Are Inhaled Corticosteroids Safe for Large Airways

OpenAlex İngilizce

Inhaled corticosteroids (ICS), as anti-inflammatory agents, remain a cornerstone in the management of asthma and chronic obstructive pulmonary disease to treat and reduce the risk for acute exacerbations. Using this route of administration, small particles of corticosteroid are thought to be delivered to the alveoli with minimal systemic effects. Dexamethasone was the first ICS, shown to be beneficial for bronchial asthma as a nebulizer solution in the early 1960s.1 The major ICS, widely used in current clinical practice, include beclomethasone dipropionate (Qvar preparations), fluticasone propionate, budesonide, and mometasone furoate. Subsequently, newer generations of ICS have been introduced, such as ciclesonide and flunisolide.1,2 Currently, over 72% of all asthma patients are prescribed ICS during the course of their illness.3 The dose of ICS varies according to the type of preparation and the severity of the disease. Although infrequent, there has always been concern about the local and systemic effects of ICS, particularly when used over a longer period of time. The safety of ICS has been investigated since their introduction into clinical practice. The frequency of adverse events depends on the dose of the drug, frequency of administration, inhalation technique, and the delivery system used. Although ICS are designed to have a local and topical effect, lack of proper inhalation technique and appropriate delivery system can precipitate systemic side effects. It may be surprising to note that approximately 10% to 20% of a dose of ICS from a metered-dose inhaler (MDI) is delivered to the respiratory tract, whereas 80% to 90% can be swallowed and absorbed through the GI tract. ICS use is associated with a number of systemic side effects, such as suppression of the hypothalamic-pituitary-adrenal axis with a higher dose ICS (>400 mcg/d) and probable risk for osteoporosis.2,4 These side effects are more pronounced with fluticasone use.5 Raised intraocular pressure and increased risk for cataract formation have also been described.2,5 The analysis from the Cochrane airways group suggests that budesonide and fluticasone use can cause adverse pneumonia events.6 A high dose of ICS can also lead to mycobacterial tuberculosis and nontubercular mycobacterial infection in chronic obstructive pulmonary disease and bronchial asthma patients.7,8 Not unpredictable though, a multitude of topical side effects can occur on the airways with ICS use. Dysphonia is the most common complaint, affecting as high as 58% of the patient population depending upon dosage and administration.9 Mucosal irritation and myopathy of laryngeal muscle are the major mechanisms of ICS-associated dysphonia.10 The ICS dry-powder inhalers have a lower risk for dysphonia compared with the MDI device.11 Other topical side effects include oropharyngeal and laryngeal candidiasis, whereas esophageal candidiasis is less common with ICS use.12,13 Allergic contact dermatitis is another reported focal effect, most commonly with budosenide.2 Dental erosion is also a possibility given the low pH of the powdered forms, if the mouth is not rinsed properly after ICS inhalation.5 On a similar discourse, a recent publication highlights that long-term use of ICS plays an important role in tracheobronchial smooth muscular atrophy and separation of the smooth muscle wall from the posterior cartilaginous ring (TB-SMAS) leading to excessive dynamic airway collapse of the bronchial wall.14 Mehta and colleagues published a case series involving 4 patients with this feature observed after chronic use (at least 7 years) of high-dose ICS, notably fluticasone. The cause is the multifaceted role of ICS on bronchial airways, including inhibition of smooth muscle proliferation due to its anticytokine and growth factor effect and smooth muscle atrophy by impairing protein synthesis. In addition, there may be a probable role of ischemia from local vasoconstriction induced by ICS.14 A critical issue is whether this measurable side effect from long-term ICS use translates into significant clinical consequences in the patients. This condition was detected during evaluation for the persistent respiratory symptoms, to which this element was likely a powerful contributory factor. The precise clinical fall-out is difficult to ascertain, as at present there is no potential fix for this condition. Further, it is unclear whether newer generation ICS are partners in the same crime. ICS medications are generally administered over a prolonged period of time, making patients prone to the adverse events. The side effects from ICS are often influenced by the cumulative dosage and mode of delivery and individual susceptibility. The higher liphophilic property and longer half-life of the fluticasone molecule particularly make them a necessary evil in this regard. To minimize the risk of this local adverse event from ICS, it is advisable to use the lowest possible dose to maintain symptom control and to evaluate for any coexistent triggers that can exacerbate the symptoms. In addition, spacers should be used with MDIs to optimize delivery to the lung, especially with a daily dose of >800 mcg in adults and 400 mcg in children. Nevertheless, concomitant use of systemic corticosteroids may have been a potential confounder to this conclusion. Notwithstanding, this unique phenomenon of “TB-SMAS” can often go unnoticed, although it may be of immense clinical significance in certain cases. A high index of suspicion should be placed on patients with a recurrence of common pulmonary symptoms who are on a prolonged course of high-dose ICS therapy.