Revisiting Decades of Research on Air Pollution and Acute Lower Respiratory Infections

The connection between air pollution and respiratory infections has been a subject of study for decades, with increasingly compelling evidence. In this issue of AnnalsATS, Zhang and colleagues (pp. 1129–1138) examine the relationship between long-term exposure to ambient air pollution and the risk of acute lower respiratory infections (ALRIs) in a cohort of Danish nurses (1). This research prompts a reevaluation of the extensive body of work on this topic.

ALRIs, including pneumonia (infection of the lung alveoli) and lower airway infections such as acute bronchitis and bronchiolitis (particularly in infants and young children), continue to be a major global health concern. ALRIs are a leading cause of illness and death, especially among vulnerable groups, such as infants, the elderly, patients with chronic obstructive pulmonary disease (COPD), and individuals living in poor socioeconomic conditions. According to the latest Global Burden of Disease Study in 2021, ALRIs were ranked as the fifth leading cause of global disability-adjusted life-years (2).

Respiratory infections are primarily caused by viruses (e.g., rhinovirus, respiratory syncytial virus, influenza, parainfluenza, and adenovirus) and bacteria (e.g., for pneumonia, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Chlamydia pneumoniae). A delicate balance exists between the virome/microbiome (viruses and bacteria) and host-related factors. Any alterations in the immune system can increase susceptibility to infections. Chronic mucus hypersecretion is a significant host factor favoring respiratory infections. Viruses induce a proinflammatory mucosal response that accelerates the growth of pathogens such as S. pneumoniae and H. influenzae, leading to secondary bacterial infections (3).

The London smog episode of 1952 marked a turning point, as it was observed that pneumonia deaths among children and the elderly increased significantly during and after the smog event. Notifications for pneumonia also rose both during the smog event and in the subsequent 2 weeks compared with the same period in previous years (4, 5).

After the episode, one of the first “panel studies” demonstrated a close association between the clinical condition of patients with chronic bronchitis and emphysema and atmospheric pollution levels in Greater London (6). Researchers postulated that a factor other than chemical irritancy of the polluted air could be related to respiratory illness. A seminal experiment in 1967 investigated the effects of particulate pollutants from London air on respiratory tract organisms. It found that H. influenzae growth was stimulated by air pollutants (7). This finding prompted further investigations into how air pollution could exacerbate respiratory infections by enhancing microbial pathogenicity or decreasing pulmonary defenses.

Chauhan and Johnston in 2003 (8) explored the relationship between air pollution and infection and some of the mechanisms of how both could act synergistically to cause respiratory illnesses, especially in exacerbating symptoms in individuals with preexisting respiratory conditions. Today, it is well understood that air pollution increases susceptibility to both viral and bacterial infections by dysregulating immune tolerance and antimicrobial responses. Controlled studies have shown that inhaled pollutants can affect host defense responses to viral infections in multiple ways, including enhancing viral entry, limiting antiviral defense responses, impairing immune signaling molecule production, and impairing immune cell functions (9).

Systematic reviews and meta-analyses have confirmed the link between short-term pollutant exposure and pneumonia in children (10) and adults (11). However, evidence for the effects of long-term exposure on ALRIs remains less compelling. For example, a systematic review on long-term particulate matter ⩽2.5 μm in aerodynamic diameter (PM_2.5) exposure and pneumonia risk in children found only a few positive studies, some with large confidence intervals (12). The follow-up of children in the ESCAPE (European Study of Cohorts for Air Pollution Effects) newborn cohort revealed an increased risk for all pollutants except fine particles (PM_2.5) (13). The Health Effects Institute Traffic Review (14) found moderate to strong evidence of the association between long-term traffic-related air pollution exposure and respiratory infections in children, particularly based on the effect of NO₂ exposure on pneumonia incidence. In adults, evidence is available on pneumonia mortality linked to NO₂ and black carbon (BC) exposure (15), but fewer studies address incidence. A population-based case-control study in Ontario, Canada, found an independent association between long-term NO₂ and PM_2.5 levels (mainly from traffic-derived pollutants) and pneumonia hospitalization (16). Danesh Yazdi and colleagues (17) examined the association between average annual PM_2.5 and ozone and first hospital admissions of Medicare participants in the southeastern United States for several conditions, including pneumonia. PM_2.5 was significantly associated with an increased risk of admissions for all studied outcomes, with the highest effects seen for pneumonia.

Given the paucity of the available evidence, new studies are crucial for advancing our understanding of the complex and evolving relationship between air pollution and respiratory health. They help to address knowledge gaps, refine exposure assessments, identify vulnerable populations, and inform public health policies to mitigate the adverse effects of air pollution. The new study by Zhang and colleagues (1) in a cohort of Danish nurses is welcome. Established in 1993, the study included 23,912 female nurses aged 44 years and older, with comprehensive data on socioeconomic status (SES), lifestyle factors, and air pollution exposure. Data on ALRIs were obtained from the Danish National Patient Register. The study used advanced models to estimate residential air pollution exposure and employed Cox regression models with time-varying exposures, adjusting for various confounders. Over an average follow-up of 21.3 years, the study observed 4,746 hospital contacts for ALRIs, of which 2,553 were incident cases. The study found significant positive associations between long-term exposure to air pollution and the risk of both incident and recurrent ALRIs. Specifically, hazard ratios were 1.19 for PM_2.5 (per 2.5-μg/m³ increase), 1.17 for NO₂ (per 8.0-μg/m³ increase), and 1.09 for BC (per 0.3-μg/m³ increase). The associations were stronger for recurrent ALRIs. Vulnerable subgroups included patients with COPD, individuals with low physical activity levels, and those with lower SES.

This study introduces several novel aspects that contribute to the existing body of knowledge on air pollution and respiratory infections:

• •Over two decades (21.3 yr, on average) of follow-up, allowing a comprehensive assessment of chronic air pollution effects on respiratory health
• •Use of high-resolution data to estimate residential air pollution levels, with monthly data on NO₂, PM_2.5, and BC from 1979 to 2018, offering a better understanding of long-term exposure–response relationships
• •Innovative statistical methods with time-varying exposures, enabling dynamic analysis of how pollutant exposure correlates with ALRI risk over time
• •Comprehensive adjustment for a wide range of potential confounders, including SES, lifestyle factors (smoking, physical activity, body mass index), and comorbidities, enhances the findings’ robustness
• •Distinction between ALRI types, differentiating between first-time (incident) ALRIs and recurrent ALRIs, providing insights into how air pollution affects both the initial onset and recurrence of respiratory infections
• •Detailed subgroup analyses, identifying specific vulnerable populations (individuals with COPD, low physical activity levels, and lower SES) to inform targeted public health interventions
• •Multiple sensitivity analyses, including adjustments for different exposure time windows

The study makes a significant contribution to understanding the long-term impacts of air pollution on respiratory infections. Only a few limitations should be noted. The cohort consists of female nurses from Denmark, limiting generalizability. Exposure assessments based on residential addresses may not fully capture total exposure. Historical air pollution data might contain inaccuracies, and temporal changes in air pollution levels, healthcare practices, and diagnostic criteria could affect the results.

Epidemiologists and toxicologists need to integrate their approaches better, combining observational and novel experimental research to expand our knowledge of disease mechanisms (18). Although progress has been made since 2003, when Chauhan and Johnston (8) called for understanding the fundamental interactions between air pollution and host factors, new efforts should include large population cohort studies to detect respiratory infections, use more laboratory data to assess the nature of the infections and the immune status of the population, and develop new designs to evaluate the effects of air pollution on incidence, severity, recurrence, and potential modulating role of vaccines (when available).

In conclusion, historical research on the link between air pollution and respiratory infections has evolved from initial observations of acute events to comprehensive studies revealing complex, long-term impacts. The evidence underscores the need for continued efforts to improve air quality to protect public health, particularly for the most vulnerable groups.