(Chest. 2006;130:41S-53S.)
© 2006
American College of Chest Physicians
Side Effects With Inhaled Corticosteroids*
The Physician’s Perception
Richard S. Irwin, MD, FCCP and
Naomi D. Richardson, MSc, MBA
* From the Pulmonary, Allergy and Critical Care Medicine Division (Dr. Irwin), University of Massachusetts Medical School, Worcester, MA; and Magenta Communications Ltd, (Ms. Richardson), Oxon, UK.
Correspondence to: Richard S. Irwin, MD, FCCP, Pulmonary, Allergy and Critical Care Medicine Division, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655; e-mail: Irwinr{at}ummhc.org
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Abstract
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The National Asthma Education and Prevention Program 1997 guidelines and 2002 update provide an overview of potential local and systemic side effects associated with inhaled corticosteroids (ICS) and suggest ways of minimizing the risk of these side effects occurring. Despite the guidelines and extensive clinical experience of the safe use of ICS, a significant number of physicians retain concerns regarding side effects. Local side effects may lead to patients discontinuing therapy, with or without the knowledge of their physicians. In particular, concerns regarding systemic side effects, such as growth retardation in children and osteoporosis, remain relatively widespread. Pharmacokinetic studies reveal that different ICS compounds and formulations result in different degrees of systemic bioavailability, indicating possible differences in their potential to cause systemic side effects. However, clinical studies that can be used to differentiate between ICS formulations are generally lacking. Consequently, there is a need to continue to further our understanding of side effects with ICS, with the aim of identifying formulations, devices, and doses with an optimal risk/benefit ratio. The introduction of new agents with potentially improved safety profiles may reassure physicians and patients as to the relative benefits of ICS therapy in asthma.
Key Words: adverse events • asthma • inhaled corticosteroids • safety • side effects
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Introduction
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Inhaled corticosteroids (ICS) are the cornerstone of asthma management and result in improved symptom control and quality of life for many patients.1 However, as for all medicines, the physician must achieve a balance between the potential benefits for the patient and the risk of side effects. For ICS therapy, the potential side effects may be local in the oropharyngeal cavity, or systemic due to absorption of ICS into the circulation through the lungs and GI tract. Increasing the dose of ICS in order to achieve improvements in asthma symptoms, or prolonged treatment over many years, will expose patients to an increased risk of side effects.1
Despite the publication of guidelines23 stressing the importance of ICS, ICS are often underused. The major reason that physicians fail to prescribe ICS appears to be due to disagreement with recommendations, particularly regarding when the balance lies between their benefits and the risk of complications and side effects.3 In addition, patients’ fears of ICS may lead to a lack of adherence with prescribed therapy, which may expose them to the unnecessary risk of an asthma exacerbation.3 Although the nature of local side effects with ICS is fairly well described and understood,1 the impact of these side effects on patient quality of life and adherence to therapy may be underestimated.4 However, the most common concerns regarding ICS therapy relate to the potential systemic effects, which are often more serious, long term, and can be difficult to detect and treat.56
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Local Side Effects of ICS Therapy
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The National Asthma Education and Prevention Program (NAEPP) 1997 guidelines for the diagnosis and management of asthma list local side effects with ICS as oral candidiasis, dysphonia, and cough.1 Oral candidiasis is a common side effect for many adult patients receiving ICS.1 The reported incidence varies from 0 to 77%, based on how oral candidiasis was defined.7 Systematic reviews8910 have yielded conflicting information. For example, some reviews8910 have found that fluticasone propionate (FP), but not budesonide (BUD), was associated with an increased risk of candidiasis compared with placebo, and this effect was dose related. However, in a similar review11 of comparative studies between FP vs BUD or beclomethasone dipropionate (BDP), there was no difference in the risk of oral candidiasis between these agents. Oral candidiasis was more frequent with FP at 880 µg/d (5.2%) than with ciclesonide (CIC) at 640 µg/d (0.4%; p < 0.0001).12 In a study13 of mometasone furoate (MF) at 200 µg and 400 µg bid compared with the BUD inhaler (Turbuhaler; AstraZeneca AB; Södertälje, Sweden), 400 µg bid, the incidence of oral candidiasis was not more than 3% in any group. However, at higher doses of MF (800 to 1,600 µg/d), oral candidiasis has been observed in 20 to 23% of patients.14
A systematic review15 compared the dose response for oral candidiasis for FP with the dose response for preventing an exacerbation. The authors15 calculated the number of patients that needed to be treated to prevent withdrawal of therapy due to worsening of asthma symptoms vs the risk of oral candidiasis. In this analysis, the number of patients who avoided asthma exacerbation by taking FP increased with increasing daily doses of FP, although the dose-response curve was relatively flat, with little benefit in efficacy between FP at 500 µg and 1,000 µg.15 However, as the dose of FP increased, so did the risk of oral candidiasis. At a dose of 100 µg, the difference between the number of additional patients that would need to be treated to avoid a loss of efficacy vs the number of patients that would need to be treated in order to see an additional case of oral candidiasis was 87 patients (Fig 1
).15 In comparison, at an FP dose of 1,000 µg, this difference had fallen to 21 patients, a narrow margin of tolerability (Fig 1).15 Thus, when increasing the dose of FP, the risk of oral candidiasis will increase much faster than the risk of an exacerbation will decrease.
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Figure 1. Comparison of the relative effects of increasing FP dose in asthma on the number of patients needed to be treated for an additional patient to benefit (NNT) vs the number of patients needed to receive an intervention for an additional patient to experience harm (NNH), in this case oral candidiasis. Reproduced with permission from Powell and Gibson.15
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Esophageal candidiasis due to ICS was not mentioned in the NAEPP guidelines and was thought to be uncommon. However, utilizing upper-GI endoscopy, Kanda et al16 reported a prevalence for this side effect of 37% in 49 patients receiving FP vs 0.3% for 700 control patients. Of the patients receiving FP, 36 were asthmatic and 13 had COPD; they had been receiving FP for a mean of 13.38 ± 7.38 (± SD) weeks (range, 5 to 42 weeks) at doses from 200 to 1,200 µg/d.16 Although five patients had diabetes, there was no evidence of immunosuppression in any of the patients. The frequency of esophageal candidiasis was dose related, present in 40%, 19%, and 75% of patients receiving FP doses of 
600, 800, and 1,200 µg/d, respectively (p < 0.05 for 1,200 µg vs 800 µg or 600 µg).16 A reduction in daily dose of FP from 1,200 or 800 µg to 800 µg or 600 µg, respectively, resolved the infection in four of five patients after 1 month.16 Esophageal candidiasis was also more frequent in patients with diabetes (29.5% without vs 100% with diabetes, p < 0.01).16 High-grade esophageal candidiasis with white moss was found by Shuto et al17 during GI endoscopy in two asthma patients receiving ICS. As a follow-up, Shuto et al17 examined 20 asthmatic patients who had been receiving long-term FP inhalation. Thirty-five percent of these patients had esophageal candidiasis, 43% had grade 1, 14% had grade 2, and 43% had grade 3.17 The authors17 also showed that immediately after inhalation of 200 µg of FP, there were significant amounts of FP in the esophagus (3.3 µg).17 Even after 30 min, FP remained detectable and the amount of drug recovered was affected by whether the patient was prone or remained upright (0.67 µg if the patient laid down immediately or 0.11 µg if they remained standing).17 This study implies that if asthmatic patients do not go to sleep immediately after FP inhalation, the remaining FP in the esophagus decreases rapidly, thereby decreasing the risk of esophageal candidiasis.17 In addition, by changing the FP inhalation times to before breakfast and dinner, the remaining FP in the esophagus would be removed by the passage of food and would not remain in the esophagus.17 Thus, physicians need to be aware of the possibility of esophageal candidiasis with FP therapy and advise patients on how to potentially minimize their risk for this side effect.17
Dysphonia or hoarseness, cough, and pharyngitis have also been reported with ICS use. Dysphonia is observed in 5 to 50% of patients receiving ICS.1 Dysphonia appears to be a direct effect of the corticosteroid, as dysphonia was absent when the propellant or excipients were administered without ICS.18 Dysphonia was associated with vocal stress and increasing dosages of ICS18 and was more frequently observed in patients using a spacer device.719 Compared with placebo, there were no differences in the rates of dysphonia with MF (100, 200, and 400 µg bid) or BDP at 168 µg bid (frequency of dysphonia was 1 to 3%).20 However, at doses of MF between 800 µg and 1,600 µg, 7 to 12% of patients reported dysphonia.14
Cough during ICS inhalation has been reported in 34% of adults, with no difference in the incidence of this side effect between BDP and BUD.21 While the risk of oropharyngeal soreness/hoarseness reported for adults in systematic reviews with BUD was no different than with placebo, it was increased with FP dose.910 Moreover, the incidence of hoarseness was 4% in patients receiving FP at 220 µg bid vs < 1% for triamcinolone acetonide (TAA) at 600 µg bid over 12 weeks.22 Although hoarseness was lower with CIC at 640 µg/d (2.4%) compared with FP at 880 µg/d (4.6%), this difference was not significant (p = 0.07),12 and there was no significant difference between the two groups in the frequency of pharyngitis (4.1% vs 5.4%, respectively; p = 0.28).12 In a systematic review11 of comparative studies, pharyngitis was more likely with FP at twice the dose of BDP or BUD.
Similar findings for local side effects are seen for ICS/long-acting ß-agonist combination therapies. With BUD/formoterol, pharyngitis was seen in 6% of patients in clinical trials, with coughing in 5%.23 For FP/salmeterol, oropharyngeal candidiasis was seen in 2 to 4% of patients, hoarseness/dysphonia in 2 to 4%, throat irritation in 1 to 3%, and cough/breathing difficulties in 1 to 3%.24 In a comparative study25 of FP/salmeterol vs FP vs salmeterol vs placebo, there was no difference in the incidence of side effects between the ICS groups and the salmeterol group, except for a higher incidence of oral candidiasis for FP/salmeterol (10%) or FP alone (6%) vs salmeterol (3%) and placebo (< 1%).
Local Side Effects in Children
Studies on local side effects in children are less common than for adults.7 However, a relatively large, prospective, observational, cross-sectional cohort study7 of 639 patients (75.9 ± 48.9 months old) with moderate-to-severe asthma showed that 61.5% of patients had at least one local side effect (Fig 2
).
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Figure 2. Frequency of local side effects in asthmatic children for all patients and for those receiving either BDP or BUD. Dysphonia, hoarseness, cough, and thirst were obtained by patient questioning and oral candidiasis was defined as a clinical observation of thrush. Adapted from Dubus et al.7 *p = 0.0001 BDP vs BUD.
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The frequencies of side effects for BDP vs BUD are shown in Figure 2.7 There was no placebo control group. Cough during inhalation was significantly higher with BDP than with BUD; otherwise, the tolerability of the two therapies was similar.7 Dysphonia was the only side effect that appeared to be dose related, with a reduced frequency at low doses of BUD (p = 0.05). Perioral dermatitis and tongue hypertrophy were also observed in 2.9% and 0.1% of patients, respectively.
The investigators7 also studied the effect of device on local side effects. The main finding was that use of a spacer device doubled the incidence of cough during inhalation, and this was independent of the ICS used. These results were confirmed in a follow-up study4 in 219 patients, which noted cough on inhalation in 53.7% of patients using a spacer device; this was not linked to asthma severity, ICS, propellant or dispersant, or type of spacer, but was linked to therapy duration and use of long-acting ß2-agonists. Dysphonia was more frequent with a pressurized metered-dose inhaler (pMDI) plus a spacer or a nebulizer vs the other devices.7 Perioral dermatitis was seen only in patients who used a spacer device with a facemask or a nebulizer with or without a facemask/mouthpiece.7
Inhaler Device and Local Side Effects
Inhaler device can also influence the occurrence of local side effects, mainly through determining the relative amount of drug deposited in the lungs vs the oropharynx. Ideally, a device should maximize the proportion of drug that reaches the lung; higher lung deposition reduces the required dose, and lower oropharyngeal deposition reduces the potential for oropharyngeal side effects.26 Two types of inhaler device are used by the majority of asthma patients.
In a pMDI, the drug is dissolved or suspended in a propellant under pressure, and when activated releases a predetermined dose.27 A pMDI can be used with or without a spacer and can be manually or breath actuated. Use of a spacer device may improve lung deposition and reduce oropharyngeal deposition for patients with poor inhaler technique.28 The choice of propellant greatly influences drug deposition. Chlorofluorocarbon (CFC) propellants used to be ubiquitous, but concern over their effect on the depletion of ozone in the upper atmosphere has led to their replacement with hydrofluoroalkane (HFA).27 The use of HFA has had some additional benefits. Because particle sizes of < 5 µm diameter will reach the lower airways when larger particles are deposited in the oropharynx,29 and because smaller particle sizes can be achieved with HFA, the use of HFA will likely lead to greater lung deposition, allowing lower doses, and lower oropharyngeal deposition.30 With CFC-based pMDI devices, lung deposition was approximately 10 to 20% depending on the exact device and method of measurement.26 In contrast, newer HFA-based inhalers are achieving levels of lung deposition 50%.31
Dry powder inhalers (DPIs) do not require propellants and use inspiratory efforts to disperse the drug and deliver it to the lungs.27 Lung deposition with these devices is approximately 15 to 40%, with considerable interdevice variability.30 Thus, modern pMDI devices that use HFA propellants are at least as good as DPI devices in achieving high lung deposition. It is important to realize that a patient who is having local side effects using one drug/device combination may tolerate the same drug very differently using a different device.
There is a great deal of variability in the reported local side effects of ICS in general and for specific agents. Much of this is due to how side effects are defined and assessed. As many studies compared active agents, without a placebo group, the accuracy of the risk estimation for side effects is often unknown. Nevertheless, the weight of evidence suggests that the risk of local side effects may be higher with FP than with BDP.
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Systemic Side Effects With ICS Therapy
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Systemic Availability of ICS
ICS absorption into the systemic circulation occurs either through the lungs or by swallowing drug that is not inhaled but deposited at the back of the throat.32 Nevertheless, other factors need to be considered and these are discussed below.
The contribution of GI absorption to systemic ICS exposure is minimal compared with that of absorption through the lungs.32 ICS that are swallowed and absorbed in the gut will undergo hepatic first-pass metabolism, greatly reducing the amount of circulating drug.33 The degree of hepatic first-pass metabolism differs between ICS: FP and MF, 99%; BUD, 90%; TAA, 80 to 90%; and BDP, 60 to 70%.33 Theoretically, agents that are inactivated by hepatic first-pass metabolism should be safer. However, highly lipophilic drugs, such as FP and MF, will be taken up more readily into tissues than drugs that are less lipophilic, such as TAA and BUD. Because more extensive tissue storage of ICS in an active form will result in a longer clearance time from the body, this not only may increase the duration of therapeutic effect but it also may increase the potential for increased systemic side effects should active drug continue to be released back into the circulation.33 There is another potential reason why there is an increased risk of systemic side effects with MF. In contrast to other ICS, MF generates an active metabolite (6ß-OH MF) in the liver and an active degradation product (9,11-epoxy MF) in the lung and plasma.34 Even though MF itself has a low systemic bioavailability, these active metabolites will contribute to the overall potential for MF therapy to cause systemic side effects.34 It has been shown that MF does cause significant overnight urinary cortisol suppression, a marker for hypothalamic-pituitary-adrenal axis suppression, to a similar extent as FP.35
Most systemic ICS originates from direct absorption into the circulation through lower airway deposition. This route avoids hepatic first-pass metabolism. Drugs that are highly protein bound in the circulation will have a low potential for causing systemic side effects because only the free fraction is biologically active. The degree of protein binding is 71% for TAA, 80% for flunisolide (FLU), 88% for BUD, 90% for FP, and > 99% for ciclesonide (CIC).3637 Protein binding for BDP is 87%, but no data are available for its active metabolite, 17 beclomethasone monopropionate.36
Factors that increase ICS airway delivery may improve efficacy but may also increase the risk of systemic side effects.32 For example, patients with mild disease have less airway obstruction than patients with more severe disease, increasing the deposition of ICS into the lower airways, possibly increasing the risk of side effects for the same ICS dose.32 For example, administration of inhaled FP (1,000 µg) to normal, healthy subjects resulted in higher peak plasma concentrations and greater total drug systemic exposure than for asthma patients.38 Systemic availability of FP was also lower in asthma patients than in healthy control subjects, with a mild correlation to lung function as measured by FEV1 (r = 0.47, p = 0.02).38
Modern delivery systems, such as HFA-based pMDI inhalers, enhance drug targeting to the lungs.30 Thus, lower ICS doses can be used, such that the clinical response is maintained but systemic exposure reduced.39 For example, conversion from CFC to HFA as a propellant moved the dose-response curve for drugs delivered using the HFA device toward the left, so lower doses are required to achieve the same therapeutic effect.4041 Conversely, a 1:1 substitution of the CFC to the more recent HFA formulations may result in greater systemic exposure and a higher potential for side effects.3241 Therefore, recommended doses of HFA devices are lower than older CFC-containing formulations.5 Large-volume spacers have also been recommended as a means of improving lung deposition, allowing dose reduction and minimization of ICS systemic bioavailability in adults and children.28
The Asthma Clinical Research Network conducted a randomized study42 to investigate the systemic bioavailability of different ICS and devices using overnight urinary cortisol suppression to assess dose response. The study took place over 6 weeks, with the first week consisting of a placebo run-in phase. Five ICS compounds were evaluated: FP (as a CFC-pMDI formulation and a DPI formulation); BUD (DPI formulation); BDP (CFC-pMDI formulation); FLU (CFC-pMDI formulation); and TAA (CFC-pMDI formulation). The results were used to relate the ICS dose and delivery mechanism to an estimated effect on cortisol suppression (ie, their systemic availability) and determine equisuppressive doses. Table 1
shows the estimated doses of the different formulations that would cause a 10% suppression of endogenous cortisol production.42 This study showed that FP delivered using a CFC-pMDI with a spacer required the lowest labeled dose to suppress cortisol production by 10%; and FLU, also delivered using a CFC-pMDI plus spacer, required the highest dose to obtain the same effect (Table 1). This study42 also showed that it is possible to conduct pharmacokinetic studies that allow comparison of hypothalamic-pituitary-adrenal axis suppression between different drug/device combinations. Such studies provide information regarding the potential for different ICS compounds, doses and formulations to cause systemic side effects.
Risk of Systemic Side Effects
While safety data have been reported for many clinical trials, there are few studies that have been adequately powered, or have long enough follow-up periods, to assess long-term systemic side effects with ICS. A systematic review6 conducted in collaboration between the American College of Chest Physicians, the American Academy of Allergy, Asthma, and Immunology, and the American College of Allergy, Asthma, and Immunology examined the evidence for potential systemic complications of ICS therapy for asthma. Evidence published up to the end of the year 2000 was considered. The results are summarized in Table 2
.
In brief, there was relatively good evidence for the effect of ICS on skin thinning and bruising, with a dose-response relationship identified. In older adults, ICS appeared to reduce bone mineral density after long-term, high-dose therapy and increased the risk of cataracts and glaucoma, although the evidence was not conclusive.
Two studies4344 investigating ICS effects on bone mineral density and fractures were not included in the systematic review. A study43 from 1998 examined the effect of ICS on bone mineral density in 34 female and 19 male patients with persistent asthma who had received high-dose ICS (inhaled BDP or BUD at doses 
1,500 µg/d) for at least 12 months, with or without a history of maintenance therapy with oral corticosteroids (> 1 month). The investigators43 found that lumbar spine and proximal femur bone mineral density was 1 SD lower than normal in men and women receiving oral corticosteroids or high-dose ICS, equal to a doubling of the risk of fracture at these sites. In women, prior exposure to oral corticosteroids was also associated with lower lumbar spine and proximal femur bone mineral density than normal, while men were more sensitive to the side effects of ICS on bone mineral density at the lumbar spine and the Ward triangle.43 All patients had evidence of suppression of both endogenous cortisol and adrenal androgen production, indicating hypothalamic-pituitary-adrenal axis suppression; this study43 therefore supports an effect of high-dose ICS on bone mineral density.
A retrospective cohort study44 conducted in the United Kingdom after the systematic review43 described above was compiled investigated the fracture risk with ICS. Patients who were using systemic corticosteroids were excluded from this study, leaving 170,818 ICS users, 108,786 bronchodilator users, and 170,818 control patients. During ICS therapy, there was an increased relative risk (RR) for nonvertebral fractures (RR, 1.15; 95% confidence interval [CI], 1.10 to 1.20), hip (RR, 1.22; 95% CI, 1.04 to 1.43), and vertebral fractures (RR, 1.5; 95% CI, 1.22 to 1.85).44 The RR of fractures was similar for BUD, FP, and BDP. However, there were no differences in fracture risk between the ICS group and the bronchodilator groups, and the authors44 suggested that the excess risk of fractures with ICS may be related to the underlying respiratory disease. Further prospective data are required on fracture risk with ICS therapy in order to clarify these findings.
Oral corticosteroids are a known risk factor for the development of subcapsular cataracts, with risk influenced by daily cumulative dose, age, and ethnic origin.45 The systematic review6 described above concluded that the risk of cataracts due to ICS was small and may only be relevant in elderly patients. Two studies4647 not included in the systematic review generally support these findings. A study46 from 1993 found that the prevalence of subcapsular cataracts in 48 patients treated with long-term BUD or BDP (750 to 1,500 µg/d) was 27%. However, the development of cataracts was correlated to prednisone but not ICS use. A study47 published in 2001, after the systematic review was compiled, suggested that the risk of cataracts with ICS may be related to age. An analysis of 103,289 subjects exposed to ICS vs 98,527 subjects in a control cohort found slightly higher incidence rates for cataracts in the ICS group compared with the nonexposed cohort (RR, 1.3; 95%, CI 1.1 to 1.5) after adjusting for age and gender.47 However, a relationship between heavy use of ICS and cataract risk that was most pronounced in subjects > 70 years old was also seen in subjects aged 40 to 49 years, but was absent in subjects aged 40 years.47
The evidence for an effect of ICS on glaucoma was poor in the systematic review.6 However, a more recent study48 of 3,654 patients found a strong association between ICS use and the presence of either glaucoma or elevated intraocular pressure (odds ratio, 2.6; 95% CI, 1.2 to 5.8), but only in those patients with a family history of glaucoma. The risk increased with higher ICS doses (odds ratio, 6.3; 95% CI, 1.0 to 38.6, for more than four puffs per day). These findings were not explained by concurrent use of oral or ocular corticosteroids.48
Systemic Side Effects in Children
ICS safety in children was reviewed in 2002 by the NAEPP guidelines update5 on selected topics. The report examined four outcomes: vertical growth, bone mineral density, ocular toxicity (including posterior subcapsular cataract and glaucoma), and suppression of hypothalamic-pituitary-adrenal axis function. The conclusions of this review are outlined in Table 3
.5 There was evidence to support a reduction in linear growth and suppression of the hypothalamic- pituitary-adrenal axis with ICS. Although ICS have the potential to decrease growth velocity, there was no evidence that ICS therapy affected final adult height. However, the authors5 drew attention to the need for further study regarding the long-term effects of ICS on bone mineral density and cataract formation, and whether the effects of ICS on growth velocity were more pronounced for certain developmental periods.
The only other systemic side effect with ICS mentioned in the NAEPP 1997 guidelines was disseminated varicella infection.1 While oral corticosteroid use, with or without immunosuppression, has been associated with a high risk of severe varicella infection compared with case-matched control subjects,49 no causal relationship has been shown with ICS,1 despite sporadic case reports of severe varicella infections in patients receiving ICS.50
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Control and Monitoring of Side Effects
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Local Side Effects
The 1997 NAEPP guidelines1 suggested the following clinical interventions to mitigate the risk of, or treat, local side effects: - Oral candidiasis (thrush): use a spacer/holding chamber, rinse mouth with water after inhalation, and administer ICS less frequently (twice daily vs four times daily). Topical or oral antifungal agents should be used to treat active infections.
- Dysphonia: use a spacer/holding chamber, temporarily reduce dosage, or rest for vocal stress.
- Reflex cough and bronchospasm: use a slower inspiration rate and/or a spacer/holding chamber or pretreat with an inhaled ß2-agonist.
These recommendations were based on the evidence available at the time. However, subsequent investigation of some of these interventions has provided contrary results. For example, in a study7 in children, mouth rinsing or spacer use had no protective effect regarding the development of oral candidiasis. In a study51 designed to assess the effect of gargling after ICS inhalation, at least in a subgroup of asthmatics using steroid inhalers, gargling with water, or even weak concentrations of amphotericin B did not prevent colonization of the throat with Candida albicans. However, gargling with amphotericin B at concentrations 100 times dilution did prevent clinically detectable oral candidiasis.51 Moreover, two studies47 in children showed that dysphonia and cough were more frequent in patients using a spacer device. It is unclear whether patients in these studies were coughing because they were using a spacer device or whether, in line with the guidelines, patients with cough on inhalation were more likely to have been administered a spacer to attempt to reduce the occurrence of this side effect. However, in adults, the use of a large-volume spacing device did not appear to protect against dysphonia or cough.21
Systemic Side Effects
The only specific recommendation for monitoring systemic side effects made in the NAEPP 1997 guidelines1 was to monitor growth in children. However, based on the evidence available at the time, the guidelines1 recommended the following measures for minimizing potential systemic side effects with ICS:
- Use a spacer device and rinse the mouth after inhalation. Selroos and Halme52 demonstrated that systemic absorption of ICS was reduced by using a spacing device with a metered-dose inhaler after using a DPI.
- Use the lowest possible dose of ICS to maintain control. In children, step down ICS dose whenever possible.
- Add additional therapies (long-acting ß2-agonist) before increasing the ICS dose.
- In postmenopausal women, consider calcium supplements (1,000 to 1,500 mg/d) and vitamin D (400 IU/d). Estrogen replacement therapy, when appropriate, may be considered for patients receiving ICS doses > 1,000 µg/d. This recommendation is no longer up to date (see next paragraph).
Varicella vaccination was not included in the recommendations for patients receiving ICS.
Since these guidelines1 were published, the recommendations have changed for postmenopausal women. While it is reasonable to recommend that women consume the recommended daily amounts of vitamin D and calcium in diet and supplements, the literature suggests that calcium and vitamin D supplementation by themselves are insufficient to prevent fractures in postmenopausal women.5354 Also, publication of the Women’s Health Initiative Estrogen Plus Progestin Trial55 on the risk/benefit profile of hormone replacement therapy has resulted in this no longer being indicated for routine use in postmenopausal women as a viable intervention for primary prevention of chronic diseases. Optimization of other steroid-sparing strategies has also been suggested, such as control of smoke and allergen exposure, influenza vaccination, and treatment of rhinitis, sinusitis, and gastroesophageal reflux disease when present.56 In patients with osteoporosis, additional therapy with agents that have been shown to decrease the risk of fractures such as antiresorptive drugs is indicated.
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Physician Perception of Side Effects With ICS Therapy
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A survey57 of 429 US family physicians and pediatricians in managed-care organizations was conducted by the Pediatric Asthma Care Patient Outcomes Research Team. This survey focused on physicians’ concerns and perceptions. Although 26% of responders thought ICS were very safe and 66% thought they were safe, 47% were at least moderately concerned regarding one or more ICS side effects (Fig 3
).57 Their greatest concern was regarding linear growth retardation in children. This survey predated the Food and Drug Administration requirement to include a warning on ICS labeling regarding linear growth retardation in children.
In a survey58 of 213 asthma specialists, 80% of whom were allergists/immunologists and 20% were pulmonologists, the aim was to determine the type and frequency of side effects due to ICS seen in their patients (Fig 4
). Only 1% of physicians reported that they saw "short stature" in children either occasionally or frequently, and only 15% reported seeing it rarely.58 The only area of agreement between these two studies was for oral thrush/oropharyngeal symptoms.
There seems to be a disconnect between the level of concern regarding side effects with ICS and the actual frequency of these side effects noted in practice. However, it is likely that the family physicians were more concerned regarding the seriousness of potential side effects, rather than their frequency.
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Participant Feedback and Discussion
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During the workshop following this presentation, participants were asked a number of questions that they could respond to anonymously using an electronic interactive keypad system. Responses to most of these questions (listed below) are shown in Figure 5
. - On a scale of 1 to 6, how would you rate ICS safety overall?
- Which local adverse event is of most concern in your practice?
- How often do you see:
- Oral candidiasis?
- Esophageal candidiasis?
- Dysphonia/hoarseness?
- Pharyngitis?
- Cough?
- Which systemic event is of most concern in your practice?
- How often do you see:
- Issues with bone mineral density?
- ICS-related glaucoma or cataracts?
- Skin bruising?
- Linear growth issues in children?
- Adrenal suppression?
- How often do you monitor for (1) systemic or (2) local adverse events?
When asked to rate the overall safety of ICS on a scale of 1 (very safe) to 6 (dangerous), 25% of participants in this meeting rated ICS as very safe, most (40%) chose 2 on the scale, and 35% chose 3 or 4. Participants believed that local side effects were most likely to lead to discontinuation of therapy.27 Approximately two thirds of the participants monitored for local side effects at each visit; the remainder relied on the patient to alert them to any problems. Most of the group (50%) investigated systemic side effects only in the event of a patient indicating that there was a problem. The remainder monitored at regular periods: every 6 months (21%), every quarter (4%), or every visit (25%). Considerable reservations remain for parents and many pediatricians regarding the effect of ICS on linear growth in children: cataracts may be more common with ICS in older patients; bone density is a risk in postmenopausal women and elderly men; patients with a family history of glaucoma may be more at risk of this side effect with ICS; and skin bruising occurs even at moderate ICS doses.
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Conclusion
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When reading the NAEPP 1997 guidelines,1 understanding the potential side effects of ICS therapy and their control and monitoring seems relatively clear and straightforward. In this context, the concerns of many physicians (and patients) may seem misplaced. However, on closer examination of the clinical trial data used to develop the guidelines, as well as subsequent studies, we see that there are many unknowns and gaps in our knowledge, leaving space for doubt and confusion.
We know that local side effects such as oral candidiasis, pharyngitis, and dysphonia/cough can be unpleasant and lead to poor therapy adherence, even though they are not serious. The fear of systemic side effects, such as reduced bone mineral density, skin bruising, glaucoma, cataracts, and growth retardation in children, may appear to be out of proportion to the risks. However, given the seriousness of these potential side effects and the lack of clear data, these fears are understandable.
We know that ICS are a highly effective therapy for control of asthma symptoms, and we must now concentrate on furthering our understanding of the risks of therapy. Different perceptions of the risks of ICS therapy will result in different balance points for the risk/benefit decision that physicians and patients must make on initiating ICS therapy. There is a need for an ICS formulation that will allow high-dose therapy for extended periods, with a confirmed dose response and with a decreased potential for side effects (ie, a broader therapeutic window). The introduction of new agents with improved safety profiles will also reassure physicians and patients as to the benefits of ICS therapy.
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Figure 5. Top: Side effects of ICS of most concern to the asthma experts participating in this meeting (n = 25): local side effects (black bars) and systemic side effects (open bars). Bottom: Asthma experts’ estimation of the frequency of ICS side effects seen in their practices.
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Footnotes
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Abbreviations: BDP = beclomethasone dipropionate; BUD = budesonide; CFC = chlorofluorocarbon; CI = confidence interval; CIC = ciclesonide; DPI = dry powder inhaler; FLU = flunisolide; FP = fluticasone propionate; HFA = hydrofluoroalkane; ICS = inhaled corticosteroids/corticosteroid; MF = mometasone furoate; NAEPP = National Asthma Education and Prevention Program; pMDI = pressurized metered-dose inhaler; RR = relative risk; TAA = triamcinolone acetonide
Dr. Irwin has no potential personal or financial conflict of interest to disclose. Ms. Richardson discloses that she was contracted to provide author support and manuscript preparation by BoomCom Communications Inc., Denver, CO. BoomCom Communications, Inc., was engaged by Altana Pharma, the sponsors of this supplement.
Received for publication July 2, 2005.
Accepted for publication March 20, 2006.
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Abstract
Introduction
