The MEDLINE and PubMed databases (from 1966 to February, 2003) and abstracts from major infectious diseases meetings held from 1992 to 2002 were searched for published reports pertaining to the association between glucocorticoid-induced immunosuppression and IFIs. Articles describing the effects of glucocorticoids on the host's immune responses and the spectrum and clinical presentation of IFIs with hypercortisolism were reviewed. Studies were selected based on significance of data (as
ReviewGlucocorticoids and invasive fungal infections
Introduction
Cushing's syndrome is a metabolic condition featuring persistently excessive plasma cortisol levels (normal morning values: 138–607 nmol/L). Its origins fall into two categories. First, endogenous Cushing's syndrome is caused primarily by pituitary adenoma (Cushing's disease), and, less commonly, by hormonally active adrenal neoplasms or ectopic production of adrenocorticotropic hormone (ACTH). Second, the far more common exogenous or iatrogenic Cushing's syndrome is seen mainly with long-term glucocorticoid therapy at supraphysiological doses, for inflammatory, autoimmune, and neoplastic conditions.1
Endogenous and iatrogenic hypercortisolism have long been recognised to predispose patients to invasive fungal infections (IFIs).2, 3, 4 Although supraphysiological glucocorticoid levels undoubtedly result in increased susceptibility to IFIs, the prevalence and attributed mortality of such infections with glucocorticoid excess, and the minimum required glucocorticoid exposure for IFI development, are difficult to quantify. This difficulty is further complicated by the frequent comorbidities and additional risk factors for IFIs in affected patients. Herein we review the spectrum and presentation of IFIs in patients with hypercortisolism and how glucocorticoids contribute to their pathogenesis.
Section snippets
Components of immunity that control fungal infections
In immunocompetent hosts, there are two lines of defence against inhaled moulds. First, resident lung macrophages facilitate phagocytosis and, primarily, nonoxidative killing of conidia (asexual spores).5, 6 These cells have a very efficient phagocytic capacity, phagocytosing more than 108 conidia daily.5 Still, some conidia escape phagocytosis, germinate to hyphae, and establish an invasive infection. Then, neutrophils are chemotactically attracted and attach to the hyphae, which are
Effects of glucocorticoids on immunity
Glucocorticoids exert many complex quantitative and qualitative immunosuppressive effects that induce cellular immunodeficiency, increasing host susceptibility to IFIs. These effects have been shown in studies both at cortisol levels typically encountered in patients with endogenous Cushing's syndrome and at glucocorticoid levels achieved in patients receiving pharmacological concentrations of glucocorticoids.9, 10, 11, 12, 13, 14, 15, 16, 17, 18 The mechanism by which glucocorticoids exert
Invasive fungal infections in endogenous Cushing's syndrome
Compared with patients with iatrogenic Cushing's syndrome, fewer IFIs arise in those with endogenous Cushing's syndrome. However, the endogenous syndrome typically results in much higher plasma cortisol levels than does iatrogenic glucocorticoid therapy.2 Thus, whenever IFIs arise in endogenous Cushing's syndrome, they carry a high fatality rate if left undiagnosed due to substantial net immunosuppression.2, 45 Dimopoulos and colleagues46 reported a high incidence of severe IFIs in patients
Invasive fungal infections after exogenous glucocorticoid therapy
Systemic glucocorticoids are extensively used in bone marrow transplantation, solid organ transplantation, and treatment of haematological malignancies (eg, leukaemia, lymphoma, multiple myeloma), vascular-collagen disorders (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis), and chronic pulmonary conditions (eg, asthma, chronic obstructive pulmonary disease, sarcoidosis; figure 2). This widespread use of glucocorticoids has expanded the population of profoundly immunocompromised
Invasive fungal infections caused by moulds
As mentioned, both lines of defence against invasive mould infections (macrophages and PMNs) are defective following glucocorticoid therapy, rendering glucocorticoid-treated patients at high risk for such infections.13, 16, 17, 29 Glucocorticoids' primary role in predisposing to such infections is most likely impairment of macrophage anticonidial activity.5, 35
Invasive fungal infections caused by yeasts
As previously mentioned, all the immunity components responsible for controlling yeast infections (monocytes and macrophages, PMNs, and T lymphocytes) are dysfunctional after glucocorticoid therapy.13, 16, 17, 29, 35 Hence, glucocorticoid-treated patients are susceptible to invasive yeast infections.
PCP
PCP is the most common opportunistic infection in patients with AIDS.106 Although glucocorticoids are a well-recognised treatment modality in severely hypoxaemic patients with PCP, the findings of several studies have associated glucocorticoids with PCP development in patients with cancer and vascular-collagen disorders, and in those receiving allogeneic bone-marrow and solid-organ transplants.77, 116, 117, 118, 119 Therefore, prophylaxis with trimethoprim/sulfamethoxazole should be considered
Invasive infections caused by endemic and dimorphic fungi
Patients receiving glucocorticoids may develop primary or reactivated infections by endemic fungi. However, glucocorticoids' role in their pathogenesis is uncertain. Histoplasmosis is the primary endemic mycosis in patients receiving glucocorticoids.129 In patients with SLE, a main risk factor for disseminated histoplasmosis is glucocorticoid treatment at doses of greater than 20 mg/day.130 Furthermore, Torres and colleagues131 noted that 43% of their cancer patients with histoplasmosis had
Conclusions
Glucocorticoids have pleiotropic effects on immunity that account for hypercortisolaemic patients' propensity for life-threatening IFIs. However, the exact prevalence and attributed mortality of such infections are difficult to quantify. As our knowledge accumulates, better understanding of glucocorticoids' precise effect on IFI pathogenesis might lead to earlier detection and initiation of treatment. Because IFI severity is associated with intensity of glucocorticoid treatment, every effort
Search strategy
References (135)
- et al.
Non-Candida fungal infections after bone marrow transplantation: risk factors and outcome
Am J Med
(1994) - et al.
The immunosuppressive potency in vitro of physiological and synthetic steroids on lymphocyte cultures
Int J Immunopharmacol
(1987) - et al.
Glucocorticoid-mediated gene suppression of rat cytokine-induced neutrophil chemoattractant CINC/gro, a member of the interleukin-8 family, through impairment of NF-kappa B activation
J Biol Chem
(1996) - et al.
Acute suppressive effect of hydrocortisone on p47 subunit of nicotinamide adenine dinucleotide phosphate oxidase
Metabolism
(2001) - et al.
Novel mechanism of glucocorticoid-mediated gene repression. Nuclear factor-kappa B is target for glucocorticoid-mediated interleukin 8-gene repression
J Biol Chem
(1994) - et al.
Molecular mechanisms and Th1/Th2 pathways in corticosteroid regulation of cytokine production
J Neuroimmunol
(2000) - et al.
Glucocorticoids inhibit apoptosis of human neutrophils
Blood
(1995) - et al.
The anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis
Mol Cell Endocrinol
(2002) - et al.
Glucocorticoids inhibit the induction of nitric oxide synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-kappa B
Mol Pharmacol
(1996) - et al.
Glucocorticoid receptor variants: clinical implications
J Steroid Biochem Mol Biol
(2002)
Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors
Blood
Alternate-day single-dose prednisone therapy: a method of reducing steroid toxicity
J Pediatr Surg
Improved outcome following renal transplantation with reduction in the immunosuppression therapy for rejection episodes
Am J Med
Cyclosporine in renal transplantation: a single institutional experience
Am J Kidney Dis
Infections associated with steroid use
Infect Dis Clin North Am
Central nervous system aspergillosis: a 20-year retrospective series
Human Path
Glucocorticoid-induced alterations of monocyte defense mechanisms against Candida albicans.
Cell Immunol
The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer
Am J Med
Cushing's syndrome
N Engl J Med
Opportunistic infections in endogenous Cushing's syndrome
Ann Intern Med
Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients
J Clin Oncol
Aspergillus fumigatus and aspergillosis
Clin Microbiol Rev
Pathogenesis I: interactions of host cells and fungi
Med Mycol
Production and function of cytokines in natural and acquired immunity to Candida albicans infection. Microbiological Reviews
Microbiol Rev
Macrophages in resistance to candidiasis
Microbiol Mol Biol Rev
Possible differences in the mechanism(s) of action of different glucocorticoid hormone compounds
Ann N Y Acad Sci
Mechanisms of corticosteroid action on lymphocyte subpopulations. II. Differential effects of in vivo hydrocortisone, prednisone and dexamethasone on in vitro expression of lymphocyte function
Clin Exp Immunol
Influence of corticosteroids on neutrophils, lymphocytes, their subsets, and T-cell activity markers in patients with active rheumatoid arthritis, compared to healthy controls
Ann N Y Acad Sci
Immunosuppressive effects of glucocorticosteroids: differential effects of acute vs chronic administration on cell-mediated immunity
J Immunol
Alternate-day prednisone therapy. Evaluation of delayed hypersensitivity responses, control of disease and steroid side effects
N Engl J Med
Natural killer cell activity in the peripheral blood of patients with Cushing's syndrome
Eur J Endocrinol
Novel pathways for glucocorticoid effects on neutrophils in chronic inflammation
Inflamm Res
Effects of corticosteroids on human monocyte function
J Clin Invest
Cushing's syndrome—transitory immune deficiency state?
Postgrad Med J
Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids
Biochem J
Suppression of nuclear factor kappa B and CD 18-mediated leukocyte adhesion to the corneal endothelium by dexamethasone
Invest Ophthalmol Vis Sci
Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor
Proc Natl Acad Sci USA
The effects of cortisone therapy on lung macrophage host defense function and glucose metabolism
Circ Shock
Kinetic study of host defense and inflammatory response to Aspergillus fumigatus in steroid-induced immunosuppressed mice
J Infect Dis
The effect of short-term prednisone therapy on the Mantoux skin test
Pediatr Infect Dis J
Th1 and Th2 cytokines in mice with invasive aspergillosis
Infect Immun
An alternate mechanism of glucocorticoid anti-proliferative effect: promotion of a Th2 cytokine-secreting profile
Clin Transplant
Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon
Infect Immun
Inhibition of monocyte-mediated damage to fungal hyphae by steroid hormones
J Infect Dis
Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon
J Clin Invest
Protection of bronchoalveolar macrophages by granulocyte-macrophage colony-stimulating factor (GM-CSF) against dexamethasone suppression of fungicidal activity for Aspergillus fumigatus conidia
Med Mycol
Regulation by Granulocyte-macrophage colony-stimulating factor and/or steroids given in vivo of proinflammatory cytokine and chemokine production by bronchoalveolar macrophages in response to
Aspergillus conidia
Glucocorticoids down-regulate dendritic cell function in vitro and in vivo
Eur J Immunol
Effect of glucocorticosteroids on epidermal cell-induced immune responses
J Immunol
Inhibition of microglial nitric oxide production by hydrocortisone and glucocorticoid precursors
Neuro Res
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