Incidental Findings on Low-Dose CT Lung Cancer Screening in the NLST and Risk of Respiratory Disease Mortality

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Paul F. Pinsky, PhD

Paul F. Pinsky, PhD

In an analysis of data from the National Lung Screening Trial (NLST) reported in Chest, Paul F. Pinsky, PhD, of the Division of Cancer Prevention, National Cancer Institute, and colleagues found that incidental respiratory disease–related findings on low-dose computed tomography (CT) screening were common and associated with an increased risk of mortality from respiratory diseases.1

Study Details

The study involved data from 25,002 subjects (of a total of 26,722) in the NLST low-dose CT group who received a baseline and subsequent low-dose CT screen; 23,574 received all three screens in the trial. Incidental findings were categorized and assessed for association with respiratory disease mortality. Covariates in a multivariate analysis of respiratory disease mortality included demographic characteristics (age, sex, race), body mass index, smoking history (current smoking status, pack-years), and reported history of respiratory disease (chronic obstructive pulmonary disease [COPD], emphysema, chronic bronchitis, asthma, pneumonia).

Prior to screening, emphysema, chronic bronchitis, or COPD were reported by 17.3% of participants, with emphysema/COPD reported by 10.6%.

Emphysema on low-dose CT was reported in 30.7% of subjects at the baseline screen and in 44.2% at any screen. Emphysema on the baseline screen was identified in 52.4% of subjects vs 28.1% without a reported history of emphysema/COPD; 18% of those with emphysema on baseline low-dose CT had a reported history of emphysema/COPD. Among subjects with vs without a reported history of emphysema/COPD, emphysema was identified at any screen in 67.3% vs 41.5%.

The most common incidental findings after emphysema were reticular opacities (including honeycombing, fibrosis, scar), identified in 20.1% of subjects at the baseline screen and in 36.8% on any screen, and pleural thickening or effusion, identified in 5.6% at baseline and in 10.6% on any screen. Less common findings included adenopathy, atelectasis, and consolidation (≤ 3% at any screen).

Among those with emphysema reported on the baseline screen, 19.3% had a screen result of negative for lung cancer but a clinically significant abnormality (Neg-CS) on the baseline or a subsequent screen where emphysema was noted; the corresponding percentage for those with emphysema reported only on postbaseline screens was 8.0%. For reticular opacities, the corresponding Neg-CS percentages were 17.5% (baseline) and 10.1% (postbaseline), and for pleural thickening/effusion, the percentages were 18.3% (baseline) and 13.6% (postbaseline).

Mortality Risks

Median follow-up for mortality was 10.3 years (interquartile range = 9.7–10.7 years). There was a total of 3,639 non–lung cancer deaths, including 708 from respiratory disease.

Among subjects with a history of emphysema/COPD, 10-year respiratory disease mortality rates ranged from 3.7% among those with neither emphysema nor reticular opacities on low-dose CT to 17.3% among those with both those abnormalities on low-dose CT. Among subjects without a history of emphysema/COPD, 10-year respiratory disease mortality rates ranged from 1.1% among those with neither abnormality on low-dose CT to 3.9% among those with both.

On a multivariate analysis, low-dose CT findings significantly associated with an increased risk of respiratory disease mortality were emphysema (hazard ratio [HR] = 2.27, 95% confidence interval [CI] = 1.92–2.7) and reticular opacities (HR = 1.39, 95% CI = 1.19–1.62), but not pleural thickening or effusion (HR = 1.07, 95% CI = 0.86–1.32). Among demographic/­disease history factors associated with significantly increased respiratory disease mortality risk were a history of emphysema/COPD (HR = 3.41, 95% CI = 2.89–4.02), older age (HRs of 2.0 for 65–69 years and 4.03 for ≥ 70 years at last screen vs 55–64 years), male sex (HR = 1.28), current smoking (HR = 1.78), ≥ 50 vs < 50 pack-year history (HR = 1.56), history of pneumonia (HR = 1.30), and history of asthma (HR = 1.58). Factors not significantly associated with an increased risk were Black race, a history of chronic bronchitis, and a body mass index of at least 30 kg/m2.

On a multivariate analysis of respiratory disease mortality risk according to baseline (prevalent) vs subsequent (incident) findings on low-dose CT screens, hazard ratios for prevalent and incident findings were 2.52 (95% CI = 2.11–3.01) and 1.74 (95% CI = 1.37–2.20) for emphysema, 1.15 (95% CI = 0.88–1.51) and 0.97 (95% CI = 0.71–1.31) for pleural thickening or effusion, and 1.30 (95% CI = 1.09–1.56) and 1.45 (95% CI = 1.20–1.75) for reticular opacities.

Among patients with emphysema on low-dose CT, the hazard ratios for respiratory disease mortality were higher among subjects with vs without a a negative for lung cancer but a clinically significant abnormality screen at baseline (HR = 3.1 vs 2.4, P = .04) and with vs without a a negative for lung cancer but a clinically significant abnormality screen on subsequent screens (HR = 4.1 vs 1.5, P < .001). No significant differences in hazard ratios were observed according to a negative for lung cancer but a clinically significant abnormality status for prevalent or incident findings of reticular opacities.

As noted by the investigators: “It is unknown what diagnostic or therapeutic interventions, if any, were performed as follow-up to the findings of non–lung cancer–related pulmonary abnormalities observed on CT scanning. However, because they were incidental findings in a lung cancer screening trial, follow-up was probably not generally intensive. For subjects with emphysema at baseline, only around 20% had an associated overall screen result of Neg-CS abnormalities, suggesting this finding was often regarded as not clinically significant.”

The investigators concluded: “Incidental respiratory disease–related findings observed on NLST [low-dose] CT screens were frequent and associated with increased mortality from respiratory diseases.” 

DISCLOSURE: Dr. Pinsky reported no conflicts of interest.


1. Pinsky PF, Lynch DA, Gierada DS: Incidental findings on low-dose CT lung cancer screenings and deaths from respiratory diseases. Chest. November 25, 2021 (early release online).