The use of systemic corticosteroids in asthma management in Latin American countries^☆

Introduction

The global prevalence of asthma is approximately 3–4%, making it one of the most common chronic respiratory diseases.¹ Symptoms of asthma include wheezing, shortness of breath, tightening of the chest, and cough, which can range in severity over time.² Approximately 4–10% of patients with asthma are considered to have severe disease, although a higher number may have difficult-to-control asthma or even untreated disease, which are often marked by frequent exacerbations (or “attacks”).2, 3, 4, 5, 6 Asthma is associated with high individual, social, and economic burdens, including high healthcare costs for medications, treatment visits, and hospitalizations.⁷ These burdens increase for patients with a more severe and poorly controlled disease.8, 9, 10

Asthma treatment

The primary goals when treating patients with asthma are to control symptoms, reduce exacerbation risk, and enable patients to perform their usual daily activities.^2,11, 12, 13 Several types of controllers and/or reliever medications may be prescribed to treat these patients. Current guidelines by the Global Initiative for Asthma (GINA) recommend low-dose inhaled corticosteroids (ICS)–formoterol as a controller and as-needed reliever medication (track 1 [preferred]) or a short-acting β2-agonist reliever (track 2 [alternative]) for patients with mild disease (Fig. 1).⁷ Then, as asthma symptoms increase in frequency and severity, or remain uncontrolled, dosing should be increased in a step-wise manner, and/or other types of controllers, such as a long-acting muscarinic antagonist, biologic agents, or systemic corticosteroids (SCS), may be incorporated for patients with severe or difficult-to-treat asthma.⁷

The burden of systemic corticosteroids for patients with asthma

Systemic corticosteroids, which can be administered by injection (intramuscular or intravenous) or orally (OCS), have been a common therapy in asthma management for many years based on their effectiveness for controlling symptoms and their low cost.14, 15, 16 These agents help reverse the pathologic processes of asthma through multiple mechanisms, including enhancing the beta-adrenergic response to relieve bronchial muscle spasms; relieving inflammation by inhibiting eosinophils, other inflammatory type 2 cells, and leukotriene-mediated activity; and reducing immune cell chemotaxis.17, 18, 19 OCS may be prescribed as short-burst regimens to treat acute exacerbations or as long-term maintenance therapy when other asthma control options have been unsuccessful.²⁰ Multiple OCS can be used to treat asthma, which are summarized in Table 1.

The adverse health effects associated with SCS have been well-established for decades;²¹ however, the issue of OCS overuse has recently garnered renewed emphasis for patients with asthma due to several studies that linked adverse outcomes with exogenous steroid exposure in these patients.22, 23, 24, 25, 26, 27 Important findings from these studies included a positive correlation between the OCS exposure and risk of adverse outcomes, which can include early minor, aesthetic complications such as corticosteroid-induced acne; more acute serious complications like infections; and chronic, severe conditions in patients who remain on long-term maintenance OCS therapy (Fig. 2A).²⁸ Recent evidence revealed that a lifetime cumulative exposure of only 0.5–1.0 g SCS (equal to 4 courses of OCS) significantly increases the risk of type 2 diabetes,^23,29 while additional evidence revealed a positive association between cumulative exposure >4.5 g SCS and organ damage.³⁰

Due to the cumulative nature of these adverse effects, patients on long-term maintenance OCS regimens have the highest risk of severe conditions, which include bone fractures, cardiovascular/cerebrovascular disease, cataracts, sleep apnea, adrenal suppression, depression/anxiety, and metabolic disorders (Fig. 2B and C).^{23,26,28,29,31} Adrenal insufficiency, which is exposure-dependent, may also occur in these patients with acute severe episodes arising after discontinuing SCS use.³² However, given that the risk of adverse outcomes increases after as few as 4 courses of SCS, even patients with mild asthma, who may occasionally receive short-burst SCS treatment for exacerbations, are also at an increased risk of SCS-related adverse outcomes. Furthermore, these acute and chronic SCS-related adverse effects can also substantially increase the health and economic burdens already experienced by patients with asthma.^33,34

In response to the mounting evidence, which links SCS use in asthma to both acute and long-term adverse outcomes, GINA recently elevated these findings to the highest level of evidence and added a series of new treatment options before the use of OCS as controller therapy in clinical practice.⁷ It also suggests exercising increased caution when prescribing OCS, factoring potential adverse effects into the decision to prescribe these drugs, and delaying their use until alternative add-on treatments, such as biologics, have been considered or deemed ineffective. GINA also added a recommendation to monitor patients for adrenal suppression if they have been prescribed SCS.⁷

Trends in systemic corticosteroids for asthma

The recent observation that 0.5–1.0 g of SCS can increase a patient's risk of developing adverse outcomes provides an essential threshold for establishing limits of acceptable SCS use.^23,29 Using this as a reference point, recent results from studies of patients with asthma worldwide suggest that SCS are widely overused.^35,36 One report from the United States revealed that up to 20% of patients, including those who originally had mild or moderate asthma or no exacerbations, eventually became users of high-dose OCS regimens (defined as ≥450 mg within 90 days).³⁶ A similar study from western Europe showed that up to 44% of patients with asthma had a history of SCS use, and up to 9% were considered high SCS users per the above definition, with cumulative annual exposures of 2.0–2.7 g.³⁵ A systematic review of patients with severe and/or uncontrolled asthma in the United States, Europe, and Asian countries revealed that up to 93% of patients had received at least one SCS burst per year, and up to 60% had received long-term SCS treatment regimens. That study also revealed dose-related increases in acute and chronic health complications, as well as increased healthcare resource utilization and associated costs, resulting from both short- and long-term SCS use, relative to patients who were not prescribed SCS.²⁸

Asthma in Latin America

Latin America is home to nearly 650 million people and covers over 20 million km². The cultural, socioeconomic, geographic, and environmental diversities throughout Latin America collectively influence health outcomes in complex ways. Furthermore, disease-related variables, such as how asthma is defined across healthcare systems, how epidemiological studies are sampled (eg, physician assessment vs patient report), and cultural differences affecting patients’ willingness to obtain or report an asthma diagnosis, have affected asthma population statistics throughout the region. One study reports the overall prevalence of asthma throughout Latin America as approximately 17% but with wide variation, ranging from 5% (some cities in Mexico) to 30% (in Costa Rica).³⁷ The Global Burden of Disease study reports the prevalence of adult asthma is 3.5%, ranging from 7.6% (Argentina) to 2.8% (Mexico).³⁸ Findings from individual countries include an overall asthma prevalence of 7% in Mexico³⁹ and 12.4% in Brazil.^40,41

Data on asthma severity and control throughout Latin America are limited; however, results from several retrospective studies have provided important insights. The international short-acting beta2-agonist (SABA) use IN Asthma (SABINA) study included a Latin American cohort comprising a cross-sectional analysis of 1100 patients with asthma recruited between March 2019 and January 2020 in Argentina, Brazil, Chile, Colombia, Costa Rica, and Mexico.⁴² Results indicated that 79% of patients with asthma have moderate-to-severe disease (defined as GINA steps 3–5), 31% have partly controlled asthma, 30% have uncontrolled asthma, and 47% of patients experienced at least one exacerbation annually.⁴² Data from the Latin America Asthma Insights and Management (LA AIM) survey, which was completed by 2169 patients throughout Argentina, Brazil, Mexico, and Venezuela, revealed that 36% of patients had uncontrolled asthma, and only 7% had well-controlled disease.⁴³ Results also showed that Brazil had the highest proportion of patients with well-controlled disease (9.3%), followed by Mexico (9.0%), while only 3.0% of patients from Venezuela were well-controlled.⁴⁴ Further analysis of LA AIM data from Brazil revealed that 57% of patients had partially-controlled disease, and 34% had uncontrolled disease.⁴⁵ The Asthma Control in Latin America study consisted of an interview of 594 patients with asthma receiving outpatient specialist care in Argentina, Chile, Colombia, and Mexico between December 2013 and December 2015. On the basis of criteria from the 2014 European Respiratory Society and American Thoracic Society guidelines, 31% of patients were considered to have severe asthma, and 57% had uncontrolled disease. Results also showed that the frequency of uncontrolled asthma was significantly increased among patients with severe disease compared with those with non-severe disease (64% vs. 53%; P < 0.001).⁴⁶

Systemic corticosteroid use for asthma in Latin America

Treatment of patients with asthma throughout Latin America is primarily guided by the recommendations published by GINA or the Latin American Thoracic Society—both of which recommend reducing SCS use in favor of other treatment options (such as biologics) for patients with the most difficult-to-treat asthma.⁴⁷ Data on SCS usage rates throughout Latin America are generally sporadic as few studies on this topic have been performed, most of which are limited to similar groups of countries. However, the currently available data generally suggest that, like in other global regions examined so far, SCS are also being overused to treat patients with asthma in Latin America. Data from the LA AIM study suggest that approximately 40% of patients in Argentina, Brazil, Mexico, and Venezuela had used SCS over the preceding 12 months, including 51% of patients with uncontrolled asthma, 37% with partially-controlled asthma, and 26% with well-controlled asthma.⁴³ In Brazil, SCS were prescribed to 46% of patients with well-controlled asthma, 41% with partially-controlled disease, and 56% with uncontrolled asthma.⁴⁵ Data from the SABINA Latin American cohort revealed that 39% of patients with asthma had received at least 1 short-term SCS burst, and 6% received maintenance treatment over a year.⁴² Finally, a prescription claims analysis based on 20,410 patients with asthma in Colombia between 2004 and 2014 revealed that 22.5% of all patients had been prescribed SCS during that time, including 2.8% of patients with mild intermittent asthma and 60.7%, 70.8%, and 84.9% of patients with persistent asthma that was mild, moderate, or severe, respectively.⁴⁸ Together, these results demonstrate the widespread use of SCS for asthma throughout Latin America, which is likely increasing the risk of long-term, adverse outcomes for these patients.

Factors influencing SCS use in Latin America

Universal factors likely influencing rates of SCS use throughout Latin America include the prevalence of severe and/or uncontrolled asthma; effectiveness, low cost, and widespread availability of corticosteroids; and experience and familiarity with corticosteroids by clinicians. However, considering the size of Latin America and its environmental, cultural, and economic diversities within and between countries, influences on asthma severity and control rates likely vary in innumerable ways throughout the region.

First, the range of climate zones occurring throughout the vast expanse of Latin America along with human-made environments, such as urban and industrial centers, undoubtedly produce locally unique combinations of weather changes, bio-organisms, pollutants, and other allergens that increase the risk of severe or uncontrolled asthma.^49,50

Latin America is also a socioeconomically diverse region with an overall poverty rate estimated at 24%, ranging from 3 to 63% between countries.⁵¹ Poverty itself is a risk factor for increased asthma severity and poor disease control, likely based on patient-specific attributes common to impoverished areas, such as poor education, high smoking rates, malnutrition, and maternal psychological stress, which can compromise neonatal health and lung development and is associated with increased pediatric respiratory morbidity.^44,52, 53, 54, 55, 56 Limited resources in such areas also reduce treatment access and options for patients, which is likely to delay or prevent one from receiving a diagnosis, appropriate treatment, and essential follow-up care. For example, a recent analysis showed that access to respiratory medications including ICS-LABA and SABA can be severely limited in low-income countries.⁵⁷

Multiple aspects of clinical practice may also affect SCS use by patients with asthma. For example, primary care physicians (PCPs) may lack the required knowledge or training on asthma treatment guidelines and prescribe SCS prematurely, ie, to patients who have yet to progress through guideline-recommended treatment steps. Data from the SABINA Latin American cohort revealed that 48% of patients who were prescribed SCS bursts by PCPs had mild disease compared with only 8% who were prescribed SCS by specialists (Table 2).⁴² SCS prescription rates may also be affected by the use of outdated record-keeping procedures. Electronic medical record (EMR) systems could facilitate effective care coordination, including providing records of a patient's current and past prescriptions to monitor the appropriate progression through treatment steps and reduce premature or excessive SCS administration. Recent rates of EMR use throughout Latin America reveal considerable opportunities to improve coordination of care. Finally, SCS usage may be driven in large part by policies at the level of payers and insurance administrators authorizing SCS based on their high effectiveness at a low cost over more expensive but safer alternatives like biologics.

Recent data suggest patient perceptions or attitudes about the state of their condition or treatment may also help to perpetuate the overuse of SCS. Notably, data from LA AIM revealed that although only 8% of study patients met GINA criteria for good asthma control, 60% reported that they felt they had good asthma control.⁵⁸ Additionally, nearly half of all patients in the study reported that having 2 urgent medical visits or one emergency department visit for asthma within a year was still considered as good asthma control.⁵⁸ Such misperceptions could prevent patients from seeking timely and necessary medical care, thereby potentially losing an important period of early intervention that may reduce a need for SCS later. LA AIM data also revealed that 60% of patients were apprehensive about using ICS for asthma control, which could contribute to treatment nonadherence, possibly resulting in the eventual need for SCS if or when symptoms become unmanageable.⁵⁸

Finally, in most Latin American countries, oral or injectable SCS may be obtained without a prescription, allowing people to self-administer them without any medical oversight, which may also contribute to SCS overuse.

Reducing SCS use in Latin America

Although certain variables such as climate, environment, and poverty are beyond the ability of the healthcare community to address, there are multiple steps that clinicians, payers, and other stakeholders can take to help decrease the widespread use of SCS for asthma in Latin America. An important first step is effectively disseminating the data on the potential harms of SCS exposure, even at low doses, to increase awareness of the problem, including the likely increases in healthcare resource utilization and costs. This is likely to require additional data collection on SCS use from more countries in Latin America to define the scope of the problem further. In the meantime, there are several other steps that could help to reduce the reliance on SCS and thereby help patients with asthma throughout Latin America to manage their disease more effectively.

First, increasing or optimizing the use of current or alternative medications with fewer side effects can effectively help patients achieve and maintain asthma control and help reduce, or perhaps eliminate, the risk of SCS-induced adverse events. For example, recent findings suggest that optimizing ICS-LABA dosing and inhaler technique can help patients increase asthma control and alleviate symptoms, which could possibly reduce the need for SCS.59, 60, 61 Yet, as previously noted, access to these medications may be limited in many Latin American countries. Additionally, several targeted biologic agents have been approved for the treatment of severe asthma. These include omalizumab, which binds immunoglobulin E to help reduce IgE-mediated inflammation; mepolizumab, benralizumab, and reslizumab, which inhibit the IL-5 pathway to reduce the eosinophil count; and dupilumab, which binds to the IL-4 receptor alpha to block both IL-4 and IL-13 signaling.⁶² Results from multiple clinical trials revealed that these agents led to effective symptom control with 30–50% reductions in SCS usage63, 64, 65, 66 and favorable adverse event profiles compared with that of SCS.^67,68 The safety, effectiveness, and steroid-sparing effects of biologics have been confirmed in real-world studies of patients with uncontrolled asthma, including the complete elimination of SCS use by 63% of patients and a reduction to <5 mg/day SCS by 91% of patients who were treated with benralizumab in the recent PONENTE trial.^67,69, 70, 71 Biologics are currently recommended by both GINA and the Latin American Thoracic Society for patients with severe, uncontrolled asthma.^7,47,62,68 However, some changes are required before widespread acceptance of biologics in clinical practice throughout Latin America will be possible. These include incorporation into government medical formularies, improved diagnostic precision for severe asthma that is often confused with recurrent acute bronchitis at the primary care level, data from pharmacoeconomic studies demonstrating a benefit for the use of biologics versus SCS, and updates to local guidelines to inform physicians how and when to incorporate biologics into patient asthma management regimens. If these updates are carried out, the high cost of biologics and limited local payer eligibility may still limit accessibility for some patients, and clinicians may remain skeptical or resistant until high quality evidence comparing efficacy and safety between biologics becomes available.⁴⁷

Another approach may include training programs specifically designed to help stakeholders understand the potential harms of SCS while also providing specific steps to reduce SCS prescriptions.⁷² Important training goals for physicians would be to expand their knowledge about the indications and health risks associated with SCS, including the low exposure requirement for potential harm to occur. Physicians would also benefit from an increased working knowledge of treatment guidelines, especially considering the recent updates to the GINA guidelines in response to the mounting evidence about the risks of SCS usage. This may be especially important for helping PCPs to understand asthma severity and symptom control better; it is also critical for helping them recognize the importance of referring patients to specialty care when appropriate, a determination that could aid physician support tools like the Asthma Referral Identifier (ReferID) tool, which is a simple, 4-item questionnaire that clinicians can use to identify patients with uncontrolled and/or potentially severe asthma.⁷³ It is also important that physicians are aware that patients with prior or current SCS exposure may need a referral to other specialists to identify secondary SCS-related adverse effects, such as evaluation by an ophthalmologist, bone densitometry examination, or metabolic testing, such as glycosylated hemoglobin levels. Patients may benefit from training on how to understand better symptom severity and control, including effective self-assessment for when symptoms require treatment. It is also important that patients recognize the importance of treatment adherence and good inhaler technique to help maximize the effectiveness of controller medications. Finally, pharmacist education is also important, considering their role as the direct medication provider and having direct access to patient treatment regimens. Pharmacists could be trained to monitor patients for potential SCS overuse based on the patient's current prescription regimen, for visible signs or symptoms reported by the patient, or by monitoring prescriptions for other medications used to address common side effects of SCS, such as diabetes or cardiovascular conditions. An active role for pharmacists in educating patients about the risks of SCS and the importance of adherence to controller therapies and proper technique, as well as providing medical advice about their asthma control to help minimize the need for SCS, is essential for patient success.

Multiple changes to regulation and/or health care policy could help reduce SCS usage. For example, as maternal health can influence neonatal respiratory development, and uncontrolled asthma at an early age could result in higher rates of severe/uncontrolled asthma in adulthood,^55,74,75 adding or enhancing early intervention policies for at-risk mothers and pediatric patients could have long-ranging implications. The implementation of laws requiring the sale of SCS only upon presentation of a medical prescription may be effective for reducing SCS overuse. Other changes could include ensuring that local or institutional policies are updated to reflect the current guidance regarding SCS use for asthma, including the potential risks, providing definitions of what constitutes appropriate SCS use, and promoting strict adherence to treatment guidelines. Policies could also be proposed at multiple levels to improve data management procedures to promote more effective multidisciplinary coordination and treatment monitoring for current/past SCS use. Health ministers may also create quality indicators related to the withdrawal of SCS in asthma centers of excellence.

Finally, the use of technology and/or social media could also aid in the reduction of SCS usage. For example, apps aimed at patients that provide primary education can help spread knowledge regarding the impact of the use or overuse of SCS (eg, the VIK asthma app), while medical influencers from social networks could facilitate understanding the side effects of improperly used steroids through targeted or personal messaging to or between patients.

Conclusion

The limited data on SCS use for asthma management in Latin American countries have revealed worrying trends suggesting SCS are not only overprescribed, which is consistent with findings from other global regions, but also that patients in Latin America can access SCS without prescriptions. Excessive use of SCS for the treatment of asthma is likely increasing the risk of additional adverse health outcomes and overall healthcare burden. Changes are needed at multiple levels throughout Latin America to improve patient outcomes while eliminating the risk of additional adverse effects caused by SCS. These may include increasing awareness of the harm of SCS, updating local asthma guidelines and policies to highlight the risks associated with SCS, and comprehensive multi-stakeholder educational programs and studies to help better define the extent of SCS overuse.

Abbreviations

EMR, electronic medical record; GBD, Global Burden of Disease; GINA, Global Initiative for Asthma; HDM, house dust mite; ICS, inhaled corticosteroids; LA AIM, Latin America Asthma Insights and Management survey; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroids; PCP, primary care physician; ReferID, asthma referral identifier; SABA, short-acting beta2-agonist; SABINA, short-acting beta2-agonist in asthma; SCS, systemic corticosteroids; SLIT, sublingual immunotherapy

Funding

This publication is supported by AstraZeneca (Cambridge, UK).

Availability of data and materials

Not applicable as this is a review paper.

Authors’ contributions

All authors have equally contributed to the manuscript and have reviewed the final version of the manuscript.

Ethics approval and consent to participate

Ethics approval or consent to participate are not required for this paper.

Consent for publication

All authors agreed for this work to be published in the World Allergy Organization Journal.

Competing interest

Jorge Fernando Maspero has received grants or speaker fees or participated in boards or as an investigator with the following companies: AstraZeneca, GlaxoSmithKline, Sanofi, Novartis, Teva, Menarini, Uriach, and Inmunotek.

Alvaro Augusto Cruz has received grants or speaker fees or participated in boards or as an investigator with the following companies: AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Sanofi, Novartis, Mylan, Chiesi, Abdi-Ibrahim, Eurofarma, Mantecorp, Crossject.

Felicia Montero-Arias has participated in clinical studies funded by AstraZeneca, Novartis, and the National Institutes of Health. She has also participated in conferences and advisory boards sponsored by AstraZeneca and Novartis.

Cesar Fireth Pozo Beltran has participated in conferences and advisory boards sponsored by the following companies: AstraZeneca, GlaxoSmithKline, Sanofi, Sandoz, Alergia Molecular, Bayer, and Nestle.

Abraham Ali Munive, Ramses Hernandez Pliego, and Hisham Farouk report no competing interests.