In this 12-year long follow-up study of the Danish Lung Cancer Screening Trial population 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, pulmonary infections, lung cancer and respiratory failure, a higher hospital admission rate, 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, pneumonia, pleural empyema and respiratory failure, after adjusting for age, sex, BMI and smoking status. 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. 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) It adds to previous findings of increased incidence of ILD in individuals with areas of increased lung attenuation.(24) 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 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.(27) 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.(28) 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.(29,30) 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.(31–34) 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.
There is a lack of standardization of ILA across different studies which makes comparisons difficult.(35) 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’. This potentially weakened our conclusions by including less severe findings in the ‘exposed’ group. However, any cut-offs between different grades of severity would be arbitrary and not easily transferred to clinical practice, which could make them difficult to interpret. In addition, we relied on qualitative descriptors of ILA rather than quantitative measures. This reduces the repeatability of our findings due to the known interobserver variability of radiologic findings even among experienced radiologists.(36) However, our approach is similar to the use of imaging in clinical practice and research.(2,4,7)
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.