Reviews focus on adverse effects of short-course corticosteroid treatment for asthma

January 2006

Systemic corticosteroids (CS) are effective treatment for acute exacerbations of asthma.

CS are administered either orally as “burst” therapy for ambulatory patients or, more commonly, parenterally for children who are hospitalized with more severe symptoms. Although some may consider parental administration to be more effective than oral administration, recent national asthma guidelines state that this is not true.

Although CS burst therapy is commonly employed in the treatment of acute exacerbations, clinicians and caregivers may harbor concerns, often unduly so, about the long-term adverse effects of CS burst therapy. Such fears may adversely affect the appropriate use of CS, manifesting as altered dose or duration of therapy. Caregivers with such concerns may not adhere to therapy.

Pharmacology

Seven agents are available in oral dosage forms for clinicians to choose from when prescribing CS therapy.

Prednisone, prednisolone and methylprednisolone are most commonly used for oral burst therapy for children with acute exacerbations. Prednisolone is the active form of prednisone, and prednisone must be hepatically activated to prednisolone. These seven agents differ in their pharmacologic actions and effects. These pharmacologic actions typically are categorized as glucocorticoid (carbohydrate metabolism-regulating) and mineralocorticoid (electrolyte balance-regulating). Anti-inflammatory effects are most closely related to glucocorticoid activity. The main endogenous CS is cortisol (hydrocortisone), a glucocorticoid, and aldosertone, a mineralocorticoid. Approximately 10 mg of cortisol is produced daily (in normal, physiologic health) by the adrenal cortex. Under severe stress, 100 mg or more of cortisol may be produced. Exogenous administration of more than an equivalent dose of cortisol is considered a pharmacologic dose.

The available CS agents may differ greatly by glucocorticoid and mineralocorticoid potency. A dose of prednisone (or prednisolone) that is equivalent in glucocorticoid (anti-inflammatory) potency to 10 mg of cortisol is 2.5 mg (ie, four times potency compared with cortisol). An equivalent dose of methylprednisolone is 2 mg (ie, 5 times as potent compared with cortisol). Prednisone/prednisolone and methylprednisolone possess 80% and 50% of the mineralocorticoid activity of cortisol, respectively. Of the seven CS agents most commonly used in clinical practice, dexamethasone is the most potent anti-inflammatory agent (25 times as potent as cortisol and six times as potent as prednisone). Dexamethsone is devoid of mineralocorticoid effects.

The CS display numerous actions upon many organ and physiologic systems, and this underlies their varied useful clinical indications. Unfortunately, these actions also allow the potential for numerous adverse effects to result, some of which may be quite significant. In the treatment of asthma, the CS have no direct effects upon airway smooth muscle to allow airway relaxation; however, they have potent anti-inflammatory effects, and thus CS are the most effective drugs for the treatment of acute exacerbations. CS possess numerous effects upon the inflammatory process. Important anti-inflammatory actions in the therapy of asthma include modulation of cytokine and chemokine production, reduced production of lipolytic and proteolytic enzymes, inhibition of accumulation of various lung tissue leukocytes, decreased vascular permeability and decreased fibrosis.

Adverse effects

Because of numerous and varied physiologic actions, CS have a wide adverse effect profile. Fortunately, and applicable to burst therapy for asthma, most of these adverse effects are unlikely to occur with short-term therapy (less than or equal to 10 days). Adverse effects associated with long-term therapy include fluid and electrolyte disturbances, hypertension, hyperglycemia, immunosuppression, osteoporosis, myopathy, behavioral disturbances, cataracts, growth retardation, striae, acne, hirsutism, fat redistribution and HPA axis suppression. The most common adverse effects associated with short-term burst therapy use include mood disturbances, increased appetite or loss of glucose control in children with diabetes.

Caregivers may not typically appreciate the difference in the occurrence of the above adverse effects in relation to CS dose and duration of therapy. Caregivers may associate “steroids” with growth suppression and other serious adverse effects well known to even the lay public. Thus, they may be hesitant to administer CS beyond several days, or beyond the first indication of improving symptoms in their child with an acute exacerbation. With subtherapeutic dosing, recovery may be delayed or incomplete. Clinicians, also mindful of the above adverse effects, may be hesitant to recommend or prescribe CS therapy beyond only a few days, or to prescribe doses sufficient enough to completely resolve symptoms. Additionally, CS prescribing may include dose tapering after three to five days of CS therapy, with the belief that tapering minimizes HPA axis suppression or reactivation of acute symptoms. Short-term dose tapering may potentially provide subtherapeutic dosing or prove confusing to some patients or caregivers.

Treatment guidelines

Several asthma treatment guidelines are available to assist clinicians with treatment decisions and strategies. The most well known may be the “Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma – Update on Select Topics 2002 (EPR – Update 2002),” from the National Heart, Lung and Blood Institute and the National Asthma Education and Prevention Program. Recommendations for outpatient burst CS (prednisone, prednisolone or methylprednisone) therapy in children from EPR – Update 2002 include 1-2 mg/kg/day (high dose), maximum 60 mg/day, for 3 to 10 days. Burst therapy should be continued until the child achieves 80% PEF (peak expiratory flow) personal best or resolution of symptoms. A 3- to 10-day treatment duration should suffice for most children, although some may require longer treatment courses. These guidelines state that no evidence exists that tapering the dose following improvement prevents relapse. Treatment guidelines are also available from the American Academy of Allergy, Asthma and Immunology, and endorsed by the AAP, “Pediatric Asthma: Promoting Best Practice – Guide for Managing Asthma in Children (1999).” Similar to the EPR recommendations, a treatment course of 3 to 10 days (1-2 mg/kg/day, maximum 60 mg/day, for prednisone, prednisolone, or methylprednisolone) is recommended for therapy of acute exacerbations. These guidelines state that dose tapering is not necessary for 3- to 10-day burst treatments.

Immune function suppression

Clinicians may be concerned with HPA axis suppression when prescribing CS burst therapy for acute asthma exacerbations. Several published studies have evaluated the potential for HPA axis suppression to occur with short-term CS use. Zora evaluated the potential for HPA axis suppression in 11 asymptomatic children (8 to 18 years) with asthma after administration of a 5-day course of prednisone (mean 1.2 mg/kg/day, range 0.7-2 mg/kg/day). No child had received inhaled CS within the previous four weeks. HPA axis function was assessed by plasma CS concentration before and after insulin-induced hypoglycemia. Of the 11 children evaluated, three had received greater than or equal to 1 CS burst treatments within the previous 12 months. (One child had received 10 CS courses.) Researchers evaluated the insulin hypoglycemic test (IHT) prior to CS treatment and at three- and 10-days post-CS treatment. At the three-day post-CS treatment IHT, six out of 11 children failed to demonstrate a normal corticosteroid response to insulin-induced hypoglycemia (P<0.05). At the 10-day, post-CS treatment IHT, all children demonstrated a normal response, including the child who had received 10 previous CS burst courses. Thus, a 5-day prednisone course (mean dose of 1.2 mg/kg/day) in the children evaluated produced a HPA axis suppression of only short duration, which had resolved by 10 days.

Dolan evaluated HPA axis function in 23 children with asthma. The researchers classified patients into three groups: children who had received less than or equal to 1 CS burst within the previous 12 months (group I, control); children who had received more than 1 CS burst within the previous 12 months (group II); and children who had received more than 1 CS burst as well as maintenance inhaled CS therapy (group III). Groups II and III had received 3 to 5 and 3 to 7 bursts in the previous 12 months, respectively, with a burst duration of 6 to 7 days. Group III had also received a mean inhaled beclomethasone-equivalent dose of 302 µg/day (low dose). Researchers measured HPA axis function by plasma cortisol in response to serial insulin-induced hypoglycemia, followed by ACTH (cosyntropin) testing. A minimum of 16 days had elapsed between the end of the last burst and HPA axis evaluation (range of 2.8-7.7 months between last burst and study evaluation). Thus, this study differs from Zora’s evaluation by the relatively longer length of time between CS administration and HPA axis function evaluation. Compared with children receiving no CS burst therapies (controls), 16% of group II children had an abnormal response of cortisol to hypoglycemia; and 20% and 10% of group III children had an abnormal response of cortisol to hypoglycemia or ACTH, respectively. All children with an abnormal HPA axis response had received more than or equal to 4 CS bursts (with or without inhaled CS) within the previous 12 months.

Although these studies provide useful information, the relatively small numbers of children evaluated limit them. Earlier studies in adults have demonstrated similar findings – HPA axis function is only transiently (<10 days) suppressed with short-term CS burst therapy (Streck). One study found similar results in adults treated with prednisolone 40 mg daily for 21 days (Webb).

In a more recent study, Ducharme evaluated the effects of CS burst treatments on HPA axis function, bone density and bone metabolism. This cross-sectional study evaluated 48 children (mean age 6 years) treated for an acute asthma exacerbation with prednisone (1-2 mg/kg/day for 5 days) who had been exposed to at least two times five day burst treatments (mean 4 bursts, range 3-11) within the previous 12 months (71% also were receiving maintenance inhaled CS). These children were compared with 35 children with asthma who had not received systemic CS within the previous 12 months (29% had received inhaled CS) or for the index exacerbation. All children maintained on inhaled CS had received a mean beclomethasone-equivalent dose of 115 µg daily. HPA axis function was evaluated with morning plasma cortisol measurement (baseline and after ACTH stimulation) 1 month after the index exacerbation. There was no difference in the basal cortisol and peak cortisol response to ACTH in the CS-exposed and CS-unexposed groups. Adverse effects of CS treatment upon bone function were transient – serum osteocalcin (the most abundant noncollagenous bone protein) was decreased by 30% at the end of the 5-day CS burst, but returned to baseline at 30 days post-CS burst. Bone density z score was similar in the exposed and unexposed groups 30 days post-CS burst treatment. Both groups, however, had lower than expected bone density z scores for age, gender and race.

Adverse effects of burst CS treatment upon immune function may also be of concern to clinicians and patients. The CS dose and duration to induce clinically significant immunosuppression in a patient with normal immune system function is not well defined. The 2003 Red Book states that, although immunosuppressive CS doses are not well defined, a prednisone dose of more than or equal to 2 mg/kg/day (to a total of more than or equal to 20 mg/day for children who weighs more than 10 kg) for a duration of more than 14 days may be potentially immunosuppressive to compromise live-viral vaccine safety. The Red Book offers more specific recommendations relating to timing of CS treatment and receipt of live-viral vaccines (pages 74-75), including circumstances, which may be applicable to treatment of acute asthma exacerbations. Children receiving fewer than 2 mg/kg/day of prednisone (or fewer than 20 mg/day for weights more than 10 kg) can receive live-viral vaccines during CS therapy. Children receiving more than or equal to 2 mg/kg/day of prednisone (or more than or equal to 20 mg/day with weights more than 10 kg) for fewer than 14 days can receive live-viral vaccines immediately after CS treatment. Delays in scheduled immunization in asthmatic children receiving short-course CS treatments may increase the risk of morbidity with the associated infectious disease.

Pharmacologic doses of systemic CS provide numerous beneficial effects for the treatment of acute asthma exacerbations, and they are accepted as standard therapy. Because of numerous pharmacologic functions, the potential for numerous adverse effects also exists. Most of these adverse effects, however, occur only with long-term therapy.

Published studies have evaluated the potential for CS to induce HPA axis suppression. Although these studies are limited by a low number of children evaluated and differences in methods of HPA function assessment, the available data indicate that CS-induced HPA axis suppression can occur, but it is likely to be of short duration (fewer than 10 days) in children who have received fewer than 4 burst treatments within the previous 12 months. Some evidence indicates that children receiving four or more burst treatments in a 12-month period may have more prolonged HPA suppression, and they may potentially benefit from the use of additional CS doses during physiologic stress.

For more information:

• Ducharme FM. Safety profile of frequent short courses of oral glucocorticoids in acute pediatric asthma: impact on bone metabolism, bone density, and adrenal function. Pediatrics. 2003;111:376-83.
• National Asthma Education and Prevention Program Expert Panel. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma – Update on Select Topics 2002. NIH Publication 02-5074. Bethesda, MD: National Institutes of Health;2003.
• Pediatric Asthma Committee. Pediatric Asthma: Promoting Best Practice – Guide for Managing Asthma in Children. Milwaukee, WI: American Academy of Allergy, Asthma and Immunology;1999.
• Dolan LM. Short-term, high-dose, systemic steroids in children with asthma: the effect on the hypothalamic-pituitary-adrenal axis. J Allergy Clin Immunol. 1987;80:81-7.
• Zora JA. Hypothalamic-pituitary-adrenal axis suppression after short-term, high-dose glucocorticoid therapy in children with asthma. J Allergy Clin Immunol. 1986;77:9-13.
• Streck WF. Pituitary recovery following short-term suppression with corticosteroids. Am J Med. 1979;66:910.
• Webb J. Recovery of plasma corticotrophin and cortisol levels after a three-week course of prednisolone. Thorax. 1981;36:22.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.