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Serum molecules differentiate types of interstitial lung disease

In patients with interstitial lung disease, a combination of serum molecules served as a differential diagnostic biomarker.

The term interstitial lung disease (ILD) is an umbrella term to describe a group of diseases all of which are characterised by inflammation or fibrosis of the alveolar wall and impairment of gas exchange. One form of ILD is connective tissue disease-associated ILD (CTD-ILD) and which occurs in patients with a connective tissue disease such as Sjogren’s syndrome, systemic lupus erythematosus and polymyositis, with an estimated incidence of 15% of the population. Other forms of ILD include idiopathic pulmonary fibrosis (IPF) and which has an estimated worldwide prevalence of 13 to 20 cases per 100,000. The diagnosis of ILD and identification of the underlying cause can be challenging and relies upon a combination of blood, imaging and pulmonary function tests.

The precise cause of ILD is unclear although proposed aetiologies have included an imbalance between oxidant-antioxidant factors, particularly in idiopathic pulmonary fibrosis as well as an increased level of advanced glycation end-products (AGE). Furthermore, increased levels of matrix metalloproteinase-7 (MMP-7) is also involved as witnessed by elevated levels in those with IPF. Nevertheless, differentiating between CTD-ILD and other forms of ILD such as IPF is important because the treatment is different. This led a team from the Respiratory Service, University of Virgen de la Victoria Hospital, Malaga, Spain, to explore whether it was possible to use several serum molecules to differentiate between IPF and CTD-ILD. The team recruited patients with both IPF and CTD-ILD and after a single visit to the hospital, blood samples were taken together and the levels of AGE, advanced oxidation protein products (AOPP) and MMP-7 determined. The performance of each marker was assessed using the area under the receiver operating characteristic curve (AUC) and used to determine the sensitivity and specificity of each biomarker.

In total there were 73 patients, 29 with IPF and 14 CTD-ILD and 30 healthy controls. The average age of participants was not significantly different and approximately 63 years. Mean levels of AGE, AOPP and MMP-7 were all elevated in both the CTD-ILD and IPF groups compared to controls. The AUC for AGE was 0.78 (95% CI 0.60–0.97) for patients with IPF, 0.80 for AOPP and 0.96 for MMP-7. In addition, the AUC for AGE was higher for CTD-ILD than for IPF (0.95, 95% CI 0.86 – 1.0). Using MMP-7 as a biomarker, for both conditions, the sensitivity was 92.3% for IPF and 100% for CTD-ILD and the corresponding specificities were both 92.9%. However, combining the biomarkers, AGE and MMP-7, increased the sensitivity for distinguishing between IPF and CTD-ILD to 93.3% and the specificity 100%.

In their discussion, the authors noted that while all three biomarkers were elevated in patients with the different forms of ILD, the combination of two of these markers (MMP-7 and AGE) was able to differentiate between the CTD-ILD and IPF and might therefore serve as an important biomarker in clinical practice.


Cesae EC et al. Biomarkers in Differential Diagnosis of Idiopathic Pulmonary Fibrosis and Connective Tissue Disease-Associated Interstitial Lung Disease. J Clin Med 2021