In this 12-year long follow-up of lung cancer screening trial participants, we show an increased disease specific morbidity and healthcare utilisation in participants with ILA. This includes a more frequent diagnosis of several respiratory diseases, such as ILD, COPD, pulmonary infections, lung cancer and respiratory failure, a higher hospital admission rates, and higher use of several therapies for these diseases.
ILA and specific diagnoses
A higher proportion of participants with ILA received a hospital diagnosis of a respiratory disease or lung cancer in the 12 years following the radiologic finding. Our results add to previous reports of increased lung cancer related mortality and to a lesser extent respiratory mortality in individuals with ILA. (7,13,24) However, the present study adds to the understanding of ILA by describing an increased frequency of several more specific respiratory diagnoses, such as ILD, COPD, pneumonia, pleural empyema and respiratory failure, after adjusting for age, sex, BMI and smoking status and correcting for multiple comparisons. It is not clear how the presence of ILA predisposes to the increased morbidity, but these rather unspecific radiological findings possibly reflect inflammatory, premalignant or pulmonary vascular changes. Further research is needed to specify the specific risk associated with the different types of ILA. ILA could also be the result of previous exposure to dust, gasses, infections or pneumotoxic medications, in a population already predisposed to respiratory diseases.
The association between ILA and the development of clinical ILD highlights the potential for an earlier diagnosis by recognizing ILA in a lung cancer screening setting.(25) An increased incidence of ILD has previously been shown in individuals with high-attenuation areas in the lung, a quantitative assessment of parenchymal abnormalities.(24) This association was found for community dwelling individuals, both smokers and non-smokers, while the present study is limited to long-term smokers.(24) There is thus growing evidence of an increased risk of developing ILD in people with areas of increased attenuation in the lung parenchyma, irrespective of the way these are determined. Further research is needed to identify radiological, clinical or genetic risk factors for the development of specific ILDs. In IPF, radiological findings can be visible many years before clinical disease, making screening by CT in conjunction with lung cancer screening an attractive option.(10,25) Considering that IPF is more common in smokers and older people, who also are the candidate population for lung cancer screening, it is possible that some cases of subclinical IPF could be detected as incidental findings from the CT scans in a lung cancer screening program.(25,26)
The association between ILA and clinically diagnosed COPD during long-term follow-up is intriguing, as it contradicts some earlier cross-sectional and case control findings but is supported by others.(6,27,28) Our results could be due to the study population derived from a lung cancer screening trial, the longitudinal follow-up or a different definition of clinical disease. First, we included long-term smokers from a lung cancer screening trial and followed them for up to 12 years, which may affect the incidence of COPD as both age and tobacco exposure are known risk factors of COPD. Second, we registered all hospital diagnoses of COPD, with no regard to disease severity. Previous studies found that people with ILA had a decrease in their odds of having COPD of stage 2 or higher.(6,29) It has previously suggested that ILA can be a marker of susceptibility to smoking related lung injury, which is supported by our findings during longitudinal follow-up.(28)
The marked increase in pulmonary infections in participants with ILA was confirmed by an increased use of antibiotics. This association could have several explanations. Firstly, patients with ILA were older and more frequently active smokers, and thus more susceptible to pneumonia.(30) Secondly, the higher frequency of COPD, a disease associated with pulmonary infections and exacerbations, in participants with ILA would lead to an expected increase in these infections.
In line with the general increase in respiratory disease, a hospital diagnosis of respiratory failure was twice as frequent in participants with ILA compared with those without ILA. A previous study has shown that critically ill patients with sepsis, who had ILA on chest CT scans taken within one week prior to ICU admission were more likely to develop acute respiratory distress syndrome.(31) We supplement these findings with longitudinal follow-up showing that a finding of ILA also increases the long-term risk of developing respiratory failure.
ILA and hospital admission rates
Participants with ILA had a higher rate of hospital admissions during both short-term and long-term follow-up. Hospital admission rates are measures of morbidity that are highly relevant to both patients and healthcare systems, and are a recommended outcome for clinical trials of IPF alongside mortality.(32,33) Our results thus highlight the clinical and economical importance of ILA as incidental findings. (13)
The most pronounced increase in hospital admissions for participants with ILA was found for respiratory and malignant causes, which corresponds with our finding of an increased incidence of these diseases in participants with ILA. The increased rate of hospital admissions with pulmonary embolism and peripheral vascular disease in participants with ILA was more surprising. Venous thromboembolic disease is associated with several ILDs, including lung fibrosis, sarcoidosis and IPF.(34–37) To our knowledge, we present for the first time an increase in pulmonary embolism morbidity also in individuals with ILA. The higher prevalence of malignancy, which is a known risk factor for thromboembolic disease, in participants with ILA could be a possible explanation. Alternatively, ILA and thromboembolic disease could share common, and possibly unknown, risk factors.
The gastrointestinal disorders which were more prevalent in patients with ILA did not result in increased hospitalisation rates, which could be expected from these diagnoses. They are likely to be handled in an outpatient setting rather than causing hospital admissions.
There is a lack of standardization of ILA across different studies which makes comparisons difficult.(38) Previous studies have analysed ILA in different ways. Many studies have excluded indeterminate ILA in their analysis (6,8,11,24), some have graded the extent of the abnormalities(4), some have studied high attenuation areas on CT rather than visually defined ILA,(5,24,39) and some have identified specific patterns(2,4). Furthermore, some studies have supplemented low dose CT findings with HRCT to exclude false positive ILA.(4,6) In contrast to other reports, we did not code any findings as ‘indeterminate’ or ‘equivocal’ but limited the analysis to a dichotomous variable of ‘ILA’ or ‘No ILA’. Other studies report a large variation in the proportion of indeterminate ILA subjects from around 12–59%.(7,8) Our conclusions are potentially affected by including less severe indeterminate findings in the ‘exposed’ group. However, previous studies have found associations between interstitial features in smokers and reduced lung function, worse quality of life and increased mortality, even in participants who did not have visually defined ILA or who were classified as indeterminate for ILA.(7,28) We also relied on qualitative descriptors of ILA rather than quantitative measures which reduces the repeatability of our findings due to the known interobserver variability of radiologic findings even among experienced radiologists.(40) These differences must be taken into account when interpreting our results and comparing them to previous studies.
We report a higher prevalence of ILA compared with other cohorts.(6–8,24) This could be due to the fact, that the population was derived from a lung cancer screening trial of long-term smokers. The higher prevalence of ILA could also be due to the reading method used. In the present study, participants were classified as having ILA if at least one observer scored it as such. A more rigorous sequential reading method, could have reduced the number of definite ILA findings. Finally, the classification used where participants were scored as ‘ILA’ or ‘No ILA’ without any ‘indeterminate’ category, could have lead to a higher prevalence of ILA in our cohort.
The data on the specific contact diagnoses were only available for secondary care contacts (hospital admissions, outpatient clinic visits and emergency department visits). This could lead to potentially underestimating the prevalence of a certain diagnosis (i.e. COPD or pneumonia) for participants treated exclusively in primary care. However, for many diagnoses of interest, such as lung cancer and ILD, participants would be expected to be diagnosed in secondary care.
The participants in the present study were mostly white northern Europeans. The generalizability to other ethnicities remains to be determined.