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Infectious Complications of Corticosteroid Therapy
Corticosteroids play a key role in the management of many neoplastic, autoimmune, allergic, and autoinflammatory disorders. Corticosteroids are used for their lympholytic and antiinflammatory effects during infection, for example, to prevent airway obstruction during croup or Epstein-Barr virus−associated tonsillitis, or to dampen immune reconstitution inflammatory syndrome (IRIS) when treating pulmonary or brain infection in patients with acquired immunodeficiency syndrome (AIDS). Corticosteroids also are given frequently after surgery on airway structures or before extubation. Despite widespread applications, utility is tempered by the occurrence of myriad adverse effects, including increased risk and severity of infections.
Corticosteroids can be either naturally produced or laboratory-synthesized hormones; glucocorticoids generally regulate inflammation and metabolism, whereas mineralocorticoids regulate water and sodium. Glucocorticoids are highly lipid soluble and readily penetrate cell membranes, binding to a specific receptor present in all nucleated cells, which allows both antiinflammatory and metabolic effects without specificity. Corticosteroids generally are metabolized by the hepatic cytochrome P450 system. Direct application to sites of inflammation (e.g., topical, inhaled, epidural) provides high local concentrations and bypasses rapid metabolism.
Glucocorticoids exert antiinflammatory effects through multiple mechanisms: reduction in circulating leukocyte populations, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils; inhibition of production of cytokine and other proinflammatory molecules; inhibition of synthesis of interleukin-2 (IL-2) receptor; and reduction of expression of major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells, leading to suppression of immunologic response. With prolonged administration, cell-mediated immunity is suppressed.
Initially, administration of glucocorticoids causes a temporary increase in the peripheral circulation of neutrophils due to enhanced release from bone marrow and reduced migration from blood vessels. Ultimately, the peripheral leukocyte count declines because of migration of lymphocytes, monocytes, basophils, and eosinophils from the peripheral vasculature to the lymphoid tissues. Neutrophil function and bactericidal activity are impaired at least in part owing to reduced adherence to vascular endothelium and diapedesis into interstitial spaces.
Infectious Adverse Effects of Glucocorticoids
It is challenging to confirm a direct causal relationship between corticosteroid use and increased risk or severity of infection because of the wide range of underlying diseases for which corticosteroids are prescribed and the combination immunosuppressive therapies that many patients receive. Although much of the available data are derived from observational studies in adults, the body of data in children suggests that extrapolation of effects to children is reasonable. Corticosteroids have been associated with increased risk for infection across multiple immunocompromised states as well as in previously immunocompetent hosts. , In a meta-analysis of adult and pediatric patients receiving corticosteroids, the relative risk (RR) for infectious complications was 1.6 (95% confidence interval [CI], 1.3−1.9; P < .001). Confining analysis to adults taking daily doses of prednisone between 20 and 40 mg, the RR of infection was 2.1 (95% CI, 1.3−3.6): a pediatric subset analysis was not reported. Increased rates of infection were not seen in adult and pediatric patients given prednisone at daily doses of <10 mg or cumulative doses of <700 mg when analyzed together. Thus, higher doses of glucocorticoids and combination therapy with other immunosuppressive agents elevate the risk for infectious complications. Excess risk or severity or infections caused by bacterial, fungal, viral, and parasitic pathogens has been reported in patients receiving glucocorticoid therapy ( Box 108.1 ). The antiinflammatory properties of the glucocorticoids also can modify typical signs and symptoms of infection, resulting in presentation at a later stage of the infection.
BOX 108.1
Infections Reported With Excess Risk or Severity in Patients Treated With Corticosteroids
| Bacteria | Gram-positive— Staphylococcus aureus, Listeria monocytogenes, Nocardia spp.Gram-negative— Pseudomonas, Klebsiella, Salmonella, Legionella spp. Mycobacterium spp. |
| Fungi | Aspergillus , Candida , Cryptococcus , endemic mycoses, Fusarium , Scedosporium , Trichosporon , zygomycetes |
| Viruses | Herpesviruses, enteroviruses, hepatitis B and hepatitis C viruses |
| Parasites | Strongyloides stercoralis |
Bacterial Infections
Bacterial infections are the most common complication of corticosteroid use, and potentially any bacterial pathogen can be causative. Bacterial sepsis occurred 1.5 times more frequently in adult and pediatric patients receiving systemic corticosteroids in one meta-analysis; among all patients in the dataset, the mean daily drug exposure was equivalent to 35 mg of prednisone, with the mean total exposure of 2200 mg. A meta-analysis of prediction models for neonatal intensive care unit (NICU)−associated sepsis found postnatal corticosteroid use to have a statistically significant predictive association. Other studies of NICU-associated sepsis have demonstrated increased rates associated with antenatal corticosteroids to promote pulmonary maturation as well as postnatal corticosteroids, primarily dexamethasone. These risks must be considered in context of demonstrated benefits of antenatal corticosteroids to reduce intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, and all-cause neonatal mortality.
Surgical site infections are significantly increased among patients receiving long-term corticosteroid immunosuppressive therapy, including neonatal and pediatric patients <5 years undergoing complex cardiac surgery, , and data suggest that corticosteroids may be associated with increased overall morbidity after cardiac surgery, particularly in lower risk patients. An increased risk for surgical site infection has been associated with corticosteroid use in adults with ulcerative colitis.
Long-term corticosteroid use increases the risk for bacterial opportunistic infections related to impaired cell-mediated immunity. Bacterial pathogens include mycobacteria and Nocardia and Legionella spp. , In a large case-control study of adults, the adjusted odds ratio of Mycobacterium tuberculosis in the group receiving corticosteroids compared with no steroid use was 4.9 (95% CI, 2.9, 8.3). Pediatric-specific data are limited.
Fungal Infections
Invasive fungal infections are most frequently observed in patients receiving chronic corticosteroid therapy who are profoundly immunocompromised, such as hematopoietic stem cell transplantation (HSCT) and solid organ transplantation patients, oncology patients, and patients with collagen-vascular disorders. Higher doses and longer duration of glucocorticoid therapy are associated with higher risk and worse prognosis for invasive fungal infection, and lower doses and alternate-day regimens have been shown to be protective. , In addition to increasing risk for invasive fungal infection, the antiinflammatory properties of glucocorticoids also can result in delayed recognition because of modified signs and symptoms of infection. Invasive aspergillosis is an important pathogen in allogeneic bone marrow transplantation and is the most common cause of infectious death among these patients, resulting in 10% of mortality in the late post-transplantation period. , However, invasive aspergillosis, the most common mold infection associated with glucocorticoid administration, has been reported in patients receiving only high-potency inhaled glucocorticoids, without other immunosuppressive therapies.
Glucocorticoids are an independent risk factor for invasive yeast infections, including invasive candidiasis and candidemia. Increased risk is reported in patients with cancer and HSCT, hemodialysis, systemic lupus erythematosus, or surgery and in premature neonates. , In one study of premature neonates, risk for invasive candidiasis was 7.5-fold higher in infants treated with glucocorticoids for hypotension compared with unexposed infants. In a recent study during routine use of antifungal prophylaxis in premature infants, corticosteroid use was not a statistically significant risk factor for invasive candidiasis, suggesting that risk can be successfully mitigated.
Pneumocystis jirovecii pneumonia (PCP) is associated with prolonged and high-dose glucocorticoid administration in children and adults with cancer, solid-organ and allogeneic bone marrow transplantations, and collagen-vascular disorders. PCP also has occurred in asthmatic children treated with high doses of systemic corticosteroids. Cryptococcal infections, including meningitis, have been described in non-AIDS patients receiving glucocorticoids, although no specific pediatric data are available. Primary and reactivated endemic fungal infections also are reported in patients receiving long-term glucocorticoids. Although histoplasmosis is reported most frequently, coccidioidomycosis, blastomycosis, penicilliosis, and sporotrichosis also have been reported, primarily in adults.
Viral Infections
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