Rational Use of Glucocorticoids in Infectious Disease

Chapter 278

Rational Use of Glucocorticoids in Infectious Disease

Evidence supporting the use of glucocorticoids for treatment of infections in small animal patients is based on anecdotal or retrospective reports. Few prospective controlled studies have evaluated critically the benefits or consequences of glucocorticoid use in this setting. Despite the fact that little scientific evidence supports their use, glucocorticoids frequently are suggested for patients with infectious disease. Frequently cited reasons for administration of glucocorticoids in treating infectious disease include suppression of harmful inflammatory or immune responses and suppression of presumed secondary immune-mediated processes. The aim of this chapter is to review the use of glucocorticoids in infectious disease situations and to offer guidelines for their use. This chapter does not address specifically the use of glucocorticoids, either topical or systemic, in patients with ocular infections or ocular manifestations of infectious disease, although they are used frequently.

Mechanism of Action

The mechanisms by which glucocorticoids mediate antiinflammatory activity are not understood completely. Glucocorticoids diffuse across the plasma membrane and bind to specific glucocorticoid receptors in the cytoplasm. The steroid-receptor complex then exerts a variety of effects. The complex can inactivate proinflammatory transcription factors and increase the production of proteins that inhibit cytokine production. Glucocorticoids also can mediate their actions through nontranscriptional means such as decreasing the half-life of messenger ribonucleic acid for inflammatory cytokines. Glucocorticoids attenuate inflammation by inducing lipocortin-1, which directly inhibits phospholipase A2, an enzyme responsible for production of inflammatory prostaglandins, leukotrienes, and eicosanoids. Through these and other mechanisms, inflammation and immune function can be altered or suppressed by glucocorticoids.

Even at physiologic concentrations, glucocorticoids are immunomodulatory, leading to a shift in cytokine production from a proinflammatory to an antiinflammatory pattern. Pharmacologic doses are immunosuppressive and inhibit cellular and humoral responses (Sternberg, 2001); however, the cellular response is thought to be most compromised. Poor cellular immune responses could enhance the pathogenic potential of some infectious organisms, prevent cell-mediated clearance of organisms, and perpetuate inflammation secondary to persistence of organisms and activation of other inflammatory pathways. Glucocorticoids commonly are thought to decrease phagocytic and oxidative functions of phagocytic cells in a dose-dependent manner, thereby compromising the ability to kill ingested organisms. These general properties support the use of glucocorticoids in patients with infectious disease and raise concerns about the potential side effects and complications associated with their use.

Glucocorticoids in Humans with Infectious Disease

A survey of the human literature on the use of glucocorticoids as adjunctive treatment for infectious disease puts into perspective many of the uncertainties in veterinary medicine. Conclusions regarding the benefits of glucocorticoids given to humans with infectious disease vary depending on the infectious agent studied, the age of the patient group studied, the dose and/or duration of glucocorticoid therapy, the parameters assessed (e.g., immunologic or infectious agent parameters such as cytokine levels or quantity of infectious agent detected), the presence of other infectious agents, and by extension, perhaps, of other concurrent diseases. Many human studies either involve small numbers of patients or lack appropriate controls. One helpful review (McGee and Hirschmann, 2008) of published randomized, double-blinded studies comparing corticosteroids with placebo in the treatment of human infectious diseases categorized the role of glucocorticoids as either improving survival with some infections (e.g., bacterial meningitis, pneumocystis pneumonia), reducing long-term disability (e.g., bacterial arthritis), improving symptoms (herpes zoster, many others), providing no or uncertain benefit, or causing harm (viral hepatitis, cerebral malaria). The range of outcomes described in people indicates that no “one size fits all” approach is appropriate for the use of glucocorticoids in small animals with infectious diseases and suggests that blanket avoidance of glucocorticoids in patients with infectious disease is not clinically appropriate.

Glucocorticoids in Small Animals with Infectious Disease

Respiratory Infections

Clinicians have proposed that antiinflammatory doses of glucocorticoids for 5 to 7 days may be effective in ameliorating cough associated with uncomplicated infectious tracheobronchitis but do not shorten significantly the clinical course of disease. It is recognized commonly that after initial administration of antifungal agents to patients with fungal pneumonia (i.e., blastomycosis and histoplasmosis) respiratory signs can worsen presumably as a consequence of heightened inflammation associated with fungal death. Glucocorticoids are thought to prevent treatment-induced inflammation from occurring. In people who develop hypoxemia or respiratory distress after initiation of antifungal therapy for histoplasmosis, or who develop other inflammatory complications of the infection, treatment with glucocorticoids is recommended (Wheat et al, 2007). However, the evidence to support this recommendation is primarily physician experience and isolated reports instead of prospective, controlled clinical studies. A preliminary report of dogs with severe respiratory blastomycosis treated with either nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids, in addition to antifungal therapy, found no difference in clinical outcomes between the two treatment groups (Munks et al, 2011). A group of dogs treated with only antifungal drugs was not described, so it is difficult to know if antiinflammatory therapy had a positive impact on the clinical course of affected dogs. In a retrospective study of chronic histoplasmosis in dogs (Schulman, McKiernan, and Schaeffer, 1999), clinical signs of coughing from airway obstruction associated with hilar lymphadenomegaly resolved more quickly with administration of immunosuppressive dosages (2 to 4 mg/kg q24h) of prednisone alone or prednisone and antifungal drugs compared with those in dogs treated with antifungal chemotherapy alone (less than 3 weeks compared with approximately 9 weeks). In this study the glucocorticoid-treated dogs did not show evidence of dissemination of disease.

Central Nervous System Infections

In central nervous system (CNS) infections, inflammatory mediators and toxic factors produced by the immune system may be more responsible for CNS damage than the primary pathogen. Treatment of bacterial organisms can result in lysis and release of inflammatory cell wall components, including lipopolysaccharides and outer membrane vesicles. No controlled studies address the use of glucocorticoids in dogs or cats with infectious meningitis. However, anecdotal experience, case reports, and the human literature suggest a potential benefit, but not all human studies ascribe advantages in reduction of mortality and neurologic sequelae to glucocorticoid therapy.

At the authors’ institution patients suspected to have CNS infection based on cerebral spinal fluid (CSF) pleocytosis, elevated CSF protein content, and/or consistent magnetic resonance imaging findings are treated with a broad-spectrum antimicrobial and antiinflammatory protocol (trimethoprim-sulfonamide 15 mg/kg q12h PO; clindamycin 12.5 mg/kg q12h PO; prednisone 0.5 mg/kg q12h PO) while awaiting more definitive results, including bacterial culture and titers or polymerase chain reaction results for viral and protozoal organisms. Diagnostic testing always should be performed before any treatment because it may affect CSF analysis and culture results. In addition, glucocorticoids may attenuate the increased blood-brain barrier permeability that results from inflammation, thereby theoretically reducing antimicrobial penetration into the CSF. Clinical studies in small animals with bacterial meningitis that address antibiotic penetration in the face of glucocorticoids are lacking, and long-term consequences of glucocorticoid therapy for infectious meningitis have not been established.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Rational Use of Glucocorticoids in Infectious Disease
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