BARCELONA, Spain — Managing an acute viral flare-up of chronic obstructive pulmonary disease (COPD) involves prescribing a course of oral corticosteroids, broad-spectrum antibiotics, and hoping the patient’s lungs recover. But experts at the European Respiratory Society (ERS) 2026 International Congress argued that this nonspecific, syndromic rescue model is ineffective. Respiratory viruses trigger roughly half of all COPD exacerbations, and even a single moderate event permanently alters a patient’s survival trajectory while accelerating lung function decline.

“COPD exacerbation is a syndrome, not an etiological diagnosis,” explained Daiana Stolz, MD, MPH, professor of respiratory medicine at the University Hospital Freiburg in Germany. As the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2026 guidelines shift the primary benchmark of care to “zero exacerbations,” experts urged clinicians to pivot away from reactive rescue and adopt precision strategies that address both the viral trigger and the underlying inflammatory terrain.

Four Challenges in Delivering Antiviral Care

Stolz outlined four fundamental challenges that currently limit the success of antivirals during COPD exacerbations.

The first challenge is that simple viral detection via PCR does not establish direct causation. A positive PCR does not mean the detected pathogen is the trigger of the exacerbation or is actively driving lung deterioration, Stolz explained. In a longitudinal study tracking of 450 patients with COPD over more than 2000 sampling points, viral detection rose sharply during upper respiratory tract infections (URTIs) and exacerbations. However, only 24% of URTI-related exacerbations shared the exact same virus identified during the preceding cold, directly undermining the assumption that simple detection proves causation.

The second barrier is a profound mismatch between viral kinetics and clinical presentation. Peak viral replication happens within the first 1-2 days of symptom onset. By the time a patient experiences escalating lower-airway deterioration on days 3-5 and finally seeks medical attention on day 5 or later, the narrow antiviral window has already closed, Soltz explained. By the time acute care is initiated, the clinical picture is dominated by secondary host inflammation and the risk for bacterial superinfection rather than by viral replication.

Thirdly, host immune responses in COPD bronchial epithelium are delayed rather than simply blunted. In differentiated primary airway epithelial cell models, healthy tissue mounts an innate antiviral gene peak at 48 hours following rhinovirus infection. In contrast, tissue from patients with asthma or COPD exhibits a delayed peak at 72-96 hours or later, permitting viral replication to proceed unchecked before host inflammation escalates. In addition, oxidative stress impairs the airway’s ability to detect viruses by lowering IFN-beta levels and suppressing key immune receptors such as TLR3. Host genetics also play a role: patients with specific IFN- lambda gene variants face nearly double the risk for severe exacerbations.

Lastly, while approved options exist for influenza and SARS-CoV-2, the viruses that bear the greatest burden in COPD, such as human rhinovirus and respiratory syncytial virus (RSV), lack approved direct-acting antivirals for routine clinical use. Real-world data in over 1300 hospitalized patients with severe COVID and underlying respiratory disease show that COVID antiviral treatment with nirmatrelvir-ritonavir reduces mortality by about 50% and shortened hospital stays by 2 days. However, Stolz cautioned that direct antiviral benefits in COVID do not justify treating non-COVID exacerbations. Moreover, the patients most likely to benefit from treatment, such as older patients with severe COPD, frequent exacerbations, and cardiovascular comorbidities, face the greatest safety barriers, such as polypharmacy, drug-drug interactions, renal and hepatic impairment, and delayed presentation due to social factors.

Stolz presented evidence supporting early, patient-initiated intervention. In the PREVENT trial, evaluating 450 patients with moderate-to-very-severe COPD, intensifying inhaled corticosteroid and long-acting beta-agonist therapy at the very first onset of URTI symptoms did not reduce overall exacerbations but reduced severe exacerbations requiring hospitalization by 72%. Preclinical screening of 800 FDA-approved drugs identified budesonide for its ability to increase cell viability, reduce viral expression, and suppress viral-induced interleukin-1 beta inflammation. Looking ahead, Stolz argued that future precision pathways must move decisions upstream by equipping high-risk patients with rapid home molecular tests and standing prescriptions to capture peak replication within hours of symptom onset.

Early-Life Infections and Lifelong Lung Trajectories

Alberto Papi, MD, professor of respiratory medicine at the University of Ferrara in Ferrara, Italy, explained that a person’s vulnerability to viral COPD is often established in early infancy, long before adult risk factors take hold.

RSV, for example, accounts for 60%-80% of infant lower respiratory tract infections (LRTIs). Longitudinal birth cohort stracking people over decades demonstrate that severe early-life RSV LRTIs permanently impair normal lung development, shifting children onto lower lifelong forced expiratory volume in 1 second (FEV₁) trajectories. These people reach early adulthood with a lower peak lung capacity, predisposing them to COPD later in life even in the absence of accelerated adult lung function decline.

In young adult smokers aged 35-45 years with preserved baseline lung function, viral infections continue to drive structural loss. Data from the BEACON cohort reveal that while upper respiratory tract infections cause an additional 8.3 mL/y loss in FEV₁, lower respiratory tract infections accelerate decline by an additional 26.5 mL/y. “Exacerbations drive disease progression, healthcare costs, hospitalizations, and mortality,” Papi said. Even a single moderate exacerbation alters the survival curve, making it essential to prevent viral insult across all age brackets to achieve GOLD’s zero-exacerbation target.

Papi also mentioned maternal RSV preF immunization and infant monoclonal antibodies such as nirsevimab as crucial primary prevention tools. Real-world studies confirm that nirsevimab achieves 75%-83% efficacy in preventing RSV-related hospitalizations and LRTIs in infants, preserving early lung development and altering long-term respiratory trajectories.

Rebuilding the Airway Terrain: The Wildfire Analogy

To address the limitations of direct antivirals in established adult disease, Sanjay Haresh Chotirmall, MD, PhD, professor of respiratory medicine at the Lee Kong Chian School of Medicine in Singapore, presented a conceptual framework that separates the viral “trigger” from the underlying host “terrain”.

“Viral exacerbations resemble wildfires,” Chotirmall explained; while the virus acts as the igniting spark, the overall severity of the flare depends on the forest terrain, represented by inflamed, mucus-obstructed, and protease-high airways. Moving toward a personalized approach requires categorizing patients by both their specific viral trigger and their type of airway inflammation, such as neutrophilic or eosinophilic profiles. Advanced genetic sequencing shows that up to 90% of viruses in the airways remain unknown. Whereas known latent viruses like Epstein-Barr are directly linked to worse breathlessness, more frequent flare-ups, and higher steroid use.

Chotirmall presented data on DPP-1 inhibitors, such as brensocatib and verducatib, that stop inflammatory neutrophil enzymes from being activated in the bone marrow before reaching the lungs.

In the phase 3 ASPEN trial in noncystic fibrosis bronchiectasis, DPP-1 inhibition significantly delayed and reduced lung flare-ups. Similarly, phase 2 data from the AIRLEAF study of verducatib showed a consistent drop in flare-up risk for patients with COPD and those with severe lung impairment.

However, Chotirmall said that DPP-1 inhibition provides proof of mechanism rather than unselected proof in general COPD. “Do not over-translate bronchiectasis evidence to COPD,” he said. “Treatment benefit is restricted to specific high-risk subgroups characterized by chronic bronchitis, sputum neutrophilia, high protease activity, and bronchiectatic overlap.”

He advocated for a pragmatic treatment architecture built on three pillars: preventing infection through vaccination and smoking cessation, detecting pathogens and inflammatory endotypes early, and treating precisely by combining pathogen-directed antivirals with host-directed anti-inflammatory therapies. “The next advance will not be a universal antiviral for all exacerbations. It will be early identification of replicating viruses, recognition of the susceptible airway, and prevention of downstream protease-driven damage — treating both the trigger and the terrain,” he said.

Overcoming Vaccine Hesitancy in Routine Care

While novel therapeutics and diagnostic frameworks evolve, immunization against influenza, RSV, COVID, and pneumococcal disease remains the most immediate, scalable line of defense against viral morbidity. Yet clinical uptake across Europe and globally remains highly uneven.

Jeremy Brown, MD, professor of respiratory medicine at University College London, London, England, said that while influenza vaccination rates among patients with COPD reach 88% in the UK due to structured general practice incentives, coverage drops to 50% in France and 23% in China. While many of the unvaccinated patients might believe a flu shot caused a prior flare-up, a COVID vaccination would make them sick, or might not be aware of RSV dangers, Brown said that ideological opposition to vaccines is rare. Socioeconomic barriers, instead, have a much bigger effect. “If you make it easy for patients, they will get a vaccine.”

Stolz and Chotirmall reported having no financial relationships. Papi reported receiving consultation fees from Apogee, Avillion, AstraZeneca, Chiesi, Generate Biomedicine, GlaxoSmithKline, Genzyme, Kinase, Kither, Kymera, Moderna, MSD, Pfizer, Prex, Regeneron, Roche, Sanofi, Teva, Uniquity, Zambon.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.