely negative up to 75% of the time. The organism may be difficult to find cytologically, particularly in the chronic phase. Thus, the PCR is the test of choice due to sensitivity. Primers are available that detect a segment of the 16S rRNA gene common to both sequenced strains of H felis.

Tetracyclines have been used classically for treatment of haemobartonellosis. Doxycycline has fewer side effects than tetracycline and should be given at 5-10 mg/kg, PO, every 12-24 hours for 14-21 days. If autoagglutination 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. In one study, experimentally infected cats treated with doxycycline had positive clinical response but the organism could still be detected by PCR when the cats were given methylprednisolone acetate. Treatment with enrofloxacin given at 5 mg/kg, PO, every 24 hours or at 10 mg/kg, PO, every 24 hours for 14 days was well tolerated by cats and was equally effective or more effective than doxycycline given at 5 mg/kg, PO, every 12 hours for 14 days. In this study, two enrofloxacin infected cats and 1 doxycycline infected cat became persistently PCR negative. Azithromycin was not effective for the treatment of hemobartonellosis in one study. Blood transfusion should be given if clinically indicated.

The prognosis is generally good for immunocompetent cats. Potential arthropod vectors should be controlled. Cats should be housed indoors to avoid vectors and fighting. In one study, approximately 7% of healthy cats were carrying Mycoplasma haemofelis or M. haemominutum, thus, clinic blood donor cats should be screened for infection by PCR.

Ehrlichoisis. Ehrlichia canis DNA and E. equi DNA have been amplified from naturally exposed cats in several countries. Ehrlichia-like morula have been detected in mononuclear cells or neutrophils of naturally-exposed cats in the United States, Kenya, Brazil, France, Sweden, and Thailand. Cats experimentally infected with E. risticii develop morulae in mononuclear cells and occasionally develop clinical signs of disease including fever, depression, lymphadenopathy, anorexia, and diarrhea. Cats experimentally infected with E. equi developed morulae in neutrophils and eosinophils, not mononuclear cells.

A presumptive diagnosis of ehrlichiosis has also been based on detection of morulae or DNA in clinically ill cats or by the combination of either positive E canis, E risticii, or E equi serology, clinical or laboratory findings consistent with ehrlichial infection, exclusion of other causes, and response to an anti-rickettsial drug. There are currently over 50 cases of suspected or proven cases of feline ehrlichiosis in the world's literature. It is unknown how the clinically ill, naturally exposed cats described in the literature were infected. Exposure to arthropods has been reported in about 30% of the cases. Ixodes spp. ticks have been associated with several cases with E. equi infection. Pathogenesis of disease associated with ehrlichiosis in cats is unknown.

Most cats from which age was reported were greater than 2 years of age, most cats were domestic short haired, and both males and females have been affected. Anorexia, fever, inappetence, lethargy, weight loss, hyperesthesia or joint pain, pale mucous membranes, splenomegaly, dyspnea, and lymphadenomegaly were the most common historical and physical examination abnormalities. Concurrent diseases are rarely reported but have included Haemobartonella felis (Mycoplasma) infection and lymphosarcoma.

Anemia is a common laboratory abnormality and is usually non-regenerative. Leukopenia, leukocytosis characterized by neutrophilia, lymphocytosis, monocytosis, and intermittent thrombocytopenia were reported for some cats. Hyperglobulinemia was reported for multiple cats; protein electrophoresis documented polyclonal gammopathy in one cat. An epidemiological link has been made between presence of Ehrlichia spp. antibodies in serum and monoclonal gammopathy.

Some cats with suspected clinical ehrlichiosis seroreacted to E. canis, E. risticii, or E equi morula. Antibodies that seroreact to more than one Ehrlichia are sometimes detected. It appears that some cats infected with E canis are seronegative. Most E equi cats have strongly positive antibody test results. Western blot immunoassay has been used to confirm some E. risticii positive results. Positive serologic test results occur in healthy cats as well as clinically ill cats and so a diagnosis of clinical ehrlichiosis should not be based on serologic test results alone. A tentative diagnosis of feline clinical ehrlichiosis can be based on the combination of positive serologic test results, clinical signs of disease consistent with Ehrlichia infection, exclusion of other causes of the disease syndrome, and response to anti-rickettsial drugs. Ehrlichia spp. has been cultured from some cats on monocyte cell cultures. Polymerase chain reaction and gene sequencing can also be used to confirm infection.

Clinical improvement after therapy with tetracycline, doxycycline, or imidocarb dipropionate was reported for most cats. Humans are not infected with Ehrlichia spp. from contact with infected cats but it is possible that cats could be a reservoir for species that infect people. Arthropod control should be recommended for cats.

Bartonellosis. Bartonella henselae is the primary cause of cat scratch disease in people. The organism can be transmitted by fleas. Once considered a subclinical infection, it is now recognized that the organism results in clinical illness in come cats. Most common are fever, lethargy, lymphadenopathy, neurologic diseases, uveitis, and gingivitis. Serologic tests, culture, and PCR are used to aid in the diagnosis. Antibiotic treatment with tetracyclines, quinolones, and macrolides improve clinical signs in some cats, but it is unclear whether the body is cleared of the organism. Flea control should always be maintained in cats.

Toxoplasmosis. Intestinal toxoplasmosis usually is only associated with self-limited diarrhea in about 10% of exposed cats; inflammatory bowel disease has been detected occasionally. Extraintestinal toxoplasmosis can be fatal; lung, liver, CNS, and pancreatic disease are most common and are usually detected in kittens and other immunosuppressed cats. Renal transplantation of cats has been associated with fatal toxoplasmosis. Chronic, sublethal extraintestinal clinical syndromes include anterior uveitis, posterior uveitis, fever, muscle hyperesthesia, and CNS disease (seizures and ataxia). Multiple diagnostic tests have been assessed including IgM, IgG, and IgA antibody tests and PCR. Detection of antibodies or organismal DNA in aqueous humor or cerebrospinal fluid can aid in the diagnosis of ocular or CNS toxoplasmosis. Clindamycin, potentiated sulfa drugs, and azithromycin are common treatments. There is currently no drug known to eliminate infection from the body.

REFERENCES

References are available on request.