Inhaled Corticosteroids: Benefits and Risks

Abstract

Airway diseases, mainly asthma and chronic obstructive pulmonary diseases (COPD), are frequently treated with inhaled corticosteroids (ICS). ICS are considered as the cornerstone of asthma management, however, in COPD the picture is different and ICS are indicated in special circumstances. The benefits of ICS are well documented in controlling disease symptomatology. But, still there are side effects of using ICS, especially the risk of pneumonia and bacterial colonization of the airways. In this chapter, I will explore the change in the use of ICS in asthma and COPD, the indications of ICS, the benefits of ICS and its drawbacks, and how we could modify our practice in order to avoid the side effects of ICS.

1. Introduction

Systemic Corticosteroids (SC) are synthetic analogs of the naturally occurring steroid hormones produced by the cortex of the adrenal gland that is administrated by oral or injectable routes. The SC hormones have glucocorticoid and mineralocorticoid properties with varying degrees. The most important is the glucocorticoids which are predominantly involved in metabolism and have immunosuppressive, anti-inflammatory, and vasoconstrictive effects. SC is widely prescribed in medicine including respiratory medicine as in airway diseases, sarcoidosis, interstitial lung diseases, pulmonary eosinophilic diseases and others [1]. Since the 1950s, SC has been proven to be an effective therapy for persistent asthma [2, 3], however, they have various side effects.

The first pressurized metered-dose inhaler (pMDI) as a bronchodilator for asthma, was introduced in 1956 namely non-selective beta-2-agonists isoprenaline and adrenaline that was associated with rapid relief of asthma symptoms [4]. In the 1960s, there was an epidemic of asthma deaths in Britain thought to be caused by the high use of inhaled bronchodilators [5, 6] and so delayed in seeking medical advice, even if not proved, resulted in suspending the use of inhaled isoprenaline that was replaced later by salbutamol, the selective short-acting beta-2-agonist, and increase the use of SC [4]. By the early 1970s, inhaled beclomethasone dipropionate started to develop as 1st inhaled corticosteroid (ICS) and placebo-controlled studies confirmed the value of ICS therapy in asthma [7, 8, 9]. Afterward, ICS became the cornerstone of asthma management and various substitutes and forms were introduced in pulmonary medicine.

2. Mechanisms of ICS

ICS have glucocorticoids effects that suppress the ongoing inflammatory process through gene transcription mechanisms [10, 11]. Glucocorticoids act by binding to glucocorticoid receptors (GRs) in the cytoplasm resulting in their activation and translocation in the nucleus to produce their anti-inflammatory effects through various molecular effects.

Corticosteroids switch off various activated inflammatory genes that encode cytokines, chemokines, inflammatory enzymes and proteins as the anti-inflammatory proteins secretory leukoprotease inhibitor, and mitogen-activated protein kinase phosphatase-1 (MKP-1) which inhibits MAP kinase pathways [12, 13]. The nuclear GR interacts with coactivator molecules as CREB-binding protein resulting in the activation of proinflammatory transcription factors, nuclear factor-κB (NF-κB) and activator protein-1, in the airways and so reduces histone acetyltransferase activity [10, 14]. Also, activated GR recruits histone deacetylase-2 (HDAC2) to the activated inflammatory gene complex which reverses histone acetylation resulting in the suppression of all nuclear-activated inflammatory genes [15].

Further, ICS increase the gene transcription encoding β₂-receptors, resulting in increased expression of β₂-receptors on the cell surface of the airways [16, 17] which protect against the β₂-receptors tolerance after long-term use. Moreover, ICS may enhance the β₂-receptors coupling to G-proteins that promote β₂-agonist effects and reverse its uncoupling in response to some inflammatory mediators as interleukin-1β through G-protein coupled receptor kinase stimulation [18]. β₂-Agonists also increase the translocation of GR to the nucleus after its activation thus enhancing corticosteroids’ anti-inflammatory effects through synchronized interactions [19, 20].

On the other hand, ICS have cellular effects by reducing the numbers of various inflammatory cells mainly eosinophils, mast cell, T-lymphocytes and dendritic cells through either inhibiting the recruitment of these cells in the airways or their survival [21]. Moreover, ICS restore the airway epithelial cell integrity thus inhibiting the transcription of inflammatory genes thus suppressing mucosal inflammation and eosinophilic recruitment into the airways that is associated with airway hyperreactivity [22, 23].

3. Types of ICS

Nowadays, there are eight different ICS molecules available. These are: beclomethasone dipropionate (BMD) which is the first known ICS, budesonide (BUD), ciclesonide (CC), flunisolide, fluticasone propionate (FP), fluticasone furoate (FF), triamcinolone acetonide (TA) and mometasone furoate (MF). The difference between these molecules is lipophilia with greater GR affinity and longer duration of action; as fluticasone furoate is the most lipophilic (i.e., high potency) and beclomethasone dipropionate the lowest [24].

The various ICS have also different pulmonary bioavailability (i.e., within the airways) and oral bioavailability (i.e., in the systemic circulation) [25]. Negligible oral bioavailability due to high first-pass metabolism is found for FF, FP, MF and CC and so fewer side effects [24]. Three factors are expected to affect the efficacy of an ICS: the potency (the lower inhaled dose occupied the same number of GRs), the delivered dose (the device efficiency) and airway residency duration. FF, FP, MF and CC have greater residency duration in the airways which allows one daily dose; however, twice daily is considered better [26, 27]. Figure 1 shows the relationship between ICS dose and its affinity to GR, whereas FF has both the higher GR affinity with the lowest dose compared to triamcinolone acetonide and flunisolide [28].

Figure 1.

Relationship between the dose of ICS and relative glucocorticoid receptor binding affinity [28].

ICS could be delivered by pressurized metered-dose (pMDI) inhaler, dry-powder (DPI) inhaler and nebulization which are expected to influence the ICS dose. The great difference between the devices is the size of respirable particles emitted that are generally <5 μm [29]. DPI and pMDI (with drugs dissolved in chlorofluorocarbon “CFC”) usually emit particles between 3 and 5 μm, however, pMDI with drugs dissolved in hydrofluoroalkane (HFA) emits ultrafine particles of about 1 μm which allow high delivery of ICS in low-mid doses with high lung deposition. Table 1 compares the low-, mid- and high-doses of ICS of different molecules and devices. Regarding fluticasone, according to the manufacturer’s summary of Product Characteristics, FF 100 μg once daily is approximately equivalent to FP 250 μg twice daily [35]. The devices nowadays are many, especially those designed to deliver the DPI either pre-metered or device-metered (Figure 2) [36].

ICS molecule	Age	Low-dose	Mid-dose	High-dose
Beclomethasone HFA/pMDI	0–4 years	NA	NA	NA
	5–11 years	80–160 μg	160–320 μg	>320 μg
	≥12 years	80–240 μg	240–480 μg	>480 μg
Budesonide DPI	0–4 years	NA	NA	NA
	5–11 years	180–400 μg	400–800 μg	>800 μg
	≥12 years	180–600 μg	600–1200 μg	>1200 μg
Fluticasone HFA/pMDI	0–4 years	176 μg	176–352 μg	352 μg
	5–11 years	88–176 μg	176–352 μg	>352 μg
	≥12 years	88–264 μg	264–440 μg	>440 μg
Fluticasone DPI	0–4 years	NA	NA	NA
	5–11 years	100–200 μg	200–400 μg	>400 μg
	≥12 years	100–300 μg	300–500 μg	>500 μg
Mometasone DPI	0–4 years	NA	NA	NA
	5–11 years	NA	NA	NA
	≥12 years	200 μg	400 μg	>400 μg
Budesonide nebulized (solution inhalation)	0–4 years	0.25–0.5 mg	0.5–1 mg	>1 mg
	5–11 years	0.5 mg	1 mg	2 mg
	≥12 years	NA	NA	NA

Table 1.

Comparison between ICS molecules classified by doses* [30, 31, 32, 33, 34].

^*

All doses are per day.

Figure 2.

Classifications of drug powder inhalers (DPI) [36].

In addition, the GINA guidelines has published equivalent doses of different ICS molecules (Table 2) [37].

ICS molecule	Age	Low-dose	Mid-dose	High-dose
Beclomethasone HFA/ pMDI	5–11 years	100–200 μg	>200–400 μg	> 400 μg
	≥12 years	200–500 μg	> 500–1000 μg	>1000 μg
Budesonide (DPI, pMDI, standard particle or HFA)	5–11 years	50–100 μg	>100–200 μg	>200 μg
	≥12 years	200–400 μg	>400–800 μg	>800 μg
Fluticasone furoate DPI	5–11 years	50 μg		NA
	≥12 years	100 μg		200 μg
Fluticasone propionate (DPI, pMDI, standard particle or HFA)	5–11 years	50–100 μg	100–200 μg	>200 μg
	≥12 years	100–250 μg	250–500 μg	>500 μg
Mometasone (pMDI, standard particle or HFA)	5–11 years	100	200	5–11 years
	≥12 years	200–400 μg		>400 μg
Ciclosonide pMDI /HFA	5–11 years	80	>80–160	>160
	≥12 years	80–160	>160–320	>320

Table 2.

Comparison between ICS molecules classified by doses as published in GINA guidelines.

4. Clinical uses and benefits of ICS

4.1 Asthma

ICS are considered as the cornerstone treatment for the management of asthma in all ages. ICS are the first line of therapy for persistent asthma with a starting low-dose that to be increased according to the level of control of the disease including the addition of other types of inhalers such as long-acting- β₂-agonist (LABA) and/or long-acting muscarinic antagonists (LAMA) in a step-wise approach [37]. In addition, in the latest GINA guidelines [37], low-dose ICS in combination with formoterol (a LABA inhaler) was approved as a reliever instead of short-acting β₂-agonist (SABA) as salbutamol that was associated with a decrease risk of severe exacerbations and is called the anti-inflammatory reliever.

Moreover, it is recommended the addition of low-dose ICS in the management of mild asthma. Juniper et al. showed that the use of low-dose ICS in mild asthma was associated with less symptoms and improvement of lung function up to being asymptomatic over several months of therapy [38]. Further, Pauwels et al. reported a reduction in asthma exacerbations among mild asthmatics treated with low-dose ICS [39]. Recent GINA guidelines recommend the use of low-dose ICS or low-dose ICS-formoterol as a reliever for mild asthma to decrease the risk of severe asthma exacerbation based on various studies [40, 41, 42]. Medium to high dose ICS are recommended for persistent asthma according to the step-wise approach of GINA guidelines [37]. ICS are also related to improvement in lung function in asthmatic children and adults [43, 44] owing to the switch-off of the chronic inflammatory process by ICS in asthma. Further, many studies showed that regular ICS use provides significant protection and reduces the risk of mortality, severe exacerbation and hospitalization of asthma population [39, 45, 46].

4.2 Chronic obstructive pulmonary disease (COPD)

The use of ICS is controversial in COPD medications. The response to ICS in COPD patients is less than asthma population [47] which reflects the resistance of airway inflammation to ICS secondary to the reduction of HDAC2 [48, 49]. According to Global Initiative Lung Disease (GOLD) guidelines of COPD [50], ICS are indicated in frequent COPD exacerbator phenotype (i.e., those who had ≥2 exacerbations/year required OCS or ≥ 1 exacerbation need hospitalization) or COPD patients with blood eosinophilia ≥300 cells/μL [51]. Also, the Spanish guidelines of COPD, recommended the use of ICS in asthma-COPD overlap (ACO) who are patients with criteria of asthma and COPD with blood eosinophil counts >300 cells/μL and/or a post-bronchodilator response of >400 mL and 15% in FEV₁ [52]. A meta-analysis of important studies in COPD reported that ICS withdrawal did not result in a significant increase in COPD exacerbations risk [53]. Miravitlles et al. proposed an algorithm for the withdrawal of ICS in COPD patients based on FEV₁% predicted and exacerbation history [54]. Figure 3 summarizes this algorithm [54].

Figure 3.

Algorithm for ICS withdrawal in COPD [54].

5. Risks and complications of ICS

5.1 Local effects

ICS are associated with some local side effects, despite being not serious but could be associated with discontinuation of therapy. Hoarseness of the voice or dysphonia is the most common local side effect that occurs in about 50% of ICS users. It is a reversible side effect of drug withdrawal that is attributed to myopathy of laryngeal muscles [55]. Oropharyngeal candidiasis is the second most common side effect, despite being more in the elderly population, a percentage of ICS users complaint of it which is related to poor inhalation technique and high doses of ICS. The use of spacers is associated with decreasing these side effects [37, 56].

Importantly, ICS are associated with an increased risk of pneumonia. Patients with COPD, older patients, active smokers, low body mass index <25 kg/m², patients with a history of exacerbations or pneumonia, and/or severe airflow limitation are associated with a higher risk of pneumonia on ICS use [57, 58]. In a meta-analysis, both inhaled fluticasone and budesonide were associated with a significant risk of pneumonia [59] that could be related to the use of a high dose of ICS alone or in-combination with bronchodilator [60]. Further, ICS use was associated with a specific bacterial infection in a subset of the severe COPD population. Shafiek et al. [61] found that ICS dose could be associated with Pseudomonas aeruginosa infection in the severe COPD population. This could be explained on the basis of impaired recognition of P. aeruginosa and activity of alveolar macrophages secondary to altered expression of Toll-like receptor 2 and various cytokine production in COPD patients receiving ICS [62]. On the other hand, O’Byrne et al. found that budesonide, as an ICS, was not associated with increased risk of pneumonia in asthmatic patients [63]. However, Qian et al. found that ICS use is associated with increased risk of pneumonia in asthma population with a risk of 1.44/1000 asthmatics/year [64].

A recent meta-analysis showed that ICS in high doses of fluticasone is associated with an increased risk of non-tuberculous mycobacteria in chronic respiratory diseases, and also may be associated with tuberculosis, especially in COPD patients [65].

5.2 Systemic effects

The use of ICS is less associated with systemic side effects compared to OCS. However, long-term ICS use is associated with an increased risk of bone fractures in patients with COPD which was reported to be up to 27% in a meta-analysis of various RCTs and observational studies with fluticasone or budesonide therapy [66]. Although bone density is less in patients taking high-dose of ICS, interpretation is confounded by the fact that these patients are also taking intermittent courses of OCS [21]. Further, osteoporosis is strongly correlated to COPD due to various lifestyle risk factors such as poor physical inactivity and smoking, vitamin D deficiency and COPD-associated inflammation [67].

Hypothalamic–pituitary–adrenal axis suppression is associated mainly with OCS for weeks even with short courses, but with ICS the results of the studies are inconsistent as often the patients have also been taking courses of OCS [68]. Increased risk of new-onset diabetes or diabetes progression has been reported in ICS users which was about 34% and is more among high doses ICS users and COPD [69]. Further, cataracts [70] and glaucoma [71] have been reported as side effects of high doses of ICS.

6. Conclusions

The introduction of ICS in respiratory medicine is crucial and modifies the management of diseases. ICS are good anti-inflammatory medication. ICS can effectively replace OCS in the control of chronic obstructive respiratory diseases, especially asthma. However, ICS has still side effects, especially in high doses; despite being less than OCS, it is associated with some morbidity that should be well controlled and managed.

Conflict of interest

I declare that I have no conflicts in relation to the current work.