Fever of unknown origin in cats (Proceedings)

Pathophysiology

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. 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. 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.

Clinical findings

The differential list for fever in cats is long. In cats, infectious causes of fever are much more common than primary immune diseases or neoplasia. Initially, the clinician should use the signalment, history and physical examination to identify the initial differential list. Diagnostic tests or therapeutic trials are then used to confirm the primary differential.

Signalment. The age, breed, and sex of the cat can help rank the differential list for fever. For example, young cats often have infectious diseases; old cats often develop neoplasia. Inbreeding can result in predisposition for infectious diseases. For example, feline infectious peritonitis is most common in pure-breed cats. Male cats are more likely to fight, partially explaining the increased incidence of feline immunodeficiency virus in this sex.

History. History can help determine the likely source of elevated body temperature. It should be determined whether the cat is being administered a drug of any type; some can induce fever, in particular, tetracyclines. It should be determined whether vaccines were administered within the previous 1 to 2 months. Vaccine reactions can induce elevated body temperatures via immune-mediated reactions (any vaccine) or if a live, attenuated vaccine is used, via replication of the attenuated agent in the host. This seems to be most common with attenuated calicivirus vaccination of kittens which results in fever and stiffness in some, several days after inoculation. It is also important to determine which vaccines the cats have been administered and the interval between vaccines. Immune responses can wane with time, predisposing the cat to infection. This is unlikely to be a problem with panleukopenia virus; administration of a killed vaccine, twice to cats resulted in 100% immunity at 7.5 years.

Since many causes of fever in cats are transmissible, it should be ascertained whether the cat has had recent exposure to other cats, excrement, or ectoparasites. For example, cats with fever and fleas might be infected with hemoplasmas or Bartonella henselae, infectious agents transmitted by fleas. Cats in housed with other cats are more likely to come in contact with cats carrying infectious agents. It should be determined whether other animals or family members have similar clinical signs of disease. Some infectious agents are regional and so it should be determined whether the cat has traveled recently. For example, in the United States, Cryptococcus neoformans infection is most common in southern California and Vancouver. Determining the prey species for outdoor cats can help rank the infectious disease differential list; ingestion of songbirds (salmonellosis), rabbits (tularemia), or rodents (Yersinia pestis or toxoplasmosis) can transmit infectious diseases associated with fever.

The owner should be questioned concerning clinical signs involving organ systems commonly associated with fever including the oral cavity, central nervous system, cardiopulmonary system, urogenital system, subcutaneous tissues, peritoneal cavity, and gastrointestinal tract.

Physical examination. Anorexia, depression, hyperpnea, reluctance to move, and stiffness from muscle, joint, or meningeal discomfort are common non-specific manifestations of fever in cats. Clinical signs or physical examination findings associated with the primary organ systems involved with the primary infection, tissue necrosis, neoplasia, or immune-mediated disease may be evident. In some cases, the only physical examination finding is fever. Hyperthermia should be differentiated from fever by determining whether the cat has been exposed recently to increased environmental temperature or has increased muscle activity due to excitement, physical exertion, or seizures. All apparently normal cats with elevated body temperature should be encouraged to lay quietly in the examination room with the client for 15-20 minutes followed by repeat measurement of the body temperature. Some normal cats will have persistently elevated body temperature in the clinic due to hyperthermia; these cats should have the body temperature measured at home during periods of rest to determine whether fever is occurring.

The oral cavity should be examined carefully for dental diseases, infiltrative diseases, increased mucus, red or pale mucous membranes, petechia, or tonsillar enlargement. The nares should be examined for evidence of discharges; mucopurulent discharge generally indicated primary bacterial infection, secondary bacterial infection, or fungal infection. The chest should be ausculted carefully for cardiac murmurs, muffled heart or lung sounds, or pulmonary crackles or wheezes and the chest should be gently compressed to evaluate for mediastinal masses. The external lymph nodes and spleen should be palpated for enlargement that may indicate immune-stimulation or neoplasia. Cats showing clinical signs of stiffness should have the muscles, long bones, spinal column, and joints palpated separately. The joints should be gently extended and flexed while evaluating for swelling, pain, or redness. The abdomen should be palpated for evidence of organomegaly, peritoneal effusion, or pain.

A thorough ophthalmic examination should be performed to evaluate for evidence of anterior or posterior segment inflammation. Uveitis occurs with several infectious agents associated with fever in cats, including T. gondii, FeLV, FIV, FIP, B. henselae, feline herpesvirus 1, Ehrlichia spp., and the systemic mycoses. However, the lack of uveitis does not exclude these differentials.

Diagnostic plan

After the physical examination and history are completed, obvious causes of fever like subcutaneous abscessation or bite wounds are treated appropriately. The further diagnostic plan is directed by results of the history and physical examination. A complete blood cell count, serum biochemical panel, urinalysis, FeLV antigen test, and FIV antibody test are indicated as the minimal diagnostic plan in most cats with fever without a readily apparent cause.

Complete blood cell count. The presence of neutrophilic leukocytosis with or without a left shift and toxic neutrophil changes are nonspecific but may indicate an inflammatory condition. Monocytosis is commonly present with chronic inflammatory diseases. Neutrophilia and monocytosis do not prove presence of an infectious disease. Neutropenia in cats results from consumption of neutrophils at a site of inflammation or decreased production of neutrophils. Extreme neutropenia is most commonly associated with panleukopenia, FeLV, FIV, and acute salmonellosis. Eosinophilia is commonly present with Type I hypersensitivity reactions and metazoan parasites including gastrointestinal parasites and dirofilariasis.

Anemia may occur with some causes of fever including primary or secondary immune-mediated hemolytic anemia, hemoplasmosis, and feline leukemia virus infection. Hemopathology may also provide information concerning primary causes. Red cell parasites like M. haemofelis or Cytauxzoon felis may be seen; spherocytes and microagglutination may indicate immune-mediated hemolytic anemia. Cats with hemolytic anemia but without haemoplasmas on red blood cells that were collected into EDTA should have fresh blood smears made from blood collected from an ear margin vein. In the United States, whole blood from cats can be assessed for M. haemofelis and M. haemominutum infections using polymerase chain reaction (PCR) assays. Thrombocytopenia develops with many immune-mediated, neoplastic, and infectious diseases.

Serum biochemical panel. Serum biochemical findings are usually non-specific for the cause of fever but may provide clues for the further diagnostic plan. Azotemia with a suboptimal urine specific gravity (< 1.035 in the cat) combined with bacteriuria and pyuria may indicate pyelonephritis. However, some cats with fever from pyelonephritis have not been azotemic. Increases in activities of liver cytosolic enzymes (ALT and AST) may indicate bacterial or immune-mediated cholangiohepatitis, hepatic abscessation, primary hepatic infections like feline infectious peritonitis virus (FIP), or neoplastic diseases of the liver. Pancreatitis in cats can result in fever but is difficult to diagnose due to poor correlation with lipase and amylase concentrations. If suspected, the combination of laboratory data, TLI, ultrasound, and comparison of lipase concentrations in serum and abdominal fluid can be used to make a tentative diagnosis. Hyperglobulinemia occurs commonly with chronic primary immune-mediated diseases, infectious diseases, and neoplasia. Lymphoma, plasmacytic stomatitis, and FIP are common causes of hyperglobulinemia in cats. Protein electrophoresis should be used to determine whether the gammopathy is monoclonal or polyclonal. Measurement of total T4 concentration may be indicated in some cats with elevated body temperature but is an uncommon cause.

Urinalysis. Pyuria and bacteriuria noted on urinalysis performed on urine obtained by cystocentesis indicate upper or lower urinary tract infection; if fever is present, pyelonephritis is likely. All cats with pyuria or bacteriuria should have urine culture and sensitivity performed. Proteinuria may indicate immune complex deposition in the glomeruli from immune-mediated diseases like systemic lupus erythematosus or chronic inflammatory infectious diseases like FIP, FeLV, ehrlichiosis or dirofilariasis. The urine protein to creatinine ratio can be used to semi-quantitate protein amounts and to monitor therapy in animals with proteinuria without an inflammatory sediment.

Cytology. Cytology can be used to help confirm the presence of inflammation and occasionally, infectious agents with characteristic morphologic form may be detected. Cats with radiographic evidence of alveolar or bronchial lung patterns not associated with cardiac failure should be evaluated with transtracheal wash or bronchoalveolar wash for cytology, culture, and antimicrobial susceptibility. Enlarged peripheral lymph nodes should be aspirated to differentiate neoplastic causes from hyperplasia due to primary immune-mediated diseases or infectious diseases. Submandibular lymph nodes from cats with fever or signs of pneumonia living in states endemic for Yersinia pestis should be aspirated carefully, stained, and examined for characteristic bipolar rods. Fluorescent antibody staining can be used to confirm the diagnosis. Fungal or protozoal agents can be detected cytologically in some cats.

Abdominal paracentesis or thoracocentesis are indicated in cats with fever and pleural or peritoneal effusions, respectively. Bacterial peritonitis or pyothorax have high protein concentration and extremely high numbers of neutrophils and macrophages. There is usually a mixed population of degenerative and nondegenerate neutrophils; bacteria may or may not be seen. Cats with pancreatitis can have peritoneal or the combination of peritoneal and pleural effusion. The fluid cytologically is similar to the bacterial diseases but the fluid is usually not septic. Detection of abdominal fluid lipase concentrations greater than serum can be used to confirm the diagnosis of pancreatitis. Fluid induced by FIP usually have high protein concentration and increased numbers of neutrophils and macrophages but the neutrophils are usually non-degenerate. Determination of the albumin to globulin ratio of peritoneal or pleural effusions can aid in the diagnosis of FIP. Cats with fluid albumin/globulin ratio > 0.8 are unlikely to have FIP; ratios < 0.4 are usually associated with FIP.

Arthrocentesis can be used to confirm neutrophilic infiltrates in synovial fluid which supports a diagnosis of immune-mediated or infectious polyarthritis even if joint effusion or pain is not readily apparent. Calicivirus, Mycoplasma, and L-form bacterial infection are several infectious agents associated with polyarthritis in cats.

Fecal tests. Rectal cytology is indicated in cats with fever and diarrhea. Fecal culture for Salmonella and Campylobacter is generally indicated for the evaluation of cats with neutrophils detected on rectal cytology. Clostridium perfringens can produce enterotoxin which can be measured in feces and is usually performed in cats with spore-forming rods detected cytologically. Cats with hemorrhagic gastroenteritis and neutropenia can be further evaluated for the presence of parvovirus infection by fecal ELISA if they are not vaccinated for panleukopenia and for salmonellosis if they are vaccinated.

Culture and sensitivity. Culture and sensitivity of body fluids, aspirates or biopsies of tissue, or feces can be used to help confirm infectious causes of fever. Bacteremia is best confirmed by blood culture but polymerase chain reaction (PCR) may be used in the future. At least 3 bacterial blood cultures over 2 hours should be collected from the jugular vein following sterile preparation of the skin. Aerobic and anaerobic bacterial cultures and fungal cultures may be indicated in some cases. Special media is required to support the growth of some organisms like Mycobacterium and Mycoplasma. L-form bacteria will not be cultured on routine culture media.

Serologic testing. Serologic testing is indicated in some cats with fever; choices are based on the combination of clinical and routine laboratory findings. A FeLV antigen test and a FIV antibody test are indicated in cats with fever of unknown origin. Fever is rarely induced by FeLV infection and when due to FIV is present most commonly in the acute phase of infection. However, both viruses cause immuodeficiency and so predispose to infection by other infectious agents.

Most cats with suspected FeLV infection are screened for FeLV antigens in neutrophils and platelets by immunofluorescent antibody (IFA) or in whole blood, plasma, serum, saliva, or tears by enzymelinked immunosorbent assay (ELISA). IFA is not positive until the bone marrow has been infected. Results of IFA are accurate 98.3% of the time. False-negative reactions may occur when leukopenia or thrombocytopenia prevents evaluation of an adequate number of cells. False-positive reactions can occur if the blood smears submitted for evaluation are too thick. A positive IFA indicates that the cat is viremic and contagious; 90-97% of cats with positive IFA results will be viremic for life. The rare combination of IFA positive and ELISA negative results suggests techniquerelated artifact. Negative ELISA results correlate well with negative IFA results and an inability to isolate FeLV.

The virus can be detected in serum by ELISA prior to infection of bone marrow and so can be positive in some cats during early stages of infection, or during self-limiting infection even though IFA results are negative. Other possibilities for discordant results (ELISA positive, IFA negative) are false positive ELISA results or false negative IFA results. Cats with positive ELISA results and negative IFA results are probably not contagious at that time, but should be isolated until retested 4-6 weeks later since progression to persistent viremia and epithelial cell infection may be occurring.

ELISA-positive cats that revert to negative have developed neutralizing antibodies, latent infection, or localized infection. Virus isolation, IFA performed on bone marrow cells, immunohistochemical staining of tissues, and polymerase chain reaction can be used to confirm localized or latent infection. Cats with localized or latent infection are not likely contagious to other cats, but infected queens may pass the virus to kittens during gestation, parturition, or by milk. Cats with localized or latent infection can have immunodeficiency and may become viremic (IFA and ELISA positive) after receiving of corticosteroids or following extreme stress.

There is generally a delay of 1 to 2 weeks after the onset of viremia before ELISA tear and saliva tests become positive, so these tests can be negative even when results using serum are positive. Antibody titers to FeLV envelope antigens (neutralizing antibody) and against virustransformed tumor cells (FOCMA antibody) are available in some research laboratories but the prognostic significance of results from these tests is unknown. Cats with suspected latent FeLV infection can be evaluated for the presence of the virus in bone marrow by IFA, polymerase chain reaction, or virus isolation.

Antibodies against FIV are detected in serum in clinical practice most frequently by ELISA. Seroconversion occurs 2-4 weeks post-inoculation in experimentally infected cats; thus, false-negative reactions can occur during peracute infection. False-positive reactions are common using ELISA. Positive ELISA results should be confirmed using Western blot immunoassay or IFA, especially if the positive cat is healthy or is from a low-risk population for infection. Kittens can have detectable colostrum-derived antibodies until 12-14 weeks of age and should not be tested until > 14 weeks of age. Detection of antibodies against FIV in the serum of cats documents exposure and correlates well with persistent infection but does not correlate to disease induced by the virus. Since many of the clinical syndromes associated with FIV can be due to opportunistic infections, further diagnostic procedures may determine treatable etiologies. For example, most FIV-seropositive cats with uveitis are coinfected by T gondii and often respond to the administration of anti-Toxoplasma drugs. Cats in the primary phase of FIV can have fever but be seronegative; the antibody test should be repeated in 6 to 8 weeks in cats with a high index of suspicion for FIV infection. A killed FIV vaccine is currently available. This vaccine induces antibodies detectable in both ELISA and western immunoblot that are indistinguishable from those induced by natural infection. Too date, PCR has not be accurate in discriminating vaccinated cats from those infected with FIV.

Detection of serum antibodies is of limited benefit in the evaluation of cats for FIP. Infection of cats by any coronavirus can cause crossreacting antibodies, so a positive antibody titer does not diagnose FIP, protect against disease, or predict when a cat may develop clinical FIP. Coronavirus antibody tests are not standardized, so results from different laboratories commonly do not correlate. Antibodies in serum against bovine serum products that result from vaccination can cause false-positive results in some coronavirus antibody tests. Cats with FIP are occasionally serologically negative because of rapidly progressive disease with a delayed rise in titer, disappearance of antibody in terminal stages of the disease, or immune complex formation. Maternal antibodies decline to undetectable concentrations by 4 to 6 weeks of age; kittens infected in the postnatal period become seropositive at 8 to 14 weeks of age. Thus, serologic testing of kittens can be used to prevent spread of coronaviruses. Serologic testing is indicated as a screening procedure in breeding colonies that are coronavirus antibody-negative. A test to detect the 7B protein of coronaviruses has been introduced and purported to correlate to FIP. However, not all cats that are positive develop FIP. Thus, all positive coronavirus tests should be interpreted with other clinical factors including signalment (generally young cats), appropriate clinical signs and physical examination abnormalities, and appropriate laboratory abnormalities like lymphopenia and hyperglobulinemia. Definitive diagnosis of FIP still requires documentation of characteristic histopathologic findings or the organism in inflamed tissues by immunohistochemistry or PCR.

Toxoplasma gondii serologic testing should be considered in cats with fever, particularly if muscle hyperesthesia or uveitis are concurrently present. Toxoplasmosis is also most common in cats that are allowed outdoors and so are more likely to ingest infected rodents. Presence of IgM in serum correlates better to clinical toxoplasmosis than IgG. Detection of T. gondii antibodies by ELISA or the organism in aqueous humor or CSF by PCR are the most accurate methods of proving ocular or CNS toxoplasmosis.

Ehrlichiosis (E. canis and possibly another related organism) and anaplasmosis (Anaplasma phagocytophilum; previously E. equi) have been shown to cause fever in cats of multiple countries around the world including France, Brazil, Sweden, Africa, Thailand, and the United States. Serologic testing is available in some countries. Like results of most other antibody tests, positive Ehrlichia spp. serology only correlates to exposure not clinical disease. Some cats with E. canis DNA in serum were seronegative; in contrast, all A. phagocytophilum cats were seropositive. However, infection by A. phagocytophilum will not be detected by E. canis antibody tests and vice versa. Thus, cats with suspected ehrlichiosis or anaplasmosis must be screened for both antibodies and PCR.

Polymerase chain reaction. DNA of infectious agents can be detected in body fluids, feces, and tissues by PCR; this technique is being used to aid in the diagnosis of multiple infectious causes of fever. The following are several examples. All forms of H. felis (Mycoplasma haemofelis; 'Candidatus M. haemominutum; 'Candidatus M. turicensis) can be detected in blood of cats with PCR and the technique is more sensitive than cytology. Bartonella henselae can be detected in blood and sensitivity may be equal to that of culture. Ehrlichia canis and A. phagocytophilum (previously E. equi) infection of cats has been detected by PCR. Coronavirus polymerase chain reaction (PCR) can document the organism in effusions and whole blood; while positive results from effusions correlate fairly well with FIP those from whole blood do not. As more PCR are introduced to the marketplace, request information concerning sensitivity, specificity, positive predictive value, and negative predictive value of each assay.

Diagnostic imaging. Thoracic and abdominal radiographs are commonly utilized in the search for the cause of fever; infections or neoplasia not obvious on physical examination can often be identified. For example, cats with unilateral pyothorax may not have a restrictive breathing patterns. Not all cats with pyelonephritis have painful kidneys; an irregularly shaped kidney could be detected on abdominal radiographs. Radiographs of the axial or appendicular skeleton can be used to evaluate for neoplasia or osteomyelitis. Contrast studies, ultrasonography, nuclear scintigraphy, and both CT and MRI can be used to evaluate different organ systems for disease resulting in fever.

Primary immune tests. Tests used most frequently in cats to aid in the diagnosis of primary immune-mediated diseases include direct Coomb's and antinuclear antibody tests. The laboratory should be consulted to determine whether the assays and controls have been validated for use with cats. Positive test results combined with appropriate clinical or laboratory evidence of disease may support a diagnosis of immune-mediated disease. Both of these tests can be positive secondary to chronic inflammatory diseases independent of primary immune disease.

Other tests. Bone marrow aspiration and cytology may aid in the identification of immune-mediated, infectious, or neoplastic diseases. For example, macrophages with ingested platelets or red blood cells may be noted and Histoplasma capsulatum is commonly detected in the bone marrow of infected cats. Protein electrophoresis can be used to determine whether a gammopathy is monoclonal or polyclonal; immunoelectrophoresis can be used to determine which antibody class is being produced in excess. Monoclonal gammopathy is most commonly associated with neoplasia but has been detected with ehrlichiosis as well. Results of protein electrophoresis of serum are not beneficial for documentation of feline infectious peritonitis virus (see cytology section). The polyclonal gammopathy that occur with FIP cannot be distinguished from that induced by other chronic inflammatory diseases.

Treatment plan

Empirical treatment is frequently used in cats with elevated body temperature. If hyperthermia is suspected, the cause should be removed if possible (seizures, increased environmental temperature etc.). In cats with suspected infectious, neoplastic, or primary immune-mediated causes of fever, multiple specific and non-specific therapeutic options are available. Intravenous administration of room temperature fluids is often all that is required to maintain body temperature at safe levels. Using a cool cage or directing a fan towards the patient may also be effective. Since fever in general is biologically helpful, artificial lowering of body temperature is usually not indicated. Thus, the use of drugs like dipyrone is usually contraindicated. If chronic fever is present that results in morbidity (depression, inappetance), aspirin at 5 mg/kg, orally once daily can be used. Multiple non-steroidal anti-inflammatory agents (like ketoprofen) are available that can be used to transiently decrease body temperature if indicated. Once infectious and neoplastic causes of fever are excluded, use of glucocorticoids may be indicated for the treatment of primary immune-mediated diseases.

Antibiotics should be given to cats with presumed bacterial, Rickettsial, or mycoplasmal infections. Ultimately, treatment should be based on results of culture and sensitivity if possible. Empirical antibiotic choices can be based on the organ system involved or the organism suspected (Table 1). Feline hemoplasmas and Ehrlichia/Anaplasma infections generally respond to doxycycline at 10 mg/kg, PO, once daily. I attempt to treat for at least 28 days to lessen chance for recurrence. I personally liquefy doxycyline at 50 mg/ml in tuna flavoring which lowers the volume needed. You can also give water after pilling or put butter or Nutrical on the tablet to lessen odds of developing esophageal strictures. For Bartonella spp. infections of cats, the AAFP Panel (aafponline.org) recommended doxycycline as the first drug of choice. Fluoroquinolones are suggested as rescue drugs for hemoplasmosis and bartonellosis if doxycycline fails. Toxoplasma gondii infections generally respond to clindamycin at 10 mg/kg, PO, twice daily or trimethoprim sulfa at 15 mg/kg, PO, twice daily. If responding, try to treat for 28 days. Azithromycin can be a rescue drug for bartonellosis and toxoplasmosis but is ineffective for hemoplasmosis.

Table 1. Antibiotics used for the treatment of bacterial infections in cats.

Most fungal infections in cats are ultimately treated with amphotericin B, itraconazole, or fluconazole. Ketaconazole should not be used in cats due to risk of toxicity. Amphotericin B should be used if life-threatening disease is present so a cidal drug is needed. Liposomal or lipid encapsulated amphotericin B are preferred because these drugs are less likely than regular amphotericin B to induce fever or nephrotoxicity but are expensive. Recently, subcutaneous administration of regular amphotericin B has been reported for treatment of cryptococcosis and is a less expensive alternative. Intraconazole or fluconazole are the drugs used most frequently for chronic therapy. Due to superior penetration, fluconazole should be used in cats with ocular or central nervous system involvement.

Fever induced by viral infections is rarely treated primarily since most are acute. AZT has been used successfully to improve quality of life in some cats infected with FeLV or FIV. If prescribed, I use 5 mg/kg, PO, q12 hours. Controlled studies are lacking that document efficacy of propriobacterium acnes, Staphylococcus protein A, acemannan, or Pind-dorf for the treatment of retroviral infections of cats. However, interferons can be effective.

Glucocorticoids are used for the treatment of noneffusive FIP, primary immune-mediated diseases, and some neoplasia. Prednisolone is more effective than prednisone in some cats and so is the first glucocorticoid of choice for many clinicians. Cats with primary immune diseases thought to have resistance to prednisolone should be treated with dexamethasone or triamcinolone prior to use of cytotoxic drugs. If cytotoxic drugs are needed, chlorambucil is apparently safer than azathioprine for long term administration.