An Eight-Century Evolution of Asthma Therapeutics in Western Countries: From Medieval Regimens to Anti-inflammatory Reliever Therapy and Precision Biologics

Abstract

The changes in our understanding of asthma etiopathogenesis has led to new therapies and a significant reduction in asthma exacerbations as well as mortality. The management of asthma has evolved over several centuries from constitutional/environmental palliation, to the recognition of recurrent reversible airway obstruction and to the recognition of inflammatory changes in the lung compartment. The therapeutic armamentarium has also shifted from using alternative therapies at first, to bronchodilator rescue alone and then to inflammation-directed controller therapy with corticosteroids. In the 2000s, biomarker- and endotype-guided therapy with biologics started a major shift in our understanding of asthma which has generated new treatments and outcomes. This review summarizes how clinicians approached patients with the therapeutic armamentarium available in each era, and how those changes translated into success or failure in reducing exacerbations, hospitalizations, relapses, and mortality. The emphasis is on Western countries, where clinicians described, implemented, and quantified the principal modern therapeutic shifts.

Key Summary Points

Why carry out this review?

Asthma therapy has repeatedly changed when clinicians adopted a new disease model, from empirical palliation to inflammation-directed and pathway-guided care.

A historical synthesis explains why bronchodilator relief alone is not a reliable surrogate for long-term safety.

What was learned from the review

Major population outcome gains followed recognition of asthma as a chronic inflammatory airway disease with measurable future risk.

Modern inhaled corticosteroids (ICS)-beta2 agonists reliever strategies and biologics extend this principle by delivering anti-inflammatory treatment at symptom onset and by matching therapy to inflammatory pathways.

Introduction

Asthma therapeutics in Western countries have progressed through five main successive discoveries: from a medieval focus on environmental and constitutional medicine, nineteenth-century clinico-pathologic management of recurrent bronchospasm, twentieth-century adrenergic bronchodilator rescue, corticosteroid-mediated anti-inflammatory control, to the current risk-based precision medicine (Table 1).

Table 1.

Major therapeutic eras in the history of asthma care

Era	Dominant disease model	Therapeutic armamentarium and clinician approach	Effect on mortality/hospitalization
Medieval to early modern	Environmental/constitutional disorder	Air and dietary regulation, vapor inhalation, sedatives, climate and hygiene measures; treatment centered on palliation and regimen [1, 3]	No quantitative evidence; likely limited symptomatic benefit only
Nineteenth century	Paroxysmal bronchospasm with recognizable triggers	Trigger-oriented history, antispasmodics, stramonium/belladonna, coffee, opiates, and climate therapy; better clinical characterization than disease modification [2–4]	Outcome effects unquantified; limited population-level impact
1900s to 1950s	Reversible bronchospasm responsive to adrenergic therapy	Epinephrine, ephedrine, nebulized bronchodilators, and early aerosols; attack abortion became feasible outside the hospital [3, 4]	Marked symptom relief; little evidence of durable protection from hospitalization or death
1956 to 1980s	Rescue bronchodilation, then recognition of safety limits	pMDI-based rescue therapy became portable; excessive reliance on potent nonselective or high-dose beta-agonists exposed mortality risk [4–6]	Mortality signals worsened in some settings; symptom relief alone proved unsafe
1970s to 1990s	Chronic inflammatory airway disease	Systemic corticosteroids for severe attacks; inhaled corticosteroids and cromones for maintenance; reliever and controller roles differentiated [4, 7–9, 17]	Post-exacerbation corticosteroids reduced relapse and hospitalization; ICS use was associated with lower death and admission risk [7–9]
1990s to 2010s	Chronic disease with measurable future risk	Guideline-directed step care, spirometry, written action plans, self-management, and ICS–LABA combination therapy [10–12, 20]	Self-management reduced hospitalization (risk ratio 0.64); combination therapy improved safety discipline [10, 20]
2019 to present	Risk-based and phenotype/endotype-directed precision medicine	ICS–formoterol anti-inflammatory reliever therapy, MART, and biomarker-guided biologics for severe asthma [13–15, 21, 22]	ED visits/hospitalizations decreased by 65% vs. SABA alone; biologics reduced hospitalization by 60% in meta-analysis [14, 15]
Future directions	Remission-oriented and disease-modifying care	Earlier biologic intervention, longer dosing intervals, next-generation or combination biologics, and locally targeted approaches [15, 18, 19, 21, 22]	Potential benefit remains to be defined by durable reductions in exacerbations, oral corticosteroid exposure, hospitalization, and death

ED emergency department, ICS inhaled corticosteroid, LABA long-acting beta2-agonist, MART maintenance and reliever therapy, pMDI pressurized metered-dose inhaler, SABA short-acting beta2-agonist

For centuries, clinicians relied on trigger avoidance, climate therapy, inhaled plant fumes, coffee, opiates, and belladonna or stramonium preparations; these measures sometimes averted and treated asthma attacks but lacked reproducible evidence for consistently reducing acute attacks, let alone hospitalizations or fatalities due to asthma [1–4].

The introduction of epinephrine, ephedrine, nebulized aerosols, and then the pressurized metered-dose inhaler dramatically improved short-term symptom relief, yet it also entrenched a rescue-centric model that proved unsafe when patients overused high-dose nonselective beta-agonist aerosols [4–6]. The decisive improvement in outcomes came when asthma was reconceptualized as a chronic inflammatory airway disorder. Short courses of systemic corticosteroids after acute exacerbations can reduce relapses and subsequent hospitalizations, while regular ICS reduce the risk of asthma hospitalizations, re-admissions, and deaths from asthma [7–9].

Guideline-based chronic disease management further improved outcomes by integrating objective lung function, written action plans, and structured self-management [10–12]. More recently, the replacement of short-acting beta2-agonist monotherapy by the combination of ICS–beta2 agonists as anti-inflammatory reliever therapies have reduced emergency department visits and hospitalizations from asthma [13, 14]. In severe asthma, biologics added to usual care with ICS and beta2-agonists now provide endotype-directed treatment with further substantial reductions in exacerbations and hospitalizations [15]. The core historical lesson is that significant improvements of asthma therapies have led to better symptom management, increased pulmonary function, better quality of life, reductions of exacerbations, hospitalizations, and mortality.

The development of therapies for asthma produced a major shift away from symptom relief alone toward inflammation-directed, risk-based, and phenotype/endotype-guided care. The history of therapies for asthma in western countries is not only a chronology of drug discovery but it is also the record of repeated changes in the disease model that clinicians used at the bedside. Clinicians in pre-modern medicine interpreted asthma through constitutional and environmental frameworks, and treatment focused on regulating the patient’s breathing air, food intake, habits, and immediate symptoms [1, 3]. By the nineteenth century, physicians such as Henry Hyde Salter (himself an asthmatic) had given asthma a more precise nosology as a recurrent paroxysmal disorder of the airways, which in turn encouraged more systematic clinical history-taking around triggers and local influences [2]. The twentieth century then produced an enormous improvement in asthma management through the use of spirometry as well as symptomatic control through adrenergic bronchodilators and portable aerosol delivery systems, but also exposed patients to the dangers of equating bronchodilator responsiveness with long-term safety [4–6]. The modern era began when pathobiology, therapeutics, and guidelines converged around a new proposition: asthma is a chronic inflammatory airway disease with future exacerbation risk, and treatment must fundamentally suppress inflammation, not merely reverse bronchospasm [7–14].

Medieval and Early Modern Care: Environmental Hygiene, Regimen, and Palliation

In the medieval period, the dominant therapeutic logic was hygienic-regimental rather than based on disease mechanisms. Maimonides’ twelfth-century Treatise on Asthma, which strongly influenced later Western and Mediterranean medical thought, emphasized clean air, avoidance of smoke and stagnant urban environments, regulated diet, sleep discipline, bowel regularity, and inhalation of medicinal vapors [1]. The clinician’s task was to identify the circumstances under which dyspnea and cough worsened, and then to modify the patient’s surroundings and body constitution accordingly. Main treatments to palliate acute distress included inhaled or fumigated plant preparations, steam, sea air, warm baths, and sedative agents [1, 3]. These interventions were often rational within the prevailing therapies and afforded intermittent symptomatic relief, but there are no reliable clinical outcomes data regarding hospitalizations, relapses, or mortality from asthma. In practical terms, success in this era should be regarded as confined to symptom palliation.

The Nineteenth-Century Clinico-Pathologic Turn: Trigger Recognition and Recurrent Bronchospasm

The nineteenth century transformed asthma from a broad descriptor of breathlessness into a more coherent clinical entity. Salter’s classic analyses described asthma as episodic, frequently reversible, airway narrowing, often linked to identifiable local influences such as dust, animal exposure, cold air, or emotional provocation [2]. This was a conceptual advance of real clinical importance that is even in use today: physicians increasingly obtained past medical histories centered on recurring triggers, symptom-free intervals, and the circumstances of attacks. Therapeutic armamentarium, however, still consisted of antispasmodics and sedatives—stramonium cigarettes, belladonna derivatives, coffee, opiates, and climate therapy—but the clinician–patient encounter became more individualized and somewhat phenotypic [2–4]. Still, management remained reactive. There was no validated long-term controller therapy, no reproducible objective monitoring, and no evidence that these strategies materially reduced population mortality or hospitalizations. The main gain in the nineteenth century was diagnostic clarity, not disease prognosis modification.

Early Twentieth Century to Mid-Century: Adrenergic Rescue and the Aerosol Revolution

The first great pharmacologic advance in asthma care was the emergence of adrenergic bronchodilation. Epinephrine and ephedrine, followed by nebulized and inhaled preparations, offered clinicians a therapy capable of rapidly reversing airway obstruction [3, 4]. In 1956, the first modern pressurized metered-dose inhaler (pMDI) converted this pharmacology into a portable, reproducible, patient-controlled delivery system [3, 4]. Clinicians started to approach the asthmatic attack as an acute physiological event that could be rapidly treated outside the hospital. This unquestionably improved short-term symptom control and day-to-day autonomy. However, the dominant clinical model still prioritized relief of bronchospasm over prevention of future risk of exacerbations. Therefore, hospitalizations and death were not yet systematically reduced because the underlying uncovered inflammatory biology of asthma was not being treated.

The Asthma Mortality Epidemic: Bronchodilator Over-reliance and the Limits of Symptom Relief

The weaknesses of a rescue-centric model became evident when the mortality epidemics were linked to intensive use of potent inhaled sympathomimetic bronchodilators. Albeit several environmental factors were present, in England and Wales asthma mortality rose sharply during the years in which sales of pressurized aerosols containing sympathomimetic bronchodilators increased. Notably, in the 10- to 14-year age group, mortality increased sevenfold between 1961 and 1966 [5]. A later New Zealand case–control study linked prescribed fenoterol by metered-dose inhaler with increased risk of asthma death, especially among patients with markers of severe disease [6]. These episodes were historically decisive. They taught clinicians that rapid bronchodilation could mask deterioration in pathobiology by not treating inflammation, and that symptom relief was an inadequate surrogate for safety. The practical response was not abandonment of bronchodilators, but their repositioning within a broader chronic anti-inflammatory strategy. Inhaled beta2-agonists retained an essential role in acute care. In near-fatal asthma, severe asphyxia and delayed escalation may culminate in respiratory arrest; acute management therefore requires rapid bronchodilation, timely systemic corticosteroids, close assessment of severity, and escalation for impending respiratory failure [16]. The historical problem was long-term reliance on rescue therapy without anti-inflammatory control, not appropriate acute bronchodilator treatment.

Corticosteroids and the Anti-inflammatory Redefinition of Asthma

Systemic corticosteroids entered asthma practice in the 1950s, in the late 1970s and early 1980s, several investigators (Hargreave/O’Byrne in Canada, Bousquet in France, and Dunnill/Brewster/Jefferey in the United Kingdom) demonstrated eosinophilic inflammation in airway tissue linking asthma severity to steroid responsiveness supporting the use of ICS therapy that had started in the early 1970s with beclomethasone dipropionate [4]. Sodium cromoglycate also emerged, but its anti-inflammatory efficacy proved weaker and less durable than corticosteroid therapy [4]. During this period, pathology, physiology, and clinical pharmacology converged around a new tenet: asthma is not merely episodic bronchospasm, it is chronic airway inflammation with airway hyper-responsiveness and structural remodeling. This reframing changed how clinicians treated patients with asthma. Physicians increasingly separated reliever therapy from controller therapy, escalated anti-inflammatory treatment in proportion to future risk, and used systemic corticosteroids aggressively during severe exacerbations [7–9].

The efficacy gains from this shift were substantial and quantifiable. In a Cochrane review, a short course of oral or intramuscular corticosteroids after discharge from an acute care setting reduced relapse to additional care within 7–10 days (RR 0.38) and reduced subsequent hospitalization (RR 0.35) [7]. Population-based studies then showed that each additional ICS canister dispensed in the prior year was associated with a 21% reduction in asthma death [8]. Regular low-dose ICS use reduced hospital admissions by 31% and re-admissions by 39% [9]. These were among the first clear demonstrations that asthma pharmacotherapy could alter hard outcomes rather than simply improve symptoms.

Airway hyper-responsiveness remains a hallmark of asthma and improves with inhaled corticosteroids, but it may be difficult to normalize in all patients because it reflects multiple inflammatory, structural, and neuroimmune mechanisms [17–19]. This helps explain why corticosteroids transformed prognosis but did not eliminate severe disease, relapse, or treatment heterogeneity.

Guideline-Based Chronic Disease Management: From Disease Control to Risk Reduction

A second major advance in asthma care occurred when asthma was organized as a chronic disease requiring longitudinal management. The National Asthma Education and Prevention Program (NAEPP) in the United States first produced national guidance in 1991, updated it in 1997 and 2007, and later issued focused updates in 2020 [11, 12]. These guidelines codified four pillars of asthma care: objective measurement of lung function, environmental control, patient education with written action plans, and stepwise pharmacologic treatment. Western countries adopted comparable principles through national guidelines and, later, through the Global Initiative for Asthma (GINA) [12–14].

Clinically, this period shifted management of asthma away from episodic treatment of wheeze toward reduction the risk of exacerbation. Routine spirometry or peak-flow assessment, inhaler technique review, adherence assessment, and treatment stepping became standard. Equally important, healthcare systems recognized structured self-management as a therapeutic intervention. In the Cochrane review of adult self-management education coupled with regular review and a written action plan, hospitalizations fell (RR 0.64) and emergency-room visits also declined (RR 0.82) [10]. Thus, in asthma, one of the most consequential innovations in history was organizational rather than molecular: the transition from physician-directed episodic rescue to collaborative, protocolized, risk-based care.

LABA-Containing Regimens and the Discipline of Combination Therapy

Long-acting beta2-agonists (LABAs) improved bronchodilation duration and nocturnal control, but they also reinforced the lesson that bronchodilation without sufficient anti-inflammatory cover is hazardous in asthma. Regulatory and guideline practice therefore moved toward fixed or concomitant ICS-LABA treatment and away from LABA monotherapy. In 2017, the U.S. Food and Drug Administration concluded that LABAs used in fixed combination with ICS did not increase serious asthma-related hospitalization, intubation, or death compared with ICS alone, whereas single-ingredient LABA use without ICS treatment remained associated with increased asthma-related death risk [16]. The clinical implication was a further refinement of the controller–reliever therapeutic approach: bronchodilation remained essential, but anti-inflammatory cover became non-negotiable.

Anti-inflammatory Reliever Therapy and Precision Biologics: The Contemporary Era

The contemporary era has produced two further paradigm shifts. First, major guidelines no longer regard mild asthma as sufficiently safe for short-acting beta2-agonist (SABA) monotherapy. GINA’s 2019 shift, reinforced in subsequent updates, repositioned low-dose ICS–formoterol as the preferred reliever strategy for adults and adolescents with the diagnosis of asthma [13, 14]. In comparative analyses summarized in the 2022 GINA update, as-needed low-dose ICS–formoterol reduced emergency department visits or hospitalizations by 65% compared with SABA alone and by 37% compared with daily low-dose ICS plus as-needed SABA [14]. In moderate-to-severe disease, maintenance and reliever therapy (MART) with ICS–formoterol reduces severe exacerbations compared with conventional regimens using a SABA reliever [14]. In practical terms, this means that every reliever actuation now delivers anti-inflammatory therapy rather than bronchodilation alone.

Second, clinicians now manage severe asthma as a set of biologically heterogeneous endotypes rather than as a uniform syndrome. Since the approval of omalizumab in 2003, the therapeutic armamentarium has expanded to anti-IL-5 or IL-5Ralpha, anti-IL-4Ralpha, and anti-TSLP therapies. A 2024 systematic review and meta-analysis of licensed biologics reported a 44% reduction in annualized exacerbation rate and a 60% reduction in hospitalization, together with improved lung function and control [15]. Furthermore, biologic therapies are also being tested during or immediately after asthma exacerbations, suggesting that pathway-directed treatment may have a role after emergency care to reduce relapses [21, 22].

The management objective is, therefore, expanding from symptom reduction to exacerbation suppression, oral corticosteroid sparing, remission-oriented care, and, in selected patients, possible disease modification.

Public-Health Success, Residual Burden, and the Historical Verdict

By contemporary standards, asthma treatment in Western countries has been successful, but only after the adoption of inflammation-directed and risk-based care. Latest U.S. surveillance data still records 1.4 million emergency department visits for asthma (2022) and 3624 deaths (2023), demonstrating that the disease remains a major public-health problem even in the era of effective controllers and biologics [23].

Nonetheless, the benefits through history are clear: mortality fell most convincingly after the widespread uptake of ICS and structured chronic disease management [8–12]. Hospitalizations proved more resistant than mortality, but they too declined when controller adherence, education, and anti-inflammatory reliever strategies improved [7–10, 14].

The trends in asthma care over time show that pre-modern and nineteenth century therapies helped some patients but were not demonstrably capable of reducing hospitalizations and fatal disease at the population level. Early bronchodilator therapy improved attack relief yet sometimes worsened population outcomes when over-relied upon. The largest durable gains in asthma exacerbation reductions, and reductions in hospitalizations and mortality, were achieved when clinicians stopped treating asthma as intermittent bronchospasm alone and instead treated it as a chronic, variably severe, inflammation-driven airway disorder with measurable future risk.

Future Directions in Asthma Therapeutics

Future asthma therapeutics are likely to extend the same trajectory toward earlier intervention in mild to moderate, greater convenience, and more precise targeting. Current development directions include testing biologics earlier in the disease course, extending dosing intervals, increasing pathway potency or breadth through next-generation antibodies or combinations, exploring inhaled or locally targeted approaches, and defining remission or disease modification as treatment goals [15, 18, 19, 21, 22].

These directions should be interpreted with appropriate caution. Historical progress in asthma has not depended on pharmacologic potency alone, but on alignment between the disease model, evidence-based patient selection, delivery system, adherence, education, access, and safety monitoring. The future of asthma treatment will therefore be judged not only by biomarker effects and symptom scores but also by durable reductions in exacerbations, hospitalization, treatment burden, oral corticosteroid exposure, and death.

Conclusions

Across eight centuries of Western medical practice, asthma management evolved from empirical palliation to pharmacologic rescue, then to controller-based prevention, and finally to biomarker-driven precision therapy (Fig. 1). The most important historical inflection points were not simply the arrival of more potent bronchodilators, but the recognition that asthma morbidity and mortality are governed by uncontrolled airway inflammation and future exacerbation risk.

Fig. 1.

Evolution of asthma therapeutics in Western medicine. Timeline summarizing major conceptual and therapeutic transitions from pre-modern regimen-based care to anti-inflammatory reliever therapy and precision biologics. ICS inhaled corticosteroid, LABA long-acting beta2-agonist, MART maintenance and reliever therapy, SABA short-acting beta2-agonist

Once clinician behavior, patient education, and pharmacologic strategy aligned with this biology, deaths and hospitalizations began to fall in a reproducible way. Contemporary asthma care retains bronchodilators, but they are now indicated within an anti-inflammatory and increasingly endotype-specific framework. This historical pattern remains clinically relevant: the treatment strategy that best improves patient outcomes is the one that couples symptomatic relief with suppression of airway inflammation and prevention of future risk.

Author Contributions

Nestor A. Molfino and Paul M. O'Byrne contributed to the conception and design of the review, drafting and critical revision of the manuscript, and approval of the final version for submission.

Funding

The manuscript was funded for Rapid service and Open access fees by Amgen, Inc, USA.

Data Availability

Data sharing is not applicable to this article because no datasets were generated or analyzed during the current review.

Declarations

Conflict of Interest

Nestor A. Molfino is an employee of Amgen Inc. Paul M. O'Byrne has obtained grants in aid of research from Novartis, AstraZeneca, Biohaven, Merck, and Jasper for research, and received personal fees for consulting or speaker fees from AstraZeneca, GSK, and Sonafi/Regeneron.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.