Impact of influenza on chronic obstructive pulmonary disease: pathophysiology, exacerbations, and preventive approaches

Abstract

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory condition associated with increased morbidity and mortality, particularly during respiratory infections such as influenza. The interaction between COPD and influenza is multifaceted, involving compromised immune responses, chronic inflammation, and impaired lung function. Influenza infection can exacerbate COPD, leading to acute exacerbations, hospitalizations, and higher mortality. This review examines the pathophysiological mechanisms underlying the exacerbation of COPD by influenza, evaluates its impact on patient outcomes, and explores the role of comorbidities in shaping disease severity. We also assess the effectiveness of influenza vaccination in preventing severe outcomes and discuss strategies to improve vaccination uptake among COPD patients. Current evidence highlights the importance of tailored prevention and management approaches, as well as the need for further research into biomarkers and optimal therapeutic strategies to mitigate the burden of influenza on COPD populations.

Plain language summary

How flu worsens COPD and ways to prevent it

Chronic Obstructive Pulmonary Disease (COPD) is a serious lung condition that makes breathing difficult. When people with COPD get the flu, it can severely worsen their symptoms, leading to hospitalizations and even death. This happens because COPD already weakens the lungs and immune system, making it harder to fight off infections like the flu. The flu virus increases inflammation in the airways, further damaging the lungs and raising the risk of complications such as pneumonia. COPD patients often have other health issues, like heart disease or diabetes, which can make flu outcomes even worse. Vaccination is the best way to protect against the flu, yet many COPD patients do not get vaccinated. Studies show that the flu vaccine reduces hospitalizations and deaths in COPD patients, but more efforts are needed to improve vaccination rates. Other preventive measures, such as antiviral medications, good hygiene, and quitting smoking, also play a key role. This review highlights the importance of tailored care for COPD patients during flu season, including vaccination, early treatment, and managing other health conditions. By taking these steps, healthcare providers can help reduce the heavy burden of flu on COPD patients and improve their quality of life. Further research is needed to develop better vaccines and treatments for this high-risk group.

Background

Chronic obstructive pulmonary disease (COPD), the third most common disease among individuals aged 50 and older,^1,2 is defined by GOLD 2023 as a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the airways and/or alveoli. ³ COPD results from cumulative gene–environment interactions over a lifetime. While cigarette remains the primary environmental risk factor, ⁴ nonsmoking exposures, such as air pollution, occupational hazards, and biomass fuel use, are particularly relevant in low- and middle-income countries. ⁵ Genetic predispositions, including alpha-1 antitrypsin deficiency and variants affecting lung development, also contribute to disease susceptibility. ⁶

Respiratory viral infections—particularly influenza—are a major trigger of acute exacerbations in COPD. Globally, seasonal influenza affects millions each year, causing significant strain on healthcare systems, with an estimated 291,243–645,832 respiratory deaths annually, particularly in sub-Saharan Africa, Southeast Asia, and among individuals aged 75 years or older. ⁷ Patients with COPD are particularly susceptible due to impaired mucociliary clearance, dysregulated immune responses, and disrupted airway microbiota. The risk of severe influenza-related complications, such as pneumonia, acute respiratory distress syndrome (ARDS), and exacerbations of chronic diseases, is markedly elevated in COPD patients.^8–10

Given the seasonal burden of influenza and its serious consequences in individuals with COPD, understanding the underlying mechanisms and identifying effective preventive strategies is essential. This review aims to explore the pathophysiological mechanisms, clinical consequences, and prevention strategies related to influenza in COPD patients, with a focus on emerging evidence and implications for clinical practice.

Pathophysiological mechanisms

The pathophysiology of COPD involves progressive airflow limitation and chronic inflammation of the airways and lung parenchyma. ¹¹ This condition leads to structural changes in the lungs, including airway remodeling, loss of elastic recoil, destruction of the alveolar walls, ¹² and shaping the airway microbiome, ¹³ all of which contribute to reduced lung function. COPD patients have impaired mucociliary clearance, reduced pathogen expulsion, and a dysregulated immune response, ¹⁴ with pulmonary bacteria dysbiosis potentially regulating pathogenesis through innate immune pathways like type I interferon and Toll-like receptor signaling. ¹⁵

These underlying mechanisms make COPD patients particularly susceptible to respiratory infections. ¹⁶ In COPD patients, impaired mucociliary clearance and a dysregulated immune response create an environment conducive to viral attachment and replication. ¹⁷ The inefficient antiviral response observed in reconstituted small-airway epithelium from COPD patients further exacerbates this, potentially allowing for prolonged viral infection and persistent inflammation. ¹⁸ Furthermore, the structural changes in the lungs, such as airway fibrosis and narrowing, can further impair the clearance of pathogens, leading to prolonged viral presence and exacerbation of disease symptoms. ¹⁹

Influenza infection exacerbates COPD in several ways. The virus directly infects the respiratory epithelial cells, triggering an inflammatory response that exacerbates the pre-existing airway inflammation in COPD patients.^20,21 Influenza activates the immune system, triggering the release of pro-inflammatory cytokines like IL-6, TNF-α, and interferons, leading to hypercytokinemia or “cytokine storm,” which contributes to severe outcomes such as ARDS and death. ²² In healthy individuals, this immune response is well-regulated and protective, but in COPD patients, the response is often exaggerated or dysregulated. This heightened inflammatory response can lead to worsening airflow limitation, increased bronchospasm, and further damage to the lung tissue. ²³ Moreover, the influenza virus impairs the innate immune defenses in COPD patients, particularly the mucociliary clearance mechanism, which is already compromised in COPD. ²⁴ This failure to clear pathogens efficiently results in more severe infections and a higher risk of secondary bacterial infections, further complicating the disease course.

Airway remodeling in COPD patients, characterized by thickened airway walls, increased smooth muscle mass, and fibrosis,^25,26 contributes to the impaired response to viral infections. Influenza infection can trigger further airway remodeling, leading to a vicious cycle of progressive lung damage and worsening COPD. ²⁷ In addition, COPD patients often exhibit an altered immune response, with reduced numbers and function of immune cells such as macrophages, which affects their ability to defend against viral infections, as macrophages play a critical role in immune defense through their M1/M2 polarization and complex signaling pathways. ²⁸ The polarization of macrophages into the pro-inflammatory M1 type is triggered by a cellular pathway known as STAT1 signaling, which is activated in response to stress or infection and promotes the expression of inflammatory genes such as iNOS, CD86, MCP1, and IL-1β, contributing to pulmonary inflammation, cell death (apoptosis), and worsening lung damage in COPD. ²⁹ Also, chronic exposure to air pollutants like PM2.5 and cigarette smoke in COPD patients impairs alveolar macrophage function, leading to reduced phagocytosis and an abnormal increase in inflammatory cytokines. ³⁰ This immune deficiency leaves COPD patients more vulnerable to both primary influenza infection and secondary bacterial infections.

Impact of influenza on COPD outcomes

Influenza is a well-established trigger for exacerbations in patients with COPD, leading to significant short-term worsening of symptoms such as dyspnea, cough, sputum production, and chest tightness.^31,32 These exacerbations are typically characterized by increased inflammation, airway obstruction, and impaired gas exchange, which can result in acute respiratory failure in severe cases.^33,34 A 2025 study found that influenza infection significantly elevated inflammatory cytokines (IL-6, IL-8, IL-1β, and TNF-α) and reduced T cell markers (CD4 and CD8) in elderly COPD patients, exacerbating airway inflammation and impairing immune responses in the acute phase. ³⁵

Beyond acute effects, studies have shown that COPD patients are more likely to experience influenza-triggered exacerbations compared to those without COPD, which are associated with increased long-term morbidity and mortality. ³⁶ For example, a large multicenter prospective cohort study in Canada analyzing 4755 hospitalized COPD patients during the 2011–2015 influenza seasons reported that influenza-positive individuals had significantly higher 30-day mortality (9.7% vs 7.9%) and critical illness (17.2% vs 12.1%) compared with influenza-negative patients, although details regarding sample size and adjustment for confounders should be considered. ³⁷ Another study in the US population between 2014 and 2019 found that elderly influenza patients with COPD had significantly higher 30-day hospitalization rates compared to matched patients without influenza (34.6% vs 6.1%). ³⁸

Figure 1 shows the forest plots for the impact of influenza on the outcome of COPD patients.^37–41 As shown in Figure 1, influenza significantly increased the intensive care unit (ICU) or Emergency Department (ED) visit rates in COPD patients (OR 3.71; 95% CI 3.31–4.15, p < 0.0001). However, the evidence for this effect of influenza on COPD exacerbation (OR 1.01, 95% CI 0.96–1.06, p = 0.63) and length of hospital stay (OR −0.08, 95% CI −0.41 to 0.25, p = 0.62) were not strong. Table 1 integrates findings from the five included clinical studies evaluating influenza-associated outcomes in COPD populations. Meanwhile, subgroup analyses by age, gender, or disease severity remain limited and warrant further investigation to better stratify risk.

Figure 1.

Forest plot for the effect of influenza on COPD exacerbation (a), ICU or ED visits (b), and Length of hospital stay and (c) in COPD patients.

COPD, Chronic obstructive pulmonary disease.

Table 1.

Summary of studies on influenza infection and influenza vaccination in COPD patients.

Study	Design	Population	Outcome	Key finding	Conclusion
Gershon AS (2020)	Test-negative case-control	Community-dwelling adults ⩾66 years with COPD (Ontario, Canada; 2010-2016 seasons)	Influenza-related hospitalizations	22%–43% reduction in hospitalizations with vaccination; consistent across subgroups	Influenza vaccine modestly reduced hospitalizations in COPD patients
Tippett A (2024)	Prospective test-negative case-control	Adults ⩾50 hospitalized with ARI or ⩾18 with CHF/COPD exacerbations (USA)	Influenza-related hospitalizations	63.1% overall VE; 80.3% for COPD/CHF versus 55.9% for ARI	Strong vaccine effectiveness in preventing COPD-related influenza hospitalizations
Liao KM (2024)	Retrospective nested case-control	COPD patients (Taiwan NHIRD 2012–2018)	Influenza infection	19% lower risk with high bronchodilator adherence; additive benefit with vaccination	Medication adherence enhances vaccine benefits
Near AM (2022)	Retrospective cohort	US elderly with COPD (propensity-matched)	30-day hospitalization /ED visits	34.6% hospitalized with flu versus 6.1% without	Influenza substantially increases hospitalization risk
Mulpuru S, (2019)	Prospective multicenter cohort	Hospitalized COPD patients (Canada 2011-2015)	Hospitalizations, mortality, ICU admission	38% lower hospitalization risk with vaccination	Vaccination protective; age/comorbidities increase risk
He R, (2024)	Cross-sectional, multicenter	AECOPD inpatients (China 2017-2021, 173 hospitals)	Vaccination rates	Only 2.09% vaccinated; disparities by region/education/smoking status	Urgent need to improve vaccination coverage
Liu C, (2025)	Prospective cohort	COPD outpatients (China 2016-2023)	Vaccination rates, exacerbations	Health education increased vaccination and reduced exacerbations	Clinician education effectively improves outcomes
Chang HC (2024)	Retrospective analysis	COPD patients stratified by Charlson Comorbidity Index scores	Healthcare utilization	Greatest reduction in low CCI patients with both vaccination and smoking cessation	Combined interventions most effective

COPD, Chronic obstructive pulmonary disease.

These exacerbations of COPD due to influenza infection lead to a cascade of detrimental effects. ⁴² First, the viral infection exacerbates the chronic inflammation in the airways, further narrowing the bronchial lumen, increasing airflow obstruction, and worsening respiratory symptoms.^43–45 This often necessitates hospitalization for supplemental oxygen therapy, ICU admissions, or mechanical ventilation in severe cases. ⁴⁶ Furthermore, recurrent exacerbations in COPD are a key factor in the progressive decline of lung function, accelerating the deterioration of pulmonary health and leading to a higher risk of long-term complications, including respiratory failure and death.^47,48 Emerging evidence suggests influenza infection may drive chronic airway remodeling and persistent immune dysregulation, though these processes remain incompletely understood. Clinically, influenza-related COPD exacerbations impose substantial healthcare burdens,^49–52 such as high ED visits, extended hospital stays, and frequent readmissions. Mortality rates are notably elevated in COPD patients with influenza, with some studies reporting a two- to threefold increase in death rates during influenza outbreaks. ⁵³ The interaction between COPD pathophysiology and influenza worsens clinical outcomes, leading to more frequent exacerbations, longer recovery, and increased long-term damage (see Figure 2).

Figure 2.

Pathophysiological mechanisms and clinical impact of influenza on COPD outcomes.

COPD, Chronic obstructive pulmonary disease.

While influenza is a well-established trigger of COPD exacerbations, growing evidence implicates other respiratory viruses—particularly rhinovirus—as significant contributors, though their pathophysiological mechanisms and clinical impacts remain incompletely understood. Recent studies suggest rhinovirus may cause more frequent but clinically distinct exacerbation patterns compared to influenza. Alsayed ⁵⁴ found rhinovirus caused 28% of virus-associated exacerbations in their Abu Dhabi cohort, typically manifesting as prolonged upper respiratory symptoms of milder severity compared to influenza’s more rapid-onset, severe lower respiratory involvement. ⁵⁵ These differences carry important therapeutic implications—influenza often necessitates antiviral therapy and careful monitoring for secondary bacterial pneumonias,^56,57 while rhinovirus exacerbations generally respond better to bronchodilators and corticosteroids. Elderly patients and those with advanced COPD experience worse outcomes with both virus types, underscoring the need for age-specific management protocols. Personalized approaches incorporating viral diagnostics may optimize care by guiding targeted antiviral use during influenza seasons while emphasizing symptom control for rhinovirus infections, thereby improving outcomes while promoting antimicrobial stewardship.

Comorbidities and complications

COPD patients often have multiple comorbidities, which complicate the management of influenza infection and its outcomes. ⁵⁸ Among the most prevalent comorbidities are cardiovascular diseases,^59,60 diabetes mellitus, and hypertension. ⁶¹ The presence of these comorbidities significantly worsens the prognosis of COPD patients during influenza infection, increasing the risk of complications such as acute myocardial infarction, stroke, and systemic infections.^62,63

Cardiovascular disease (CVD) is especially concerning in COPD patients with influenza. COPD itself is associated with chronic systemic inflammation, endothelial dysfunction, and increased cardiac workload, which can predispose individuals to cardiovascular events.^59,64 During influenza infection, these risks are amplified due to the additional inflammatory burden placed on the cardiovascular system. ⁶⁵ Studies show that the incidence of acute myocardial infarction and arrhythmias increases in COPD patients during flu seasons, especially when co-infected with influenza, with influenza myocarditis being rare but potentially fatal.^66,67

Diabetes mellitus is another common comorbidity that amplifies the risk of influenza-related complications.^68–70 Hyperglycemia impairs both innate and adaptive immune responses, leading to prolonged viral shedding and increased susceptibility to secondary infections.^71,72 This immune dysregulation, coupled with COPD-related impairments such as reduced mucociliary clearance and dysbiosis of the lung microbiota, creates a synergistic risk environment. Moreover, acute influenza illness often complicates glycemic control due to factors such as systemic inflammation, altered nutritional intake, and the use of corticosteroids or supportive therapies, further worsening clinical outcomes. ⁷³

Other comorbidities, such as obesity and chronic kidney disease, ⁷⁴ also contribute to poor outcomes during influenza infection. Obesity, in particular, increases the risk of severe influenza due to its association with systemic inflammation and decreased respiratory function, ⁷⁵ while kidney disease may complicate the management of flu-related sepsis and electrolyte disturbances.^76–78

Given the interplay between COPD and its comorbidities, there is an urgent need for more integrated care approaches.^79,80 Multidisciplinary teams involving pulmonologists, cardiologists, endocrinologists, and infectious disease specialists are essential to optimizing care for COPD patients with influenza.^81,82 A comprehensive approach that addresses both the acute viral infection and the management of comorbid conditions is critical to improving outcomes and reducing complications.

Prevention and vaccination

Seasonal influenza epidemics pose significant public health challenges, ⁸³ with annual vaccination being the primary preventive measure. ⁸⁴ Influenza vaccination remains the most effective method for preventing severe influenza-related outcomes in COPD patients, ⁸⁵ though challenges in vaccination arise due to variable efficacy across virus subtypes and impaired immune responses. High-dose and adjuvanted vaccines have emerged as potential solutions to address these challenges. ⁸⁶

Current guidelines from organizations such as the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend that all individuals with chronic respiratory diseases, including COPD, receive the annual influenza vaccine.^87,88 Studies have consistently shown that influenza vaccination reduces the risk of hospitalization and death in COPD patients, although the vaccine’s efficacy can be influenced by factors such as the patient’s age, the presence of comorbidities, and the match between the vaccine strain and circulating influenza strains.^89–93

A study of 4755 hospitalized COPD patients found that influenza vaccination significantly reduced influenza-related hospitalizations by 38% in vaccinated individuals compared to unvaccinated ones. ³⁷ However, vaccine efficacy in COPD patients can vary, and certain subgroups, such as the elderly and those with more severe COPD, may not respond as robustly to vaccination. For instance, one study reported an overall vaccine efficacy (VE) of 63.1%, with higher efficacy in preventing influenza-related exacerbations in adults with COPD (80.3%) compared to those aged ⩾50 years (55.9%) during the 2018–2020 seasons. ³⁹ A cross-sectional study using BRFSS data from 2017 to 2022 (n = 822,783 adults aged 50–79 years) found that individuals with a history of COPD had significantly higher odds of receiving seasonal influenza vaccination compared to those without COPD. ⁹⁴

Despite these encouraging data, vaccination coverage remains suboptimal. A hospital-based study conducted between 2017 and 2021 in China revealed that influenza vaccination coverage among COPD patients remains extremely low. ⁹⁵ Except for influenza vaccination, a territory-wide retrospective study conducted in Hong Kong from January 1, 2016, to June 30, 2023, showed that completed pneumococcal vaccination conferred protection against secondary bacterial pneumonia, all-cause mortality, and respiratory-related mortality in COPD patients hospitalized for influenza. ⁹⁶ In addition, disease severity appears to influence the clinical benefit of influenza vaccination. A meta-analysis performed a subgroup analysis based on disease severity and found that influenza vaccination significantly reduced acute exacerbations and hospitalizations in patients with severe-to-very-severe COPD (FEV₁ < 50% predicted), but not in those with mild-to-moderate COPD (FEV₁ ⩾ 50%). These findings underscore the importance of stratifying clinical outcomes and preventive strategies by disease severity and support the need for more personalized vaccination approaches. ⁹⁷

Figure 3 presents the forest plots depicting the effects of influenza vaccination on clinical outcomes in COPD patients.^{37,41,95,98,99} The analysis demonstrated that influenza vaccination significantly reduced the length of hospital stay (OR −1.54, 95% CI −2.75 to −0.33, p = 0.01). However, an unexpected finding was observed regarding acute exacerbations, which showed a significant increase in the vaccinated group (OR 1.41; 95% CI 1.34–1.49, p < 0.0001). Table 1 systematically synthesizes evidence from key studies evaluating the clinical impact of influenza vaccination in COPD populations.

Figure 3.

Forest plot for the effect of influenza vaccination on acute exacerbation (a) and Length of hospital stay (b) of COPD patients. The study by Chang HC (2024) includes three subgroup results stratified by CCI scores (CCI I: 0–3, CCI II: 4–6, CCI III: ⩾7), demonstrating differential reductions in hospital stay duration based on comorbidity burden.

CCI, Charlson Comorbidity Index.

In addition to vaccination, other preventative measures play a critical role in protecting COPD patients from influenza infection. First, both smoking cessation and influenza vaccination independently correlated with decreased emergency room visits, hospital admissions, days, and costs, thereby reducing healthcare resource utilization in COPD patients, with the combination yielding synergistic benefits. ⁹⁹ Antiviral medications such as neuraminidase inhibitors (e.g., oseltamivir), traditional Chinese medicine (e.g., Lianhua Qingke) ¹⁰⁰ and long-acting bronchodilators, ⁴⁰ can be used to reduce the severity and duration of influenza symptoms when administered early in the course of infection. Antivirals are particularly important in high-risk populations, including those with COPD, to reduce the risk of complications and exacerbations. These interventions face notable limitations, including delayed antiviral administration (>48 h), insufficient evidence for traditional medicines for COPD, low smoking cessation success rates, and reduced effectiveness in elderly or advanced COPD subgroups. These limitations underscore the need for pragmatic trials to optimize tailored strategies across diverse populations and healthcare settings.

A 2025 study demonstrates that the sialidase fusion protein DAS181 reduces viral burden, mitigates inflammation, and preserves lung function in a COPD mouse model infected with influenza, showing promise as a therapeutic option for smokers at risk for influenza-related respiratory failure. ¹⁰¹ Similarly, another recent study in a COPD mouse model found that melatonin helped improve lung function and reduce lung damage caused by influenza A virus infection. This protective effect was associated with melatonin’s ability to reduce lung inflammation by preventing macrophages from shifting into a pro-inflammatory M1 state and by inhibiting pyroptosis, a form of cell damage triggered by excessive reactive oxygen species (ROS). ¹⁰² However, as these findings are derived from preclinical models, their relevance to human treatment requires further validation through clinical studies. In addition to pharmacological strategies, non-pharmacological preventive measures, such as maintaining good hygiene, engaging in regular physical activity, and participating in pulmonary rehabilitation,^103–105 can significantly reduce the transmission of influenza in healthcare settings and among family members.

Improving vaccine uptake in COPD patients remains a challenge, as they continue to be under-vaccinated, especially in low-resource settings, despite improvements in vaccination rates in the general population. Educational campaigns targeting both patients and healthcare providers, alongside addressing barriers to vaccine access, are essential to increase vaccination rates. Personalized approaches, such as setting vaccination reminders for high-risk patients, can further enhance uptake. ¹⁰⁶ A combination of vaccination, antiviral therapy, and preventive hygiene measures is critical to reducing the burden of influenza in COPD patients. For optimal outcomes, these strategies should be integrated into a comprehensive care plan that includes proactive COPD management, early detection of respiratory infections, and timely intervention to prevent complications.

Conclusion

Influenza infection poses a substantial threat to patients with COPD, exacerbating airway inflammation, weakening immune defenses, and significantly increasing the risk of acute exacerbations, hospitalizations, and mortality. This review highlights current understanding of the shared pathophysiological pathways and clinical consequences of coexisting influenza and COPD. Despite advances, important gaps remain—particularly in understanding the molecular interactions between influenza viruses and innate immune cells, such as alveolar macrophages, within the COPD lung environment. Moreover, the long-term effects of recurrent viral infections on airway remodeling and disease progression warrant further investigation. Preventive and therapeutic strategies, including vaccination, antiviral agents, and supportive care, are essential to mitigate influenza-related complications in COPD. However, future research should focus on personalized therapies with particular attention to disease severity stratification, improved vaccine formulations, and host-directed treatments such as STAT1 inhibitors, melatonin, or DAS181. A deeper understanding of virus-host interactions and better integration of care models will be key to reducing disease burden and improving long-term outcomes for COPD patients.