Background Oral corticosteroid use increases the risk of systemic adverse effects including osteoporosis, bone fractures, diabetes, ocular disorders and respiratory infections. We sought to understand if inhaled corticosteroid (ICS) use in asthma is also associated with increased risk of systemic effects.
Methods MEDLINE and Embase databases were searched to identify studies that were designed to investigate ICS-related systemic adverse effects in people with asthma. Studies were grouped by outcome: bone mineral density (BMD), respiratory infection (pneumonia or mycobacterial infection), diabetes and ocular disorder (glaucoma or cataracts). Study information was extracted using the PICO checklist. Risk of bias was assessed using the Cochrane Risk of Bias tool (randomised controlled trials) and Risk of Bias In Non-randomised Studies of Interventions-I tool (observational studies). A narrative synthesis was carried out due to the low number of studies reporting each outcome.
Results Thirteen studies met the inclusion criteria, 2 trials and 11 observational studies. Study numbers by outcome were: six BMD, six respiratory infections (four pneumonia, one tuberculosis (TB), one non-TB mycobacteria), one ocular disorder (cataracts) and no diabetes. BMD studies found conflicting results (three found loss of BMD and three found no loss), but were limited by study size, short follow-up and lack of generalisability. Studies addressing infection risk generally found positive associations but suffered from a lack of power, misclassification and selection bias. The one study which assessed ocular disorders found an increased risk of cataracts. Most studies were not able to fully adjust for known confounders, including oral corticosteroids.
Conclusion There is a paucity of studies assessing systemic adverse effects associated with ICS use in asthma. Those studies that have been carried out present conflicting findings and are limited by multiple biases and residual confounding. Further appropriately designed studies are needed to quantify the magnitude of the risk for ICS-related systemic effects in people with asthma.
- asthma pharmacology
- drug reactions
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What is the key question?
Do inhaled corticosteroids in people with asthma increase the risk of systemic adverse effects that are known to occur with oral corticosteroid use?
What is the bottom line?
There are few studies addressing this question, and those studies are limited by multiple biases, but they suggest an increased risk of bone mineral density loss, respiratory infections and cataracts.
Why read on?
This review reports on the few studies that have been carried out on this topic, and highlights current evidence gaps.
Asthma is a highly prevalent global disease; for example, around 8% of adults in the UK and the USA have active asthma.1 2 Since the 1970s, inhaled corticosteroids (ICS) have been the mainstay of treatment—significantly reducing morbidity and mortality, thus they are recommended as first-line preventer treatment in national and international guidelines.3–5 For most people, maximal clinical benefit can be achieved with low-dose ICS.6–8 Yet in the UK, the number of adults with asthma that are prescribed medium-dose or high-dose ICS has increased considerably over the past decade (to around 70% in 2017).9 Oral corticosteroid use in people with asthma has been found to increase the risk of conditions including osteoporosis, bone fractures, cataracts, pneumonia, opportunistic lung infections, diabetes and obesity.10 Studies evaluating the dose equivalence of oral corticosteroids to ICS, in terms of systemic effects, found most of the oral corticosteroid-sparing effect that occurs with high-dose ICS is ascribed to their systemic absorption; suggesting high-dose ICS requires similar consideration as starting maintenance low-dose oral corticosteroids.11 But patients at higher risk of systemic side effects (those that are already diagnosed with osteopenia, osteoporosis, diabetes and cataracts) are not preferentially started on low-dose ICS or stepped down from higher ICS doses,9 even though people with asthma do consider potential side effects a priority when choosing treatment.12
The benefits of an ICS undoubtedly outweigh the risks when used in clinically effective doses, however, long-term ICS use may cause systemic side effects.13 There has only been one previous systematic review (published in 1999) of all major potential adverse systemic effects associated with ICS, including people with asthma. Due to a dearth of studies the author was unable to perform a meta-analysis, except for the numerous studies evaluating adrenal insufficiency.14 The aim of this present systematic review was to review the latest scientific evidence of adverse systemic effects associated with ICS use in asthma (excluding adrenal insufficiency which was recently reviewed elsewhere).15
The systematic review protocol was registered with the International Prospective Register of Systematic Reviews, registration number: CRD42020187770 and we followed the guidelines published by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Consortium (PRISMA).16
Our objective was to quantify, in adults with asthma, any association between adverse systematic effects (known to occur with oral corticosteroids) and ICS use. We sought to assess the following effects: bone mineral loss (bone density or fractures), respiratory infections (pneumonia, tuberculosis (TB), or non-TB mycobacteria), ophthalmic effects (cataracts/glaucoma) and diabetes.
We systematically searched MEDLINE and Embase (from 10 June 1999 through 10 June 2020) using both Medical Subject Headings terms and free-text searching to identify literature related to asthma, ICS-containing medication and the systemic adverse effects listed in the objectives (online supplemental table 1). These three concepts were combined using the Boolean operator ‘AND’. The database search was supplemented by a manual scan of the reference lists of included studies.
Selection of studies
We selected randomised controlled trials (RCTs) and observational studies that included adults with asthma (≥18 years), or that included at most 20% of the study population aged 12–18 years. We considered observational studies where at least one of our outcomes of interest was measured as the primary outcome, and primary or secondary analyses of RCTs. The exposure considered for this review were ICS-containing inhalers (single component or dual component with a long-acting β agonist); those not exposed were using a placebo or non-ICS-containing medication. For observational studies only, we included studies where the control group could contain people without asthma. We only included studies that were designed to evaluate at least one of our outcomes of interest: bone density loss (measure by ultrasound or X-ray absorptiometry), pneumonia, TB, non-TB mycobacteria, cataracts, glaucoma and diabetes (new diagnosis or hyperglycaemia). Articles were excluded if they contained <100 patients that met the inclusion criteria, mixed-study population encompassing more than 10% of people with COPD (chronic obstructive pulmonary disease) or were a study of pregnant women. Abstracts, case histories, reviews/pooled analysis, guidelines, commentaries, animal/in vitro studies and articles not written in English language were also excluded.
Data extraction, quality assessment and data synthesis
Data were extracted following predetermined criteria based on the PICO (Patient Information Comparison Outcome) checklist (online supplemental table 2). Study details included: study name; patient number; length of follow-up; study inclusion and exclusion criteria; population characteristics including how asthma was defined, gender and age range; primary and secondary outcomes; non-ICS comparison; ICS type where reported; confounding factors; crude and adjusted effect estimates; statistical analysis; and any additional notes. Two reviewers extracted relevant data, which were compared, and inconsistencies discussed.
Quality of RCTs were assessed using the Cochrane Risk of Bias tool. Quality of studies was reported as high, moderate, low bias or unclear. Quality of observational studies was assessed using Risk of Bias In Non-randomised Studies of Interventions. Quality of studies was reported as critical, serious, moderate or low bias. Studies were grouped according to study design (RCT or observational), outcome (including by measurement tool, for example, bone density was measured using ultrasound, single or dual energy X-ray absorptiometry) and effect estimate (HR or OR). There were no more than two studies in each group, therefore it was deemed inappropriate to calculate pooled effect estimates, and a narrative synthesis was conducted.
Patient and public involvement statement
Six patients, from a community asthma clinic and a large UK asthma charity, were consulted in a focus group as to their perceived need of this review and the study design, specifically regarding the inclusion and exclusion criteria to be used. Two patients subsequently critically reviewed the manuscript.
Study selection and characteristics
Following our database searches, we identified a total of 5102 studies. After screening for criteria outlined in the methods and illustrated in the PRISMA flow chart, 5089 papers were excluded, leaving a total of 13 articles to be included in this systematic review (online supplemental figure 1 and tables 1–3).
Inclusion and exclusion criteria within papers
A common inclusion criterion was for patients to have a minimum number of months (for example, some studies had a minum of 6 months) since their asthma was first diagnosed, although many papers failed to provide a definition for the diagnosis of asthma (online supplemental table 3a-d). Two studies specified that patients should have mild asthma (according to forced expiratory volume in 1 s or peak flow readings prebronchodilator) but no study specified moderate or severe asthma. Common exclusion criteria that many, but not all, studies included: COPD diagnosis/hospital admission for COPD exacerbations, use of oral/parenteral steroids in a specified time prestudy commencement and medical conditions known to affect the outcomes being measured.
Bone density studies
Six studies specified the measurement of bone mineral density (BMD) as the primary outcome17–22 (table 1). The studies (four observational, two RCT) each included under 250 participants, except one observational study which included 8624 participants.21 BMD was measured using ultrasound or X-ray absorptiometry (single or dual), or a combination of both, and in different bones (wrist, femur, hip and spine); therefore, findings could not be directly compared between more than two trials. Three of the studies found a decrease in BMD,18 19 21 while three found no change in BMD;17 20 22 one found an increased risk of fractures but no loss of BMD. Study follow-up varied between 6 months to several years and the total time of ICS exposure was not reported. In addition, previous OCS (oral corticosteroids) use was not accounted for in two of the four observational studies.20 22
Respiratory infection studies: pneumonia
Four observational studies identified pneumonia, diagnosed by a general practitioner, hospital admission or insurance codes, as a primary outcome (table 2). All four studies found an increased risk of pneumonia,23–26 although one study found the risk was only increased with fluticasone, not budesonide;25 however, it was likely the subanalysis was underpowered due to the low event rates. Another study due to its cross-sectional design had a high risk of reverse causality,26 one study had a high risk of misclassification as it did not include hospitalised pneumonia,23 and the fourth study only included people aged 12–35 years old.24
Respiratory infection studies: mycobacterial infection
Two case-control studies measured the odds of mycobacterial infection in patients with asthma on ICS to people without asthma and not on ICS (table 2). One study used a South Korean database (n=2779 patients aged over 20 years) to measure the odds of TB,27 the other study used a Canadian administrative database (n=1091 patients aged over 66 years) to measure the risk of TB and non-tuberculous mycobacterial pulmonary disease (NTM-PD);28 both studies found approximately 50% increase in the odds of TB, although this was not statistically significant in the study by Brode et al. However, there was a statistically significant increase in the odds of NTM-PD associated with fluticasone, but not budesonide.
Ocular disorder studies
One case-control study analysed the impact of ICS on the development of cataracts in a primary care population of over 30 000 patients aged above 40 years (table 3). Controls had no previous use of ICS and findings were adjusted for OCS use.29 Exposed patients had to have at least one ICS prescription in a 180-day period, but accumulative ICS use was not accounted for. Adjusted results found a 5% significant increase in the odds of developing cataract in patients using an ICS.
Risk of bias
With regards to the RCTs, both successfully demonstrated low levels of selection bias,17 19 but one showed a potentially high risk of performance bias by keeping the study ‘open’ and unblinded to participants and personnel19 (table 4). We found varying levels of bias in terms of observational studies (table 5). Six of the 11 studies had at least a moderate risk of bias due to confounding, including not accounting for any confounders,22 or only one to three confounders,20 25 29 or not including oral corticosteroids—potentially the largest confounder.20 22 24–26 Seven studies had at least a moderate risk of selection bias,18 20–25 for example, by only selecting a limited young age range at lower risk of BMD loss.17–19 Seven studies showed at least moderate bias in intervention classification;18 22–24 26 27 29 many did not take any account of how long participants were on ICS for.18 21–23 25 26 28 29 Only three studies had low bias of missing data,19 24 29 most did not report on missing data20–22 25–28 and one had serious bias risk.23 Three studies had at least moderate risk of bias in measurement of outcomes20 23 26 and three studies did not report if the investigators were aware of the intervention status.21 22 28 All studies had low risk of bias in reporting results.17–29
This systematic review investigated the potential risk of adverse systemic effects, known to occur with OCS, in people with asthma using ICS. We found 2 RCTs and 11 observational studies meeting the inclusion criteria. The most common reason for excluding articles was that people with asthma were not identified, either because the reason for ICS use was not reported or because the effects on people with asthma were not reported separately from the effects on people with COPD.
The main outcomes of studies eligible to be included were loss of BMD and risk of a respiratory infection. However, due to small sample size, insufficiently recorded ICS and/or OCS exposure, and studies using alternative ways of measuring BMD, there is currently a deficiency of evidence to determine if ICS reduces BMD in people with asthma. Furthermore, only one study specifically addressed the risk of bone fractures. The four studies addressing risk of pneumonia were much larger and mostly found an increased risk, but the studies had significant bias—including misclassification, due to the lack of hospital diagnosed pneumonia—and lack of generalisability, including a study population of only young adults. Two studies assessed pulmonary mycobacterial infection risk, and both reported an elevated risk with ICS, but the studies’ low outcome prevalence is likely to have caused a lack of statistical power to make firm conclusions. Only one study that measured an ocular disorder as the outcome was eligible to be included. The study, which had moderate bias in the confounding and intervention classification categories, found an increased risk associated with ICS use.
Although most of the studies in this systematic review had biases and limitations in generalisability, there is a suggestion that ICS use in people with asthma can lead to systemic adverse effects. This is perhaps not surprising as all ICS have been found to exhibit dose-related systemic adverse effects when measuring adrenal suppression,14 and high dose ICS has been shown to have an equivalent systemic absorption as low dose OCS.11 In addition, several adverse systemic effects have been found to be associated with ICS use in people with COPD, although caution should be used in extrapolating findings in people with COPD to those with asthma. First, people with COPD tend to be older, have more comorbidities, have higher exposure to cigarette smoke and have differing underlying pulmonary immunopathology and systemic inflammation, which may affect the risk of developing adverse effects. For example, osteoporosis has been found to be increased in people with COPD, even without ICS use.30 Second, many people with asthma use much higher doses of ICS and have used ICS for much of their lifetime—unlike COPD, where lower doses of ICS are licensed as treatment and patients typically start ICS treatment at between 60 years and 70 years of age.31 There is little debate that ICS use in people with COPD is associated with elevated risk of pneumonia.32 Studies of patients with COPD have also found an increased risk of TB in at-risk populations,33 a modest but statistically significant augmented risk of fractures34 and in studies not distinguishing between patients with asthma and COPD, the risk of cataracts is around 25% for each 1000 mcg per day (beclometasone equivalent).35 Very few studies have assessed the risk of new-onset diabetes or worsening glycaemia, allied to ICS use, in any population.36
The main limitation of this review is the small number of studies eligible to be included, which precludes the calculation of an overall effect estimate for any of the outcomes. Furthermore, in the BMD articles, different studies used different density measurement tools, in different bones. The lack of adequate control for confounding from OCS exposure represents another inherent limitation. It was not possible to draw conclusions on the association between systemic adverse effects and the dose, duration or type of ICS from the included studies. In studies with a short follow-up it was not possible to consider longer-term adverse effects that may occur, such as bone mineral loss. In this systematic review we have chosen not to include all trials reporting adverse effects as these rely on spontaneous adverse event reports in short-term clinical trials, with no formal measurement of the outcome; furthermore, there is always a high risk of selection bias as only around 10% of people with asthma are eligible to participate in clinical trials.
Asthma is a highly prevalent disorder that in many people requires regular ICS to ensure symptom control and prevent asthma attacks, most of whom are prescribed medium dose or high dose ICS.2 Yet, we found in this review that surprisingly few studies have assessed the potential risk, in an asthma population, of the known adverse systemic effects that accompany OCS use. While these limited studies do suggest ICS use increases the risk of respiratory infections, cataracts and loss of BMD in people with asthma, there were several biases and limitations associated with the studies. A key message from this review is the urgent need for further well-controlled and detailed longitudinal cohort studies to quantify the nature and magnitude of the risk of systemic adverse effects. These studies should try to establish which ICS drugs, which patients and what doses are associated with the highest risk for each outcome. This information is crucial for making informed, shared decisions with patients about how to manage their asthma. Although the risk of side effects is often not considered by primary care physicians, it is considered by patients to be a priority in treatment choices;12 37 bridging this evidence gap will help improve joint management decisions.
The authors thank Vivienne Tickle and Sharon Simons for their critical review of the manuscript.
RP and SAN are joint first authors.
Contributors CIB, RP and SAN conducted the literature search, reviewed titles and full-text articles, extracted data, analysed data, wrote the manuscript. CG critically revised the manuscript. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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