Immunosuppression in pets may be the result of an acquired immune deficiency, such as that due to neoplastic disease, immune-mediated disease, endocrine disease, or drug therapy; or more rarely, a congenital immune deficiency.
Immunosuppression in pets may be the result of an acquired immune deficiency, such as that due to neoplastic disease, immune-mediated disease, endocrine disease, or drug therapy; or more rarely, a congenital immune deficiency. In general, the risk of opportunistic infectious disease is associated with the level and duration of immunosuppressive disease or drug therapy. In recent years, the increasing use of potent immunosuppressive drugs such as cyclosporine to prevent renal transplant rejection and to treat immune-mediated diseases in dogs and cats has been associated with the more frequent identification of unusual opportunistic infectious diseases.
Cyclosporine (also known as ciclosporin) is a small, cyclic peptide produced by the fungus Tolypocladium infantum Gams. It acts by binding the cytosolic protein cyclophilin in lymphocytes, in particular T-lymphocytes. This complex inhibits calcineurin, which normally activates transcription of Il-2. Transcription of Il-4 and IFN-gamma is also decreased. Inhibition of eosinophil recruitment and activation, keratinocyte cytokine production and mast cell degranulation also occurs. A number of adverse drug reactions have been associated with cyclosporine, including gingival hyperplasia, gastrointestinal signs, hepatotoxicity, nephrotoxicity, hypertension, hirsuitism, lameness, and opportunistic infectious diseases (see below), although nephrotoxicity and hypertension appear to be more commonly a problem in humans than in dogs and cats. Chronic treatment with cyclosporine may also predispose to diabetes mellitus and lymphoma. Cyclosporine interacts with drugs metabolized by the P450 system of the liver. Drugs metabolized by this route, especially the azole antifungal drug ketoconazole, may increase the concentration of cyclosporine in the blood. Metoclopromide, macrolide antibiotics and some fluoroquinolones have also been reported to increase serum levels of cyclosporine, although whether these interactions are clinically significant is unknown. Finally, cyclosporine binds to P-glycoprotein and therefore may predispose to ivermectin neurotoxicity.
Because of variable drug absorption between individuals, there is a need to monitor whole blood levels of cyclosporine in dogs and cats being treated with this drug for immunosuppression to prevent excessive or suboptimal immunosuppression. Currently, measuring trough levels is recommended; we typically would start with a dose of 3-5 mg/kg q24h and check levels 5-7 days after starting therapy or dose adjustment, with regular monitoring (every 3-6 months) for patients on long term therapy. The currently accepted target whole blood concentration for immunosuppression is 300-500 ng/mL. Cyclosporine is marketed by Novartis under the brand names Sandimmune (the original formulation), Neoral, a microemulsified formulation that has improved gastrointestinal absorption, and Atopica, a microemulsified formulation which is specifically indicated for treatment of canine atopic dermatitis. Generic preparations are now available such as Gengraf (Abbott). Dosage recommendations for Atopica for the treatment of atopic dermatitis are 5 mg/kg q24h until satisfactory clinical improvement is seen (usually within 4-8 weeks), followed by tapering of the dose to every second day then every 3-4 days, provided clinical signs do not return. It is also suggested that treatment be stopped should the clinical signs disappear on this dose, with intermittent periods of therapy if needed. Several retrospective and prospective studies have been published evaluating the safety and efficacy of cyclosporine for treatment of canine atopic dermatitis, and have found the drug to be efficacious and well tolerated, with rare adverse effects. The most common adverse effects have been gastrointestinal in nature. A study of cyclosporine pharmacokinetics and efficacy in the treatment of canine atopic dermatitis concluded that considering the large margin of safety of cyclosporine in dogs, the limited interindividual variability, and the lack of correlation between blood concentrations and clinical response, routine monitoring of blood cyclosporine levels may not be necessary in dogs with atopic dermatitis. Blood monitoring should be considered when drugs that increase cyclosporine concentrations or potentiate immunosuppression are being used concurrently.
Diseases that cyclosporine has been reportedly effective for include vesicular cutaneous lupus erythematosus, perianal fistulae, sebaceous adenitis, pemphigus foliaceous, erythema multiforme, reactive histiocytosis, inflammatory bowel disease, immune-mediated cytopenias, myasthenia gravis, and immune-mediated polyarthritis.
In cats presenting to UC Davis, the most common reason for using cyclosporine is to prevent renal transplant rejection, although cyclosporine has also been used to treat immune-mediated hemolytic anemia. A retrospective study of 169 feline renal transplant recipients at UC Davis VMTH revealed that at least 25% of cats receiving prednisone and cyclosporine develop infectious complications. Infectious complications were second only to acute transplant rejection as a cause of death, accounting for mortality in 14% of all cats. Bacterial infections were most common, accounting for 53% of infections, followed by viral infections (28%), fungal infections (13%) and protozoal infections, including Toxoplasma and Giardia infections (6%). Of the cats with bacterial infections, 25% had cutaneous infections associated with feeding tubes. Infections with mycobacteria, Nocardia and Actinomyces were also noted. Six cats developed fungal infections, which included cryptococcosis, dermatophytosis, cutaneous and disseminated candidiasis, and disseminated cladosporiosis. Median duration to infection after transplantation was 2.5 months; infections likely to result from reactivation such as viral upper respiratory tract infection and toxoplasmosis tended to occur soon after surgery, and fungal infections tended to occur much later, as has been documented in human organ recipients. The median duration to fungal infection was 6 months. Sex, increasing age, neoplasia after transplantation, and treatment for rejection were not associated with development of infection, but the odds of developing infection increased 6-fold in cats that developed diabetes mellitus. Currently, we routinely screen donor and recipient cats for Toxoplasma gondii antibodies prior to transplantation; seropositive recipients are no longer excluded from the program but placed on lifelong prophylactic clindamycin treatment.
In dogs, cyclosporine has also been used to prevent renal transplant rejection. Of 17 dogs that received renal transplants at UC Davis that had complete follow-up, 5 (29%) developed infectious complications. Bacterial infections accounted for the vast majority of infections, and 4 dogs had moderate to severe bacterial pyodermas. Disseminated papillomatosis has been reported in 2 dogs. An additional dog that developed protothecosis, with cutaneous involvement. More commonly, cyclosporine is used in dogs to treat immune-mediated disease. Infectious complications in these patients have included cryptococcosis, phaeohyphomycosis (Curvularia, Alternaria), oral papillomatosis, and toxoplasmosis. Other serious systemic infections that have been seen include nocardioisis and disseminated aspergillosis.
Prevention of infections in patients receiving cyclosporine for immunosuppression should include screening for latent Toxoplasma gondii infections, as well as FIV and FeLV using serology, routine monitoring for urinary tract infections before and after therapy, limiting outdoor exposure and minimizing hospitalization time when possible, and early detection and aggressive management of diabetes mellitus.