INTRODUCTION — Inhaled glucocorticoids (also called inhaled corticosteroids or ICS) have fewer and less severe adverse effects than orally-administered glucocorticoids, and they are widely used to treat asthma and chronic obstructive pulmonary disease (COPD) . However, there are concerns about the systemic effects of ICS, particularly as they are likely to be used over long periods of time, in infants, children, and older adults [2,3]. The safety of ICS has been extensively investigated since their introduction for the treatment of asthma 30 years ago [4-9].
This topic review will present the local and systemic side effects of ICS, and address other concerns that are often raised by patients regarding these medications. The various types of inhalers used for asthma therapy and the numerous side effects of orally administered glucocorticoids are reviewed in detail separately. (See "The use of inhaler devices in adults" and "The use of inhaler devices in children" and "Major side effects of systemic glucocorticoids".)
EFFECTS OF LOCAL DEPOSITION — Side effects due to the local deposition of inhaled glucocorticoid in the oropharynx and larynx may occur. The frequency of complaints depends on the specific drug, dose, frequency of administration, inhaler technique, and the delivery system used.
Dysphonia — Dysphonia (hoarse voice) is a common complaint among users of inhaled glucocorticoids (ICS). Reported incidences vary from 1 to 60 percent, depending on the patient population, device, dose, length of observation, and manner of data collection [10-13]. Limited data are available for hydrofluoroalkane (HFA)-based metered dose inhalers (MDIs), but it appears that HFA-based inhalers have a lower risk for dysphonia than older chlorofluorocarbon (CFC)-based MDIs . Dysphonia is sometimes reduced by using a spacer with the MDI, although results are variable [12,13]. The risk of dysphonia may be lower with budesonide dry powder inhaler (DPI) compared with CFC-MDIs or fluticasone propionate DPI . In one study of patients using fluticasone propionate DPI, the rate of dysphonia was 20 percent overall and 36 percent among women over the age of 65 .
The mechanism of ICS-associated dysphonia may involve factors such as myopathy of laryngeal muscles (manifest as incomplete closure or bowing of the vocal cords on adduction), mucosal irritation, and laryngeal candidiasis . Dysphonia due to myopathy or mucosal irritation is reversible when treatment is withdrawn . Dysphonia may be disabling in singers and lecturers, although it is not troublesome for many patients.
Topical candidiasis — Oropharyngeal candidiasis (thrush) may be a problem in some patients, particularly elderly patients, patients taking concomitant oral glucocorticoids, immunosuppressants, or antibiotics, and patients inhaling glucocorticoids at high dose or more often than twice daily [16,17]. In a systematic review of trials of ICS for COPD, the risk of oropharyngeal candidiasis was increased among ICS users compared with placebo (OR 2.65, 95% CI 2.03-3.46; 5586 participants) .
For patients using MDIs, large volume spacer devices may protect against thrush by reducing the amount of drug deposited in the oropharynx. In addition, rinsing the mouth and throat with water and expectorating the rinsate after use of all forms of ICS is preventative. The treatment of oropharyngeal candidiasis is discussed separately. (See "Oropharyngeal candidiasis in adults".)
Laryngeal candidiasis is a less common complication of ICS, but has been reported in up to 15 percent of patients complaining of dysphonia during ICS therapy. Isolated laryngeal candidiasis, presenting with dysphonia and sometimes throat pain, has been described in association with ICS in case reports [12,18,19]. (See 'Dysphonia' above.)
Case reports have also described esophageal candidiasis among a few patients using high dose ICS .
Contact hypersensitivity — Allergic contact dermatitis has occasionally been described due to ICS, particularly budesonide [21-24]. An erythematous, eczematoid eruption is typically noted around the mouth, nostrils, or eyes. Typically, the patient taking inhaled glucocorticoids is affected, although individuals administering these medications have also been affected in cases of occupational contact hypersensitivity .
The diagnosis can be confirmed with patch testing, and most budesonide-allergic patients can be managed by changing to another inhaled glucocorticoid that does not cross-react with budesonide, such as beclomethasone, mometasone, or fluticasone . (See "Topical corticosteroids: Use and adverse effects", section on 'Cutaneous' and "Common allergens in allergic contact dermatitis", section on 'Corticosteroids'.)
Other — Cough and throat irritation, sometimes accompanied by reflex bronchoconstriction, may occur when ICS are given via MDIs, although less commonly with the hydrofluoroalkane (HFA) than the previous CFC preparations. These adverse effects may be rectified by switching to a dry powder inhaler (DPI), although some patients (1 to 9 percent) report cough or dysphonia with ICS administered by DPI and rare patients with milk sensitivity react to milk proteins contaminating the lactose in DPI formulations.
SYSTEMIC ADVERSE EFFECTS — Given the known adverse effects of systemic glucocorticoids, concerns have been raised regarding the potential for inhaled glucocorticoids (ICS) to have similar effects. A critical issue in the study of systemic side effects from ICS is whether a measurable effect translates into a significant clinical consequence. As biochemical markers of systemic glucocorticoid effects become more sensitive, systemic effects are more readily detectable. However, determining clinical relevance necessitates careful, long-term follow-up studies, which are difficult to perform and are often confounded by the effects of the diseases themselves, the administration of intermittent oral glucocorticoids, and other co-morbidities.
Factors influencing risk — A patient's risk of developing adverse systemic effects from ICS is influenced by several factors, including the dose delivered to the patient, the site of delivery (ie, mouth, lungs, gastrointestinal tract), the delivery system used, individual differences in the response to the glucocorticoid, and individual comorbidities (eg, age, sex, cigarette smoking, dietary calcium and vitamin D, activity level). Sporadic case reports of dramatic adverse systemic effects from ICS are likely due to idiosyncratic reactions caused by abnormal pharmacokinetic handling of the drug in a particular individual.
The pharmacokinetics of ICS administered by metered dose inhaler (MDI) or dry powder inhaler (DPI) are depicted in the figure (figure 1):
●Approximately 60 to 90 percent of a dose delivered from a MDI/DPI is deposited in the oropharynx, swallowed, and subsequently absorbed from the gastrointestinal tract . Drug that is absorbed from the gastrointestinal tract undergoes "first pass metabolism" in the liver, primarily by the CYP3A2 enzyme subfamily . This first pass metabolism results in the majority of the absorbed drug being converted into inactive forms for excretion. The remainder enters the systemic circulation and contributes to systemic side effects.
●Ten to 40 percent of a dose from an MDI enters the airways of the lungs, although the proportion varies among formulations. As examples, ciclesonide HFA has approximately 60 percent delivery to the lungs compared with about 55 to 60 percent for beclomethasone HFA and 80 percent for mometasone HFA and fluticasone propionate HFA . The budesonide dry powder inhaler (DPI) has approximately 15 to 28 percent lung deposition, while the fluticasone propionate DPI has 20 percent . The lung fraction exerts the therapeutic effect and is then absorbed directly into the systemic circulation. Thus, the drug that is absorbed from the lung has relatively greater systemic impact compared to that absorbed through the gut because there is no first pass after lung absorption.
●Systemic effects of ICS may be less detectable in patients with more severe asthma, possibly because airflow limitation inhibits delivery of drug to the lung periphery where systemic absorption occurs [28,29].
●The pharmacokinetics of ciclesonide are slightly different from other ICS because ciclesonide is delivered to the airways as an inactive compound that is subsequently converted by esterases to the active metabolite. It also has low oral bioavailability and a high clearance rate, potentially decreasing systemic side effects, such as adrenal suppression [30-32]. However, further testing is needed, using well-controlled, dose ranging, long duration studies with relevant clinical outcomes, before these theoretical advantages can be considered clinically important.
Certain medications can influence the risk of systemic adverse effects. Medications that inhibit cytochrome p450 3A4 (CYP450 3A4) have the potential to impair the metabolism of inhaled glucocorticoids, particularly budesonide, ciclesonide, and fluticasone, and increase their serum levels (table 1) . The co-administration of budesonide and the potent CYP450 3A4 inhibitor, itraconazole, has been reported to result in adrenal suppression . Co-administration of fluticasone (propionate or furoate) and ritonavir has been associated with iatrogenic Cushing syndrome, due to CYP450 3A4 inhibition [35,36].
The addition of intranasal glucocorticoids to high-dose ICS (eg, in patients with allergic rhinitis and asthma) likely increases the systemic exposure to glucocorticoids, although the contribution to adverse effects has not been specifically quantified . (See "Pharmacotherapy of allergic rhinitis", section on 'Safety and adverse effects'.)
Adrenal suppression — Systemic administration of glucocorticoids causes hypothalamic-pituitary-adrenal (HPA) axis suppression by reducing corticotropin (ACTH) production, which reduces cortisol secretion by the adrenal gland. The degree of HPA suppression is dependent on dose, duration, frequency, and timing of glucocorticoid administration. The risk of symptomatic adrenal suppression or acute adrenal crisis by ICS therapy is small, particularly when the doses used are within the recommended ranges.
The evaluation of adrenal insufficiency in adults is discussed separately. (See "Clinical manifestations of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults".)
Measures to reduce the risk for systemic adverse effects, such as adrenal suppression, in patients receiving prolonged ICS are discussed below. (See 'Measures to minimize systemic side effects' below.)
Children and adolescents — The Pediatric Endocrine Society Drugs and Therapeutics Committee released guidelines regarding adrenal insufficiency in children on long-term ICS . The guidelines recommend having a high level of suspicion for adrenal insufficiency, as clinically significant acute adrenal insufficiency has been reported in children on ICS, albeit rarely .
Thus, testing for adrenal insufficiency should be performed in children and adolescents who are taking long-term ICS (eg, >6 months)  and have symptoms suggesting adrenal insufficiency, including hypoglycemia, altered mental status, fatigue, weakness, anorexia, Cushingoid features, growth failure, or weight loss. Those with hypoglycemia, altered mental status, or hypotension should be evaluated urgently for adrenal crisis, and treated presumptively with stress glucocorticoids, if indicated (table 2).
The guidelines also suggest screening asymptomatic children and adolescents who are at high risk, which they define as taking a high daily dose of ICS (eg, age 5 to 11 years, fluticasone propionate 500 mcg/day), particularly those with a low BMI. However, we prefer to determine the need for screening of asymptomatic patients individually, based on the presence of the following risk factors:
●Long-term use of intranasal glucocorticoids in addition to high-dose ICS (see "Pharmacotherapy of allergic rhinitis", section on 'Safety and adverse effects')
●Intermittent use of systemic glucocorticoids and long-term high-dose ICS
●A low BMI (eg, <15th percentile for age)
To screen for adrenal insufficiency, the first step is measurement of serum cortisol in the morning (eg, 8 AM). Because cortisol normally peaks in the morning, a low level suggests adrenal insufficiency. The results are interpreted as follows:
●A morning cortisol <3 mcg/dL, suggests probable adrenal insufficiency. This is sufficient to make the diagnosis if the patient is symptomatic. If the patient is asymptomatic, an ACTH stimulation test should be performed to evaluate further for adrenal insufficiency.
●A morning cortisol 3 to 10 mcg/dL is inconclusive. In most cases, the child should be further evaluated with an ACTH stimulation test or referred to a specialist, especially if the child is symptomatic.
●A morning cortisol level >10 mcg/dL is reassuring, but does not completely exclude adrenal insufficiency. Further evaluation with an ACTH stimulation test may be appropriate if the patient is symptomatic.
When the ACTH stimulation test is performed, the guideline recommends using the low-dose of ACTH (1 mcg intravenously), with measurements of cortisol at baseline and 30 minutes at a minimum . A peak cortisol level below 18 mcg/dL is consistent with adrenal insufficiency. This low-dose version of the ACTH stimulation test may be more sensitive than the standard high-dose test, although the guideline acknowledges that it is not definitively superior. The assessment and treatment of patients for adrenal suppression are presented separately. (See "Diagnosis of adrenal insufficiency in adults" and "Treatment of adrenal insufficiency in children" and "Treatment of adrenal insufficiency in adults".)
Studies assessing HPA axis function — A number of studies have assessed HPA axis function in asthmatic patients being treated with ICS. However, the results are inconsistent because the studies have been uncontrolled and patients have often received intermittent courses of oral glucocorticoids (which may affect the HPA axis for weeks) .
An effect of ICS on HPA axis function is supported by the following studies [3,41-46]:
●A meta-analysis of 21 studies of urinary cortisol concentrations and 13 studies of morning plasma cortisol concentrations found evidence of hypothalamic-pituitary-adrenal axis suppression that was most common in the presence of fluticasone propionate doses greater than 800 mcg daily, although suppression was frequently absent even at higher doses [3,46].
●Adrenal suppression (eg, reduction in serum or urinary cortisol) was seen with lower doses of fluticasone propionate than with beclomethasone or budesonide, a finding subsequently reproduced in other studies [41-43].
●Several studies of children have shown a dose-dependent effect of ICS on the hypothalamic-pituitary-adrenal (HPA) axis [47-51]. One retrospective survey identified several cases of acute adrenal crisis (ie, hypoglycemia, convulsions, coma) in the population of the United Kingdom in association with ICS use (at doses ranging from 500 to 2000 mcg daily), which appeared to occur disproportionately in children and with the use of fluticasone propionate .
While HPA axis function can be affected by ICS, the effect appears infrequent. In a meta-analysis of five randomized trials (732 adults), abnormal adrenal function was found in only 6, 7, 10, and 13 percent of patients taking 500, 1000, 1500, and 2000 mcg/day of fluticasone propionate, respectively . This analysis should be interpreted with caution because only one study contained data for fluticasone propionate doses greater than 1000 mcg/day; thus, the data for the higher doses were derived by extrapolation.
Lung infection — In some studies, ICS use has been associated with an increased risk for bacterial colonization, bacterial pneumonia, or mycobacterial lung infections. ICS have been shown to be safe and possibly beneficial in respiratory infection due to COVID-19. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)
●Airway bacterial colonization – ICS use alters the local environment of the airways and has been found to increase bacterial airway load in COPD. Although bacterial load and colonization have been linked to exacerbation risk in COPD [54,55], addition of ICS to COPD regimens has been found to be beneficial or neutral on the exacerbation rate in large trials. (See "Role of inhaled glucocorticoid therapy in stable COPD", section on 'Exacerbations'.)
As an example, in a randomized trial including 60 steroid-naïve patients with mild-moderate COPD, those assigned to salmeterol 50 mcg/budesonide 500 mcg experienced an approximately 10-fold increase in median bacterial load at 12 months follow-up compared with those assigned to salmeterol alone . Nevertheless, there was a trend toward reduced COPD exacerbation frequency compared with baseline in the ICS-receiving patients.
An epidemiological cohort study of 21,408 COPD patients examined ICS use as a risk factor for the development of pseudomonas airway colonization, which occurred in 3.6 percent of the population during the median three-year follow-up . ICS use was strongly associated with risk of pseudomonas colonization (hazard ratio [HR] 2.3, 95% CI 1.8-2.9) after adjustment for age, sex, forced expiratory volume in one second, smoking status, antibiotics, and oral corticosteroid use; the relationship was also dose-dependent.
●Pneumonia – Data are somewhat mixed regarding the risk of pneumonia among patients with COPD or asthma taking ICS, although a small increase in risk is usually reported [58-70].
Among patients with COPD, meta-analyses and a large case control study have found a slight increase in the risk of pneumonia associated with ICS [58-61]. One meta-analysis found a slight increase in the risk of pneumonia among 21,247 patients on fluticasone propionate, odds ratio (OR) 1.78 (95% CI 1.5-2.12), and among 10,150 patients on budesonide, OR 1.62 (95% CI 1.0-2.62), although the latter relationship was less definitive . This would correlate with an excess of 18 pneumonias per 1000 treated patients taking fluticasone propionate for 18 months or six more pneumonias per 1000 treated patients taking budesonide for nine months. In the individual studies, pneumonia was uncommon, often poorly defined, and not always a predetermined endpoint. Neither pneumonia-related mortality nor overall mortality was significantly increased with combination therapy. An indirect comparison of fluticasone propionate and budesonide in this analysis revealed no significant difference in the rate of serious adverse events or mortality.
In contrast, a study that pooled data from seven clinical trials with 7042 COPD patients of whom 3801 were on inhaled budesonide found that the risk of pneumonia was NOT increased among those on budesonide .
A separate study examined the relative risk of pneumonia of different ICS and long-acting beta-agonist formulations. In this retrospective cohort study of 2734 patients with chronic obstructive pulmonary disease (COPD) receiving fluticasone propionate/salmeterol or budesonide/formoterol, the rates of pneumonia (rate ratio 1.73, 95% CI 1.57-1.90) and admission to hospital (RR 1.74, 95% CI 1.56-1.94) were higher in patients treated with fluticasone propionate/salmeterol . Pneumonia-related mortality was higher in the fluticasone propionate/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths; HR 1.76, 95% CI 1.22-2.53), but all-cause mortality did not differ between the groups. The retrospective design, lack of determination of disease severity, and greater baseline use of antibiotics in the fluticasone propionate/salmeterol group limit the conclusions that can be drawn.
Despite the increased risk for pneumonia, the risk of mortality associated with pneumonia does not appear to be increased [64,70]. Among 6353 patients with COPD and pneumonia hospitalized at US Veterans Affairs hospitals, mortality at 30 and 90 days was not increased in those taking outpatient inhaled glucocorticoids compared with those who were not . (See "Role of inhaled glucocorticoid therapy in stable COPD", section on 'Mortality'.)
A retrospective analysis of 14,993 patients with asthma who were enrolled in clinical trials of inhaled budesonide versus placebo found no increase in the risk of pneumonia . On the other hand, a nested case control study found that patients with asthma who used the highest dose of inhaled glucocorticoids (≥1000 mcg/day) had an increased risk of pneumonia or lower respiratory tract infection (2.04, 95% CI 1.59-2.64), compared with those who did not have a prescription for ICS within the previous 90 days .
●Tuberculosis – In a nested case control study that included over 400,000 patients with asthma or COPD (564 cases of tuberculosis), the risk of tuberculosis was slightly increased among all users of ICS (RR 1.26, 95% CI 1.18-1.56), particularly those using doses equivalent to fluticasone propionate 1000 mcg per day or more (RR 1.97, 95% CI 1.18-3.3) . It is not known whether this observation was influenced by confounders, such as cigarette smoking, socioeconomic status, or use of medications that inhibit cytochrome p450 3A4, thereby decreasing clearance of ICS.
In a cohort study, ICS use by patients with COPD was an independent risk factor for the development of pulmonary tuberculosis: in the presence of radiographic evidence of prior tuberculosis the HR was 24.94 (95% CI 3.09-201.36) and with a previously normal chest radiograph the HR was 9.08 (95% CI 1.01-81.43) . However, this study was substantially smaller than the nested case control study above, and the small study size limits confidence in the size of the effect.
●Nontuberculous mycobacterial infection – A separate study raised the possibility of an increased risk of non-tuberculous mycobacterial (NTM) disease among COPD patients treated with ICS. In a population-based case control study of over 400,000 patients with obstructive lung disease, the risk of development of NTM was 0.8 percent . Compared with matched control patients, patients who developed NTM were more likely to have current ICS use (64 versus 42 percent, adjusted odds ratio 1.9, 95% CI 1.6-2.2). Increased cumulative ICS dose in the previous year was also associated with a greater risk of NTM development (adjusted OR 1.06 for low, 1.48 for moderate, and 2.28 for high-dose ICS use). However, the absolute risk of NTM was low and the retrospective nature of the study limits confidence in the strength of the association. In addition, early symptoms of NTM could have been misattributed to COPD, creating a further source of bias [74-76].
Ocular effects — Systemic glucocorticoids can contribute to increased intraocular pressure and increased risk of cataract formation. A few studies have examined whether ICS can have similar effects. (See "Major side effects of systemic glucocorticoids".)
Intraocular pressure — Conflicting data have been reported regarding whether ICS are associated with an increased risk of ocular hypertension [77-79]. In a case control study of 2291 subjects with glaucoma and 13,445 controls, neither current use nor continuous use of high-dose ICS for three or more months was associated with an increased risk of glaucoma . On the other hand, a separate study found an increased risk of ocular hypertension among patients with a family history of glaucoma who were using ICS (OR 2.6, 95% CI 1.2-5.8), particularly those on a high dose of ICS . The investigators suggested that ocular pressure should be monitored in older adults with a family history of glaucoma who are using high dose ICS.
Cataracts — The use of systemic glucocorticoids is a definite risk factor for the development of posterior subcapsular cataracts. In contrast, the risk with ICS use is less clear, since the majority of studies could not control for the confounding use of systemic glucocorticoids [80-87]. (See "Major side effects of systemic glucocorticoids" and "Cataract in adults".)
●A population-based cross-sectional study of 3654 patients from Australia, ages 49 to 97 years, found a higher prevalence of nuclear cataracts and posterior subcapsular cataracts (relative prevalence, 1.5 and 1.9, respectively) among current or previous users of ICS, compared with those who never used ICS . Higher cumulative lifetime doses of beclomethasone were associated with a greater risk of posterior subcapsular cataracts; the highest prevalence (27 percent) occurred in those whose lifetime dose was above 2000 mg (relative prevalence, 5.5). This dose roughly corresponds to the use of a beclomethasone chlorofluorocarbon (CFC) inhaler, 600 mcg/day, for over 10 years. Adjusting for the use of systemic glucocorticoids had little effect on the magnitude of the associations.
●These results were supported in a subsequent report that found that the prolonged administration (greater than three years) of high doses of ICS (average >1 mg/day of beclomethasone or budesonide) increased the likelihood of undergoing cataract extraction in individuals over the age of 70 .
●The risk of cataract development was also addressed in a population-based case-control study that matched more than 15,000 patients with and without cataracts to assess the impact of ICS use on this disorder . A linear association between exposure and the development of cataracts was noted. However, the difference between groups was only significant for patients using high-dose ICS (≥1600 mcg/day). Coadministration of systemic glucocorticoids was a possible confounder in this study.
These studies did not address the effect of ICS on the development of cataracts in children, although children who receive systemic steroids appear to be more susceptible to this complication than adults. However, in a cross-sectional study in patients aged 5 to 25 years taking either inhaled beclomethasone or budesonide, no cataracts were found on slit-lamp examination, even in patients taking 2000 mcg daily for over 10 years . Other studies have also found no evidence of increased cataract formation in children [84,88].
For all age groups, prospective studies are needed to discern whether this is a true causal relationship.
Skeletal effects — The potential skeletal effects of ICS include growth deceleration in children and increased risk for osteoporosis in both adults and children.
Growth deceleration — Despite concerns that ICS might be associated with growth deceleration in children, the effect of ICS on adult height appears small based on a number of studies described below. Asthma itself (as with other chronic diseases) has been associated with a deceleration of growth velocity, which is most pronounced with severe disease . However, asthma is also associated with a delayed onset of puberty, such that asthmatic children may continue to grow over a longer period of time . Further research is needed to determine whether individual ICS have differing effects on growth and to better define the long-term effect of ICS on adult height.
In clinical trials, growth is often assessed by knemometry, which measures the distance between heel and knee of the sitting child and is considered to be a very sensitive method for assessing short-term leg growth. However, the relationship between knemometric measurements and final height is uncertain, because low doses of oral glucocorticoid, which have no effect on final adult height, cause profound suppression of knemometric parameters.
The following studies provide evidence that ICS cause a small decrease in linear growth velocity when assessed by techniques such as knemometry [3,88-101]:
●In a systematic review and meta-analysis of 25 trials involving 8471 children with mild to moderate persistent asthma, six different ICS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, mometasone furoate) were given at low or moderate daily doses during a period of three months to six years . Regular use of ICS at these doses was associated with a mean reduction in linear growth velocity of 0.48 cm/year. ICS-induced growth suppression appeared maximal in the first year of therapy.
●A separate systematic review and meta-analysis included 10 trials involving 3394 prepubescent children with mild to moderate persistent asthma and assessed the effect on linear growth of increasing the dose of hydrofluoroalkane (HFA)-beclomethasone (or the equivalent) from low (50 to 100 mcg) to medium (200 mcg) . A small but statistically significant difference in growth velocity over 12 months was observed between the groups (mean difference 0.20 cm/year, 95% CI 0.02-0.39). A number of trials could not be included due to incomplete recording.
●In the Childhood Asthma Management Program (CAMP), 1041 children (ages 5 to 12) with asthma were randomly assigned to take inhaled budesonide, inhaled nedocromil, or placebo for four to six years . A reduction in growth velocity was noted in the budesonide group in the first year, but growth velocities were the same in all groups by the end of the study. The budesonide group had a 1.1 cm lower mean increase in height compared with placebo at the end of the study.
The effect of childhood administration of ICS on adult height does not appear to be progressive or cumulative [94,95,102,103]. In a follow up to the CAMP trial described above , the adult height of 943 of the original 1041 participants was assessed at age 24.9 ± 2.7 years . After controlling for demographic features and asthma severity, the mean adult height was 1.2 cm lower in the budesonide group than in the placebo group, compared with a growth difference of 1.1 cm at the time of the trial.
The specific inhaled glucocorticoid molecule and delivery device may also influence the effect on growth, although the data are insufficient for guiding selection among agents and delivery devices .
Other smaller studies have found that adult height in people with asthma is normal despite ICS therapy [3,95,103]. As an example, in a prospective study of 142 children with asthma who had been treated with inhaled budesonide for 3 to 13 years, normal adult height was attained . In addition, the budesonide-treated children reached their predicted adult height to the same degree as their healthy siblings and a control group of children with asthma who did not receive budesonide.
Osteoporosis and fracture risk in adults — The effects of oral glucocorticoids on bone metabolism and osteoporotic vertebral and rib fractures are well known. However, studies of the impact of ICS on the risk of osteoporosis and the more clinically relevant outcome of osteoporotic fracture have yielded conflicting results in adults. The difficulty in studying this question arises from the fact that most heavy users of inhaled glucocorticoids are occasional or even frequent users of oral or periodic parenteral glucocorticoids. Nonetheless, the majority of studies suggest that doses of ICS below the equivalent of budesonide 800 mcg/day have minimal effect on fracture risk, while higher doses may be associated with an accelerated decline in bone mineral density and increased risk of fracture [17,58,105-120].
Until the risks for osteoporosis and fracture are better defined for ICS therapy, measures to decrease the likelihood of osteoporosis are warranted (table 5), particularly in patients using high dose ICS (table 4). Adult patients receiving chronic therapy with inhaled glucocorticoids who have a moderate risk of osteoporosis should undergo bone density measurement to assess the need for preventive therapy. (See 'Measures to minimize systemic side effects' below and "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Osteoporotic fracture risk assessment".)
Data in support of an increase in risk of osteoporotic fracture among adult ICS users include the following:
●Four of six systematic reviews published since 2003 have concluded that ICS are associated with an increased risk of fracture [58,121-125], while a fifth found an association with high dose ICS . The one that did not find an association included only randomized controlled trial data and not observational studies . One review that used observational data found an increased relative risk for nonvertebral fracture of 1.12 (95% CI 1.00-1.26) .
●One case-control study (16,341 patients with hip fracture) found that the use of ICS was associated with a small, but significant increase in the odds ratio for hip fracture (OR 1.26). This increased risk persisted after adjustments were made for potential confounders, including the number of courses of oral glucocorticoids a patient required (OR 1.19, 95% CI 1.10-1.28) .
●ICS use was found to be an independent risk factor for fracture in a longitudinal cohort study of 1671 subjects with asthma or COPD (mean age, 81 years) . The dose-response relationship between ICS exposure and time to first fracture was determined using Cox regression . Mean follow-up period was nine years. A dose-related increase in fracture risk with exposure to ICS was identified (rate ratio for mean daily dose >600 mcg, 2.53). The results were similar after adjusting for oral glucocorticoid exposure, airflow obstruction diagnosis, historical fracture, and bronchodilator use and also in the subset of people with no exposure to oral glucocorticoids (rate ratio, 4.54, 95% CI 1.23-16.74).
●A meta-review examined the risk of fracture (vertebral and nonvertebral) among patients taking ICS and found a small increase in the risk of fracture (Peto OR 1.27, 95% CI 1.01-1.58) .
ICS may affect bone health more in certain populations, such as postmenopausal women, those taking higher doses of ICS, and men with more severe COPD [117,128]. In one study, for example, the effect of ICS on bone mineral density was more prominent among postmenopausal women with asthma, than premenopausal . Cross-sectional studies have shown an inverse correlation between the ICS daily dose and cumulative dose and spine bone density in asthmatics (figure 2) [107,108]. In a separate case control study, fracture risk increased with the dose of ICS, and for those taking >1600 mcg/day of ICS the odds ratio for fracture was 1.8 (95% CI 1.04-3.11) .
A few prospective studies and a meta-analysis found no association between ICS use and decline in bone mineral density or risk of fracture [17,58,113-116,129,130]. It is possible that the duration of follow-up and size of these studies were insufficient to detect an effect because changes in bone mass take years to develop. Among patients with respiratory disease, bone mineral density is also affected by factors such as cigarette smoking and activity level. In a retrospective cohort study, the relative risk of nonvertebral, vertebral, and hip fractures were modestly increased among ICS users compared with healthy controls, but not different from those using inhaled bronchodilator therapy, suggesting that some of the risk of fracture was related to respiratory disease rather than ICS . Alternatively, studies showing no increase in fracture risk with ICS use could suggest that increased mobility due to improved respiratory status associated with ICS may partially offset the deleterious effects of ICS therapy on bone metabolism.
Bone health in children — A dose-dependent reduction in bone formation with use of ICS has been demonstrated in older children by monitoring sensitive markers for bone metabolism (serum alkaline phosphatase, bone alkaline phosphatase, osteocalcin, carboxypropeptide) [132,133]. However, fracture risk does not appear to be increased in children using ICS [110,134,135]. In a nested case control study of 19,420 children aged 2 to 18 years and a physician diagnosis of asthma, no significant association was noted between fracture and current, recent or past use of ICS, although an association was noted with oral glucocorticoid use in the previous year .
The guidelines from the Pediatric Endocrine Society Drugs and Therapeutics Committee suggest that routine testing of bone mineral density NOT be performed in children on ICS as decreases in bone density are generally not of clinical significance . However, vitamin D and calcium sufficiency should be ensured with adequate dietary intake of vitamin D (ie, 400 to 800 IU/day) and calcium (ie, 1000 to 1300 mg/day). Monitoring of vitamin D levels is generally not needed.
Whether infants are particularly sensitive to glucocorticoid-induced osteopenia is unknown, but doses should be minimized as much as possible.
Other potential concerns
●Skin changes and bruising – Topical and oral glucocorticoids cause thinning of the skin, telangiectasia, and easy bruising. These effects may result from loss of extracellular ground substance within the dermis, due to an inhibitory effect on dermal fibroblasts. There are reports of increased skin bruising and purpura in patients using high doses of inhaled beclomethasone, but the degree to which these patients were also receiving intermittent oral glucocorticoids was not described . Easy bruising in association with ICS is more frequent in elderly patients ; there are no reports of this problem in children. Long-term prospective studies with objective measurements of skin thickness are needed to definitively determine if ICS affect the skin.
●Myopathy – As mentioned above, ICS can cause dysphonia resulting from a localized myopathy of the vocal cords due to local deposition. (See 'Dysphonia' above.) Whether systemic absorption of ICS can cause more generalized myopathy is less clear. Isolated case reports describe skeletal muscle weakness that resolved with cessation of ICS therapy . Myopathy is more commonly seen with oral glucocorticoid therapy and is presented in more detail separately. (See 'Dysphonia' above and "Glucocorticoid-induced myopathy".)
●Atrophy of airway epithelium – Given the cutaneous effects of systemic glucocorticoids, the effect of ICS on the airway epithelium was examined. There is no evidence for atrophy of the airway epithelium; even after 10 years of treatment with ICS, structural changes in the epithelium are not seen .
●Psychiatric effects – There are various reports of psychiatric disturbance, including emotional lability, euphoria, depression, aggressiveness, and insomnia, associated with use of ICS. Few such patients have so far been reported, suggesting that this is very infrequent, and a causal link with ICS has not been established in most of the cases.
●Pregnancy – Based on extensive clinical experience, ICS appear to be safe in pregnancy, although controlled studies have not been performed for obvious reasons. There is no evidence for adverse effects of ICS on the pregnancy, the delivery, or on the fetus. In contrast, poorly controlled asthma may increase the incidence of perinatal mortality and retard intrauterine growth, and more effective control of asthma with ICS may reduce these problems. (See "Management of asthma during pregnancy", section on 'Inhaled glucocorticoids'.)
●Glucose metabolism – The effect of ICS on glucose metabolism appears minimal and limited to those using high doses of ICS, although conflicting results have been reported [140-145], as shown in the following studies:
•Fasting glucose and insulin were unchanged in adults after doses of beclomethasone up to 2000 mcg daily, and in children with budesonide up to 800 mcg daily [140,141]. In normal individuals, high dose inhaled beclomethasone may slightly increase resistance to insulin . However, in patients with poorly-controlled asthma, high doses of beclomethasone and budesonide paradoxically decrease insulin resistance and improved glucose tolerance, suggesting that the disease itself may lead to abnormalities in carbohydrate metabolism.
•A cohort study of 1698 adults using ICS for obstructive lung disease found no association between ICS and serum glucose in subjects without diabetes, but noted a small increase in serum glucose, 1.82 mg/dL (95% CI, 0.49-3.15) per 100 mcg/day increase in ICS dose, among those with diabetes . There was no evidence that these increases leveled off, so this may represent a clinically meaningful increase at high ICS doses.
•In a study using a Quebec health insurance database of 388,584 patients treated for respiratory disease, current use of ICS was associated with an increase in the rate of diabetes onset defined as new use of an anti-diabetic agent . However, the study did not assess the role of obesity, which is associated with more severe asthma, or the effect of potential differences in activity levels between patients with and without respiratory disease.
Guidelines from the Pediatric Endocrine Society Drugs and Therapeutics Committee suggest obtaining an annual fasting blood glucose and hemoglobin A1c in children at increased risk for diabetes mellitus due to obesity who have an additional risk factor (eg, ethnicity, family history) . In addition, patients on treatment for diabetes mellitus may need adjustment in the dose of hypoglycemic medication with changes in ICS dosing.
●Lipid metabolism – Minimal to no effect of ICS has been found on lipid metabolism. In a small observational study, neither beclomethasone 2000 mcg daily in adults nor budesonide 800 mcg daily in children had any effect on plasma cholesterol or triglycerides . However, in a review of data from the Third National Health and Nutrition Examination Survey (1988-1994), inhaled glucocorticoid use was associated with a slightly higher serum high density cholesterol level among subjects aged 60 or older . A separate study examined the effect of introduction of inhaled budesonide 1600 mcg/day in 11 adults with asthma and found a slight increase in fasting total cholesterol, but no change in fasting triglyceride after four weeks .
MEASURES TO MINIMIZE SYSTEMIC SIDE EFFECTS — A number of measures may help to minimize the risk of adverse effects from inhaled glucocorticoids (ICS) therapy.
●Step down treatment to the lowest possible dose of ICS that maintains symptom control
●Optimize compliance with ICS therapy to maintain disease control
●Optimize delivery: use spacer with metered dose inhalers (MDI), use spacer and facemask with MDIs in young children
●Advise patients to rinse mouth and pharynx, and then expectorate the rinsate after using all ICS 
●Evaluate and treat for complicating features of asthma or COPD
●Add long-acting bronchodilator as indicated by guidelines (see "An overview of asthma management", section on 'Initiating therapy in previously untreated patients')
●Maximize nonpharmacologic treatment (eg, trigger avoidance, vaccination against respiratory infection)
Spacers and valved holding chambers — Efforts should be made to optimize delivery to the lung, to enhance the therapeutic effect and reduce oral deposition that does not contribute therapeutically. If a greater proportion of each dose reaches the lung, the total amount of drug needed to maintain asthma control will be reduced, resulting in a lower risk for systemic side effects. (See "Delivery of inhaled medication in adults" and "Delivery of inhaled medication in children" and "The use of inhaler devices in adults" and "The use of inhaler devices in children".)
Spacers and valved holding chambers, which are used with MDIs, are designed to improve delivery to the lower airway and reduce upper airway deposition. Use of a large volume spacer device with a MDI can increase the amount of drug delivered to the lung to about 20 percent . Although increasing the proportion of drug that is absorbed through the lung means that more of the dose is escaping first-pass metabolism and entering the systemic circulation directly, this is offset by a reduction in the overall required dose. (See 'Factors influencing risk' above and "The use of inhaler devices in adults", section on 'Spacers and holding chambers' and "The use of inhaler devices in children", section on 'Spacers and holding chambers'.)
Medication interactions — Clinicians should use caution when combining high-dose ICS with potent CYP450 3A4 inhibitors, such as clarithromycin, itraconazole, and ritonavir, as these agents may enhance the systemic effects of ICS (table 1). (See 'Factors influencing risk' above.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Inhaled corticosteroid medicines (The Basics)")
●Beyond the Basics topics (see "Patient education: Asthma inhaler techniques in children (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)" and "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Inhaled glucocorticoids (inhaled GC or ICS) have fewer and significantly less severe adverse effects compared with orally-administered glucocorticoids. Concerns about adverse effects arise with ICS because these medications are typically used over many years and are administered to infants, children, and older adults who may be more susceptible to the adverse effects. (See 'Introduction' above.)
●Local deposition of ICS in the oropharynx and larynx most commonly causes dysphonia or thrush. Dysphonia may be less common with devices that produce smaller-sized particles. Thrush can often be avoided by use of a large volume spacer/chamber with metered dose inhalers (MDI) and rinsing of the mouth and pharynx thoroughly and expectorating the rinsate after each administration of ICS with all devices. (See 'Effects of local deposition' above.)
●An individual's risk of systemic side effects from ICS is influenced by the cumulative dose, delivery system, individual differences in response to the glucocorticoid, and degree to which the drug is absorbed at different sites (eg, lung versus gastrointestinal tract). The pharmacokinetics of ICS administered by MDI are depicted in the figure (figure 1). (See 'Factors influencing risk' above.)
●A critical issue in the study of systemic side effects from ICS is whether a measurable short-term effect translates into a significant clinical consequence with long-term use. Careful follow-up studies are needed to determine this. (See 'Systemic adverse effects' above.)
●In children, both ICS therapy and untreated asthma itself have been associated with deceleration of growth velocity. The effects are most pronounced with severe asthma. Inhaled GC cause growth deceleration when assessed by very sensitive measures of growth velocity. However, asthmatic children continue to grow over a long period of time, and their ultimate adult height is approximately 1.2 cm less than without ICS. (See 'Skeletal effects' above.)
●Therapy with ICS can affect hypothalamic-pituitary-adrenal (HPA) axis function, although the effects seem to be infrequent and largely subclinical. For patients receiving ICS therapy within the recommended ranges, the risk of symptomatic adrenal suppression or acute adrenal crisis appears to be very small. However, clinically significant acute adrenal insufficiency has been reported, albeit rarely. (See 'Adrenal suppression' above.)
●ICS can increase intraocular pressure and enhance the formation of cataracts. The magnitude of these effects appears to be small, although prospective studies are required to better define them. Until the risk is better defined, adults receiving ICS therapy over years should be monitored for these complications with regular ophthalmologic exams. (See 'Ocular effects' above.)
●In adults, the impact of ICS on the bone density and osteoporotic fracture is not well defined. The majority of studies suggest that ICS therapy is associated with an accelerated decrease in bone mineral density, and at least a few studies have detected a small but significant increased risk for fracture. Suggestions for monitoring and protecting bone health in adult patients receiving high-dose ICS are listed in the table (table 5). (See 'Osteoporosis and fracture risk in adults' above.)
●To minimize the risk of adverse effects from ICS, we advise use of the lowest dose that maintains asthma control, attention to compliance, and regular evaluation for co-existent conditions and triggers that can exacerbate asthma symptoms. In addition, spacers should be used with metered dose inhalers to optimize delivery to the lung, especially in adults receiving ≥800 mcg daily and children receiving ≥400 mcg daily through a MDI device. (See 'Measures to minimize systemic side effects' above.)
●Medications that inhibit cytochrome p450 3A4 should be used with caution in patients receiving high dose ICS, as these may increase systemic levels of glucocorticoid (table 1). (See 'Measures to minimize systemic side effects' above.)
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