Chronic sarcoidosis progresses to fibrotic disease in approximately 10–20% of patients [1
]. Fibrotic disease is characterized by a progression of chronic inflammation to fibrotic transformation, and may include upper and middle lung predominant findings of traction bronchiectasis, bronchial distortion, linear opacities, fibrotic masses, honeycombing, or cysts [1
Patients with fibrotic sarcoidosis commonly experience acute episodes of clinical worsening and lung function decline [3
]. These acute pulmonary exacerbations of sarcoidosis (APES) have been described by decline in pulmonary function, worsening pulmonary symptoms such as cough, sputum, and shortness of breath, increase in biomarkers of disease activity, need to start or restart corticosteroid therapy, and exclusion of alternative causes of pulmonary symptoms and dysfunction [3
]. Risk factors for exacerbations include underlying bronchiectasis, longer disease duration, African American race, previous steroid treatment, and anti-tumor necrosis factor (TNF) therapy [4
]. Acute pulmonary exacerbations are typically treated with antibiotics and/or corticosteroid therapy [3
Short-term air pollution exposure is associated with exacerbations of other pulmonary diseases such as chronic obstructive pulmonary disease (COPD) [6
], asthma [7
], and cystic fibrosis [8
], which share clinical characteristics with exacerbations of fibrotic sarcoidosis. The effect of elevated short-term air pollution exposure on sarcoidosis is unknown. We aimed to evaluate if short-term exposure to ozone and fine particulate matter (PM2.5
) is associated with increased symptoms or lung function decline in an exploratory study of a small cohort of patients with fibrotic sarcoidosis.
Sixteen patients living in Ohio completed three or more testing visits between June 2013 and June 2015 and had complete pollutant exposure data available for their home address. There were a total of 69 testing visits, with an average of 3.6 per patient.
Patient characteristics and outcomes are shown in Table 1
We observed low to moderate levels of PM2.5
and ozone during the study period, shown in Table 2
levels were similar between warm and cold seasons, with a mean 14-day average level of 11.9 μg/m3
and maximum of 23.5 μg/m3
. Ozone levels were higher during the warm season, with mean 46 ppb and maximum 55 ppb. Interquartile range (IQR) for PM2.5
averaged over 7, 10, and 14 days was 4.92, 4.64, and 4.38 μg/m3
, respectively. IQR for ozone averaged over 7, 10, and 14 days was 0.014, 0.014, and 0.014 ppm, respectively.
and Figure 1
show results for lung function outcomes. Average PM2.5
was not associated with FVC (percentage change <0.01 per IQR increase in 14-day average PM2.5
, 95% confidence interval (CI) −2.25 to 2.31), FEV1
(percentage change 0.76 per IQR increase in 14-day average PM2.5
, CI −2.99 to 4.70), or episodes of FEV1
decline > 10% (Odds ratio (OR) 0.85 per IQR increase in 14-day average PM2.5
, CI 0.32 to 1.38). Average ozone was not associated with FVC (percentage change 0.80 per IQR increase in 14-day average ozone, CI −3.13 to 4.88), FEV1
(percentage change −0.03, CI −5.18 to 5.40), or episodes of FEV1
decline > 10% (OR 0.98, CI 0.04 to 1.93).
and Figure 2
show results for questionnaire outcomes. PM2.5
level averaged over 14 days was associated with lower KSQ general health status (score change −6.60 per IQR increase in 14-day average PM2.5
, 95% confidence interval (CI) −12.51 to −0.68). PM2.5
level averaged over 10 and 14 days was associated with lower KSQ lung specific health status (score change −6.93 per IQR increase in 10-day average PM2.5
, 95% confidence interval (CI) −12.67 to −1.21, and score change −6.91 per IQR increase in 14-day average PM2.5
, CI −12.73 to −1.09). PM2.5
levels were not associated with respiratory symptoms measured by SGRQ (score change 1.87 per IQR increase in 14-day average PM2.5
, CI −1.96 to 5.70) or LCQ (score change −0.66, CI −2.03 to 0.70). Short-term ozone exposure was not associated with respiratory symptoms measured by SGRQ, LCG, or KSQ.
In this small cohort of patients with fibrotic sarcoidosis, increased PM2.5 exposure was associated with increased severity of respiratory and quality of life symptoms indicated by a decrease in lung specific health status and general health status using the validated King’s Sarcoidosis Questionnaire. These findings suggest that short-term exposure to PM2.5 may adversely affect patients with fibrotic sarcoidosis.
To our knowledge, this is the first study to evaluate effects of short-term air pollution exposure on health outcomes in fibrotic sarcoidosis. Prior epidemiologic studies have demonstrated associations between environmental exposures and development of sarcoidosis. These have included microbially-rich environments such as agricultural exposures and mold and mildew, insecticides, industrial organic and inorganic dust, particulate matter and debris from the World Trade Center disaster, and metal industries [19
]. These studies suggest that exposure to many different antigens in the environment and workplace may play a role in triggering a granulomatous immune response leading to sarcoidosis. Our study suggests that environmental exposures may also contribute to episodes of clinical worsening in this disease.
We did not detect an association of air pollution exposure with lung function outcomes. Even in the absence of objective changes in pulmonary function, increased respiratory symptoms carry significance for patients’ overall health status. In idiopathic pulmonary fibrosis, dyspnea is a stronger prognostic parameter than other physiologic markers in predicting survival [26
]. Patients with pulmonary fibrosis due to sarcoidosis have increased risk for respiratory failure and death and this phase of the disease does not respond as well to the usual treatments in sarcoidosis [27
]. Identification of environmental exposures that contribute to clinical worsening may lead to opportunities for clinical improvement by reducing exposure.
We did not find any association of ozone exposure with lung function or symptom outcomes. Ozone levels were very low during this study and therefore we cannot exclude the possibility of health effects at higher levels. Additionally, there was less ozone data available during the winter months of the year due to some monitors only recording during warm months.
There are several important features of our study. We evaluated a well-defined cohort of patients with uncommon and severe manifestations of sarcoidosis. All participants had experienced two or more exacerbations of sarcoidosis requiring pharmacologic treatment in the year prior to the study period. This is the first time air pollution exposure effects have been evaluated in this specific disease state. Multiple evaluations of lung function and respiratory symptoms allowed for an evaluation of exposures over multiple time points. We were able to estimate air pollutant exposure at individual place of residence based on data from 18 monitors.
We recognize several limitations to our study. Exposure measures were imperfect, as they were based on observations from multiple monitoring stations recording pollutant data only every three days, and some ozone monitors were without year-round measurements. Similarly, the pollutant concentration estimates were made only for the place of residence, ignoring variability in exposure due to time spent indoors and at locations other than the primary residence. We were only able to evaluate effects of PM2.5 and ozone due to a limited number of monitoring stations in the region measuring other air pollutants. Air pollutants other than PM2.5 and ozone may have also contributed to respiratory symptoms. PM2.5 and ozone exposure levels in this region of Southwest Ohio, USA, were low to moderate, and thus our findings may not accurately reflect exposure effects for patients residing in regions with more extreme exposure patterns. Our sample size was very small, thus we were unable to accurately estimate the effect size, and can only identify that there is an association between PM2.5 exposure and increased respiratory symptoms. We consider this study to be exploratory, and our findings suggest further study with larger sample sizes is warranted to better explore the association of short-term air pollution exposure with health outcomes in fibrotic sarcoidosis.