How to implement the anti-inflammatory reliever treatment proposed by the Global Initiative for Asthma in low- and middle-income countries

Abstract

There are no plausible arguments to consider that the best evidence-based asthma treatment should be different in low- and middle-income countries (LMICs). A few decades ago, the recognition of asthma as an inflammatory disease of the airways positioned the inhaled corticosteroids (ICS) as the cornerstone of the treatment of this disease, maintaining bronchodilators, especially the short-acting beta-agonists (SABA), as symptom-reliever medications for use as needed. However, adherence to regular use of ICS is very low, especially in LMICs, favoring the overuse of SABA, which has been related to an excess of exacerbations and mortality. Recently, the Global Initiative for Asthma (GINA) strategy has recommended the mandatory use of ICS every time a bronchodilator is used as needed (for symptoms relief), whether only as needed or with a background of regular dose of ICS, and has named it: anti-inflammatory reliever (AIR) therapy. This form of therapy, which has been related to a significant reduction of asthma exacerbations, is very attractive for LMICs where patients do not have guaranteed a proper medical follow-up and the access to on-the-counter medications is high. However, the implementation of AIR therapy in LMICs will face many of the already recognized barriers for the diagnosis and treatment of asthma in these countries, especially related to limited access to care in very different health systems, low education level of patients and communities, insufficient health personnel training in asthma in primary care, the unfordable cost of medications, and the lack of political commitment. This review analyzes some of these challenges and strategies for facing them in LMICs.

Keywords

Reliever / asthma / inhaled-corticosteroids / short-acting beta-agonists (SABA) / long-acting beta-agonists (LABA) / MART / rescue-therapy

References

[1] The Global Asthma Network. The Global Asthma Report 2022. Int J Tuberc Lung Dis. 2022; 26: 1-104.

[2] Enilari O, Sinha S. The Global Impact of Asthma in Adult Populations. Ann Glob Health. 2019; 85: 2.

[3] Wang Z, Li Y, Gao Y, Fu Y, Lin J, Lei X, et al. Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019. Respir Res. 2023; 24: 169.

[4] García-Marcos L, Chiang CY, Asher MI, Marks GB, El Sony A, Masekela R, et al. ; Global Asthma Network Phase I Study Group. Asthma management and control in children, adolescents, and adults in 25 countries: a Global Asthma Network Phase I cross-sectional study. Lancet Glob Health. 2023; 11: e218-28.

[5] Mortimer K, Reddel HK, Pitrez PM, Bateman ED. Asthma management in low and middle income countries: case for change. Eur Respir J. 2022; 60: 2103179.

[6] Meghji J, Mortimer K, Agusti A, Allwood BW, Asher I, Bateman ED, et al. Improving lung health in low-income and middle-income countries: from challenges to solutions. Lancet. 2021; 397: 928-40.

[7] Beran D, Zar HJ, Perrin C, Menezes AM, Burney P ; Forum of International Respiratory Societies working group collaboration. Burden of asthma and chronic obstructive pulmonary disease and access to essential medicines in low-income and middle-income countries. Lancet Respir Med. 2015; 3: 159-70.

[8] Pitrez PM. The challenges of asthma care in low- and middle-income countries: what’s next? J Bras Pneumol. 2023; 49: e20230215.

[9] Barne M. Gaps in asthma diagnosis and treatment in low- and middle-income countries. Front Allergy. 2023; 4: 1240259.

[10] Fischer GB, Sarria EE, Camargos P, Mocelin HT, Soto-Quiroz M, Cruz AA, et al. Childhood asthma in low and middle-income countries: Where are we now? Paediatr Respir Rev. 2019; 31: 52-7.

[11] Hills T, Beasley R. The history and future of short-acting beta₂-agonist therapy in asthma . Respirology. 2020; 25: 246-8.

[12] Domingo C, Singh D. The Changing Asthma Management Landscape and Need for Appropriate SABA Prescription. Adv Ther. 2023; 40: 1301-16.

[13] Boulet LP, Reddel HK, Bateman E, Pedersen S, FitzGerald JM, O’Byrne PM. The Global Initiative for Asthma (GINA): 25 years later. Eur Respir J. 2019; 54: 1900598.

[14] Bårnes CB, Ulrik CS. Asthma and adherence to inhaled corticosteroids: current status and future perspectives. Respir Care. 2015; 60: 455-68.

[15] Nwaru BI, Ekström M, Hasvold P, Wiklund F, Telg G, Janson C. Overuse of short-acting β₂-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme . Eur Respir J. 2020; 55: 1901872.

[16] (*NEW) 2019 GINA Report: Global Strategy for Asthma Management and Prevention [Internet]. Fontana (WI): Global Initiative for Asthma (GINA); c2024 [cited 2023 Sep 11]. Available from: https://ginasthma.org/reports/2019-gina-report-global-strategy-for-asthma-management-and-prevention/

[17] Global Initiative For Asthma (GINA) [Internet]. Fontana (WI): GINA; c2024 [cited 2023 Sep 11]. Available from: www.ginasthma.org

[18] Beasley R, Bruce P, Houghton C, Hatter L. The ICS/Formoterol Reliever Therapy Regimen in Asthma: A Review. J Allergy Clin Immunol Pract. 2023; 11: 762-72.e1.

[19] Chiang CY, Bissell K, Macé C, Perrin C, Marks G, Mortimer K, et al. The Asthma Drug Facility and the future management of asthma. Int J Tuberc Lung Dis. 2022; 26: 388-91.

[20] Asher I, Bissell K, Chiang CY, El Sony A, Ellwood P, García-Marcos L, et al. Calling time on asthma deaths in tropical regions-how much longer must people wait for essential medicines? Lancet Respir Med. 2019; 7: 13-5.

[21] Montero-Arias F, Garcia JCH, Gallego MP, Antila MA, Schonffeldt P, Mattarucco WJ, et al. Over-prescription of short-acting β₂-agonists is associated with poor asthma outcomes: results from the Latin American cohort of the SABINA III study . J Asthma. 2023; 60: 574-87.

[22] Soto-Martínez ME, Soto-Quiros ME, Custovic A. Childhood Asthma: Low and Middle-Income Countries Perspective. Acta Med Acad. 2020; 49: 181-90.

[23] Stolbrink M, Chinouya MJ, Jayasooriya S, Nightingale R, Evans-Hill L, Allan K, et al. Improving access to affordable quality-assured inhaled medicines in low- and middle-income countries. Int J Tuberc Lung Dis. 2022; 26: 1023-32.

[24] Stolbrink M, Thomson H, Hadfield RM, Ozoh OB, Nantanda R, Jayasooriya S, et al. The availability, cost, and affordability of essential medicines for asthma and COPD in low-income and middle-income countries: a systematic review. Lancet Glob Health. 2022; 10: e1423-42.

[25] Trikamjee T, Comberiati P, Peter J. Pediatric asthma in developing countries: challenges and future directions. Curr Opin Allergy Clin Immunol. 2022; 22: 80-5.

[26] Yasaratne D, Idrose NS, Dharmage SC. Asthma in developing countries in the Asia-Pacific Region (APR). Respirology. 2023; 28: 992-1004.

[27] WHO Model List of Essential Medicines - 23rd list, 2023 [Internet]. Geneva: World Health Organization; c2024 [cited 2023 Aug 24]. Available from: https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02

[28] Caraballo L, Zakzuk J, Lee BW, Acevedo N, Soh JY, Sánchez-Borges M, et al. Particularities of allergy in the Tropics. World Allergy Organ J. 2016; 9: 20.

[29] Gonzalez-Garcia M, Caballero A, Jaramillo C, Maldonado D, Torres-Duque CA. Prevalence, risk factors and underdiagnosis of asthma and wheezing in adults 40 years and older: A population-based study. J Asthma. 2015; 52: 823-30.

[30] Xu XF, Li YJ, Sheng YJ, Liu JL, Tang LF, Chen ZM. Effect of low birth weight on childhood asthma: a meta-analysis. BMC Pediatr. 2014; 14: 275.

[31] Rantala AK, Jaakkola MS, Mäkikyrö EM, Hugg TT, Jaakkola JJ. Early Respiratory Infections and the Development of Asthma in the First 27 Years of Life. Am J Epidemiol. 2015; 182: 615-23.

[32] Torres-Duque C, Maldonado D, Pérez-Padilla R, Ezzati M, Viegi G ; Forum of International Respiratory Studies (FIRS) Task Force on Health Effects of Biomass Exposure. Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc. 2008; 5: 577-90.

[33] Gautier C, Charpin D. Environmental triggers and avoidance in the management of asthma. J Asthma Allergy. 2017; 10: 47-56.

[34] Acevedo N, Zakzuk J, Caraballo L. House Dust Mite Allergy Under Changing Environments. Allergy Asthma Immunol Res. 2019; 11: 450-69.

[35] Torres-Duque CA, Alí-Munive A, Severiche-Bueno D, Durán-Silva M, Aguirre-Franco CE, González-Florez A, et al. Tropical high altitude and severe asthma in adults: house dust mite sensitization and phenotypic distribution. J Asthma. 2024; 61: 222-31.

[36] Martinez FD. The coming-of-age of the hygiene hypothesis. Respir Res. 2001; 2: 129-32.

[37] van Tilburg Bernardes E, Arrieta MC. Hygiene Hypothesis in Asthma Development: Is Hygiene to Blame? Arch Med Res. 2017; 48: 717-26.

[38] Orellano P, Quaranta N, Reynoso J, Balbi B, Vasquez J. Association of outdoor air pollution with the prevalence of asthma in children of Latin America and the Caribbean: A systematic review and meta-analysis. J Asthma. 2018; 55: 1174-86.

[39] Wiggans R. Work and respiratory health: Lessons from occupational lung disease. In: Sinha IP, Lee A, Katikireddi SV, Quint JK, editors. Inequalities in Respiratory Health. European Respiratory Society; 2023. pp. 89-98.

[40] Gold LS, Montealegre F, Allen-Ramey FC, Jardim J, Smith N, Sansores R, et al. Level of asthma control and healthcare utilization in Latin America. Allergy. 2013; 68: 1463-6.

[41] Soto-Martínez M, Avila L, Soto N, Chaves A, Celedón JC, Soto-Quiros ME. Trends in hospitalizations and mortality from asthma in Costa Rica over a 12- to 15-year period. J Allergy Clin Immunol Pract. 2014; 2: 85-90.

[42] Dhar R, Ip M, Kulkarni T, Kim SH, Perng DW, Yao X, et al. Challenges faced in managing adult asthma: A perspective from Asian countries. Respirology. 2020; 25: 1235-42.

[43] GBD Results [Internet]. Seattle (WA): Institute for Health Metrics and Evaluation (IHME); c2024 [cited 2023 Oct 4]. Available from: https://vizhub.healthdata.org/gbd-results/

[44] Tabyshova A, Sooronbaev T, Akylbekov A, Mademilov M, Isakova A, Erkinbaeva A, et al. Medication availability and economic barriers to adherence in asthma and COPD patients in low-resource settings. NPJ Prim Care Respir Med. 2022; 32: 20.

[45] Celano MP, Linzer JF, Demi A, Bakeman R, Smith CO, Croft S, et al. Treatment adherence among low-income, African American children with persistent asthma. J Asthma. 2010; 47: 317-22.

[46] Di Marco F, D’Amato M, Lombardo FP, Micheletto C, Heiman F, Pegoraro V, et al. The Burden of Short-Acting β₂-Agonist Use in Asthma: Is There an Italian Case? An Update from SABINA Program . Adv Ther. 2021; 38: 3816-30.

[47] Hancox RJ, Cowan JO, Flannery EM, Herbison GP, McLachlan CR, Taylor DR. Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment. Respir Med. 2000; 94: 767-71.

[48] Bateman ED, Price DB, Wang HC, Khattab A, Schonffeldt P, Catanzariti A, et al. Short-acting β₂-agonist prescriptions are associated with poor clinical outcomes of asthma: the multi-country, cross-sectional SABINA III study . Eur Respir J. 2022; 59: 2101402.

[49] Loh ZC, Hussain R, Ong SC, Saini B, Muneswarao J, Ur-Rehman A, et al. Over-the-counter use of short-acting beta-2 agonists: a systematic review. J Pharm Policy Pract. 2023; 16: 119.

[50] Crossingham I, Turner S, Ramakrishnan S, Fries A, Gowell M, Yasmin F, et al. Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma. Cochrane Database Syst Rev. 2021; 5: CD013518.

[51] Cardet JC, Papi A, Reddel HK. “As-Needed” Inhaled Corticosteroids for Patients With Asthma. J Allergy Clin Immunol Pract. 2023; 11: 726-34.

[52] Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, et al. ; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007; 356: 2040-52.

[53] Papi A, Chipps BE, Beasley R, Panettieri RA Jr, Israel E, Cooper M, et al. Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med. 2022; 386: 2071-83.

[54] Calhoun WJ, Ameredes BT, King TS, Icitovic N, Bleecker ER, Castro M, et al. ; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA. 2012; 308: 987-97.

[55] Israel E, Cardet JC, Carroll JK, Fuhlbrigge AL, Pace WD, Maher NE, et al. A randomized, open-label, pragmatic study to assess reliever-triggered inhaled corticosteroid in African American/Black and Hispanic/Latinx adults with asthma: Design and methods of the PREPARE trial. Contemp Clin Trials. 2021; 101: 106246.

[56] Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006; 130: 1733-43.

[57] Sobieraj DM, Weeda ER, Nguyen E, Coleman CI, White CM, Lazarus SC, et al. Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis. JAMA. 2018; 319: 1485-96.

[58] Reddel HK, Bateman ED, Schatz M, Krishnan JA, Cloutier MM. A Practical Guide to Implementing SMART in Asthma Management. J Allergy Clin Immunol Pract. 2022; 10: S31-8.

[59] Jorup C, Lythgoe D, Bisgaard H. Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma. Eur Respir J. 2018; 51: 1701688.

[60] Beasley R, Harrison T, Peterson S, Gustafson P, Hamblin A, Bengtsson T, et al. Evaluation of Budesonide-Formoterol for Maintenance and Reliever Therapy Among Patients With Poorly Controlled Asthma: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022; 5: e220615.

[61] Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharmacol Ther. 2006; 19: 139-47.

[62] Aithal S, Bhargava V, Adekoya A, Chaudhary N, Tyagi S, Kurmi O. Air quality in low- and middle-income countries: what is the impact on respiratory morbidity and mortality? Eur Respir Soc Monograph. 2023; 99: 203-13.

[63] Blakey JD, Price DB, Pizzichini E, Popov TA, Dimitrov BD, Postma DS, et al. Identifying Risk of Future Asthma Attacks Using UK Medical Record Data: A Respiratory Effectiveness Group Initiative. J Allergy Clin Immunol Pract. 2017; 5: 1015-24.e8.

[64] Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017; 357: j1415.

[65] Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018; 11: 193-204.

[66] Price D, Castro M, Bourdin A, Fucile S, Altman P. Short-course systemic corticosteroids in asthma: striking the balance between efficacy and safety. Eur Respir Rev. 2020; 29: 190151.

[67] Papi A, Blasi F, Canonica GW, Morandi L, Richeldi L, Rossi A. Treatment strategies for asthma: reshaping the concept of asthma management. Allergy Asthma Clin Immunol. 2020; 16: 75.

[68] Karmali D, Siddharthan T. Access to essential respiratory medications remains elusive in LMICs. Lancet Glob Health. 2022; 10: e1365-6.

[69] Babar ZU, Lessing C, Mace C, Bissell K. The availability, pricing and affordability of three essential asthma medicines in 52 low- and middle-income countries. Pharmacoeconomics. 2013; 31: 1063-82.

[70] Siddharthan T, Robertson NM, Rykiel NA, Underhill LJ, Rahman N, Kafle S, et al. Availability, affordability and access to essential medications for asthma and chronic obstructive pulmonary disease in three low- and middle-income country settings. PLOS Glob Public Health. 2022; 2: e0001309.

[71] Mohiuddin M, Kasahara K. Potential therapeutic role of budesonide to reduce COVID-19 severity. J Infect Public Health. 2022; 15: 109-11.

[72] Ramakrishnan S, Nicolau DV Jr, Langford B, Mahdi M, Jeffers H, Mwasuku C, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021; 9: 763-72.

[73] Bafadhel M, Faner R, Taillé C, Russell REK, Welte T, Barnes PJ, et al. Inhaled corticosteroids for the treatment of COVID-19. Eur Respir Rev. 2022; 31: 220099.

[74] Samajdar SS, Mukherjee S, Moitra S, Pal J, Joshi S, Tripathi SK. Effectiveness of budesonide formoterol fixed-dose combination MDI in reducing cough symptoms in COVID-19 patients: A real-world evidence study. Lung India. 2023; 40: 107-11.

[75] Crook J, Weinman J, Gupta A. Changes in rates of prescriptions for inhaled corticosteroids during the COVID-19 pandemic. Lancet Respir Med. 2022; 10: 6-7.

[76] Rodríguez I, López-Caro JC, Gonzalez-Carranza S, Cerrato ME, De Prado MM, Gomez-Molleda F, et al. Adherence to inhaled corticosteroids in patients with asthma prior to and during the COVID-19 pandemic. Sci Rep. 2023; 13: 13086.

[77] Eger K, Paroczai D, Bacon A, Schleich F, Sergejeva S, Bourdin A, et al. The effect of the COVID-19 pandemic on severe asthma care in Europe: will care change for good? ERJ Open Res. 2022; 8: 00065-2022.

[78] Klouda T, Pillarisetti A, Xie A, Kabra S, Saradhi N, Katwa U. Asthma Management in the Era of the COVID-19 Pandemic. Indian J Pediatr. 2022; 89: 163-8.

[79] Pitrez PM, Giavina-Bianchi P, Rizzo JÂ, Souza-Machado A, Garcia GF, Pizzichini MMM. An expert review on breaking barriers in severe asthma in Brazil: Time to act. Chron Respir Dis. 2021; 18: 14799731211028259.

[80] Ade G, Gninafon M, Tawo L, Aït-Khaled N, Enarson DA, Chiang CY. Management of asthma in Benin: the challenge of loss to follow-up. Public Health Action. 2013; 3: 76-80.

[81] El Sony AI, Chiang CY, Malik E, Hassanain SA, Hussien H, Khamis AH, et al. Standard case management of asthma in Sudan: a pilot project. Public Health Action. 2013; 3: 247-52.

[82] Kan XH, Chiang CY, Enarson DA, Rao HL, Chen Q, Aït-Khaled N, et al. Asthma as a hidden disease in rural China: opportunities and challenges of standard case management. Public Health Action. 2012; 2: 87-91.