Simple method for detecting idiopathic interstitial pneumonias by measuring vertical lung length on chest X-ray

Detection of idiopathic interstitial pneumonias (IIPs) on chest X-ray is difficult for non-specialist physicians, especially in patients with mild IIPs. The current study aimed to evaluate the usefulness of a simple method for detecting IIPs by measuring vertical lung length (VLL) in chest X-rays to quantify decreased lung volume. A total of 280 consecutive patients with IIPs were randomly allocated to exploratory and validation cohorts, and 140 controls were selected for each cohort by propensity score-matching. Upper (uVLL; from apex to tracheal carina), lower (lVLL; from carina to costophrenic angle), and total VLL (tVLL; from apex to costophrenic angle), and the l/uVLL ratio were measured on chest X-rays. Patients in the exploratory cohort had significantly decreased uVLL, lVLL, tVLL, and l/uVLL ratio compared with controls (all p < 0.001). Receiver operating characteristic curve analyses demonstrated that lVLL (area under the curve [AUC] 0.86, sensitivity 0.65, specificity 0.92), tVLL (AUC 0.83, sensitivity 0.75, specificity 0.80), and l/uVLL ratio (AUC 0.80, sensitivity 0.72, specificity 0.79) had high diagnostic accuracies for IIPs. These results were reproduced in the validation cohort. IIP patients thus have decreased VLLs, and measurements of VLL may thus aid the accurate detection of IIPs.

Decreased lung volume, resulting from pulmonary fibrosis, is another feature of IIPs 16,18 and can be confirmed by reduced lung fields and an elevated diaphragm on chest X-ray. However, precise evaluation of IIP-related pulmonary abnormalities on chest X-ray is difficult for non-pulmonologists, such as primary physicians or oncologists, and even well-trained pulmonologists and radiologists may not find it easy to detect early-stage IIPs on chest X-ray 18,19 . In contrast, reduced lung fields and an elevated diaphragm are easily evaluable and quantifiable on chest X-rays, even by doctors without expertise in diagnostic radiology, by measuring the vertical length of the lung. However, whether or how decreased lung volume is quantified on chest X-rays in patients with IIPs remain unclear. In the present study, we aimed to develop a method to quantify decreased lung volume by measuring the vertical lung length (VLL) on chest X-ray, and to evaluate its usefulness for the detection of IIPs.

Results
Patient characteristics. The current study included an exploratory and validation cohort, each comprising 140 patients with IIPs and 140 propensity-score matched control subjects (Fig. 1). The patient characteristics are presented in Table 1. A total of 137 patients (48.9%) had > 80% of %predicted forced vital capacity (FVC), indicating mild IIP. The patients with IIPs and matched control subjects in each cohort had comparable characteristics, except in terms of spirometry results. The exploratory and validation cohorts had comparable characteristics. The most dominant IIP subtype was IPF (74.2%). All of the patients with IIPs had a reticular pattern on chest CT images, and 70.4% and 94.3% had honeycombing and ground-glass opacity (GGO), respectively ( Table 2).
In the exploratory cohort, patients with IIPs had significantly lower uVLL, lVLL, tVLL, and l/uVLL ratio compared with the control subjects (p = 0.003, < 0.001, < 0.001, and < 0.001, respectively) ( Fig. 3A-D, Supplementary Table 1). Patients with IIPs were grouped into mild IIPs (%predicted FVC ≥ 80%) and moderate/severe IIPs (< 80%). Patients with moderate/severe IIPs had significantly lower uVLL, lVLL, tVLL, and l/uVLL ratio compared with those with mild IIPs and control subjects (all p < 0.001, except p = 0.009 for l/uVLL ratio for mild IIPs). In addition, patients with mild IIPs also had significantly lower lVLL, tVLL, and l/uVLL ratio, but not uVLL, compared with the control subjects (all p < 0.001, except uVLL).  Patients with idiopathic interstitial pneumonias (IIPs) were randomized, stratified according to sex and %predicted forced vital capacity. Controls were selected by one-to-one propensity score-matching using age, sex, and body mass index.

Validation of differences in VLLs and cut-off values in validation cohort. The differences in VLLs
between patients with IIPs and the control subjects were reproduced in the validation cohort. Patients with IIPs had significantly lower uVLL, lVLL, tVLL, and l/uVLL ratio compared with the control subjects (p = 0.038, < 0.001, < 0.001, and < 0.001, respectively) ( Fig. 3E-H, Supplementary Table 1). Patients with moderate/severe IIPs also had significantly lower uVLL, lVLL, tVLL, and l/uVLL ratio compared with patients with mild IIPs and control subjects (all p < 0.001, except p = 0.001 and 0.003 for uVLL and l/uVLL ratio for mild IIP, respectively). Patients with mild IIPs had significantly lower lVLL, tVLL, and l/uVLL ratio, but not uVLL, compared with the control subjects (all p < 0.001, except uVLL).
When using the VLL cutoff values in round numbers in clinical practice, an lVLL of 100 mm/m had a sensitivity of 0.71 and specificity of 0.86 for all IIPs, and a sensitivity of 0.54 and specificity of 0.86 for mild IIPs. A tVLL of 160 mm/m had a sensitivity of 0.70 and specificity of 0.83 for all IIPs, and a sensitivity of 0.49 and specificity of 0.83 for mild IIPs. An l/uVLL ratio of 1.70 had a sensitivity of 0.76 and a specificity of 0.75 for all IIPs, and a sensitivity of 0.70 and specificity of 0.75 for mild IIPs.

Figure 3. Comparison of vertical lung lengths (VLLs) between patients with IIPs and controls. VLLs in the exploratory (A-D) and validation cohorts (E-H).
Mild and moderate/severe idiopathic interstitial pneumonias (IIPs) were defined as patients with %predicted forced vital capacity ≥ 80% and < 80%, respectively. White, black, light grey, and grey boxes represent controls, all patients with IIPs, mild IIPs, and moderate/severe IIPs, respectively.

Discussion
In the present study, we evaluated reduced lung volume by measuring VLLs on chest X-rays, and found that VLLs were significantly decreased in patients with IIPs. Among the measured VLLs, lVLL, tVLL, and l/uVLL ratio demonstrated high diagnostic accuracies for the detection of IIPs, with lVLL having the highest accuracy. Importantly, decreases in lVLL, tVLL, and l/uVLL ratio were also observed in patients with mild IIPs, with a %predicted FVC > 80%. Chest X-rays are a non-invasive, low-radiation exposure, and low-cost diagnostic method, and the measurement of VLLs is simple and easy, even for doctors with no expertise in diagnostic radiology, thus aiding the early detection of IIPs in clinical practice. Among the decreases in VLLs observed in patients with IIPs, the decrease in lVLL was more prominent compared with uVLL, possibly because pulmonary fibrosis occurs predominantly in the lower lobe of the lungs. Although the uneven distribution of pulmonary fibrosis in the lower lungs is well known in IPF [14][15][16]20 , the underlying mechanisms are unknown. One hypothesis suggests that mechanical stress caused by repeated ventilation is stronger in the lower lobe because of the large motion of the chest wall and diaphragm [20][21][22] . In addition to IPF, most IIPs demonstrate predominantly lower lobe lesions 16,19,20,23 . Patients in the current study with non-IPF IIPs showed decreased lVLL and l/uVLL ratio, similar to patients with IPF.
Interestingly, VLLs were decreased in patients with IIP but with no decline in %predicted FVC. In addition to lung elasticity, pulmonary function also depends on thoracic elasticity and the respiratory muscles, and patients with IPF were reported to show only a weak or moderate correlation between pulmonary function and radiologic severity at baseline and changes during follow-up 17,24 . In the present study, VLLs were only moderately correlated with %predicted FVC, and the decreases in VLLs were independent of clinical factors, including %predicted FVC. In addition, differences in the cut-off values between all IIPs and mild IIPs were small. These characteristics of VLLs thus enable the detection of early-stage IIPs, but conversely, VLLs may be of little clinical use for estimating the deterioration of pulmonary function.
Among the measured VLLs, although lVLL demonstrated the highest AUC for the detection of IIPs, the diagnostic accuracies of lVLL, tVLL, and l/uVLL ratio were similar from a clinical perspective. In contrast to lVLL and tVLL, which need to be adjusted for body height, l/uVLL ratio does not depend on height and can be calculated from chest X-ray images, and can thus be used as an alternative to lVLL. The current study had three main limitations. First, VLLs are only evaluable on chest X-rays performed in an upright position, in patients with no abnormal changes other than interstitial pneumonias. Chest CT should be used to screen for IIPs in patients in the decubitus position, or those with a history of chest surgery or other obvious chest abnormalities. Similarly, severely obese patients may have an elevated diaphragm due to visceral fat and may therefore be unsuitable for the evaluation of VLLs. Second, the differential distribution of pulmonary fibrosis affects VLLs. Patients with secondary IPs demonstrated lower uVLL and higher lVLL than those with IIPs. This may be because secondary IPs, including sarcoidosis, CHP, and pneumoconiosis, demonstrate upperlobe-predominant fibrosis, whereas IPF, the most dominant phenotype among IIPs, demonstrates lower-lobepredominant fibrosis [25][26][27] . Furthermore, CVD-IPs are a heterogeneous group of different disease phenotypes, each with distinct lung abnormalities varying according to the phenotype. The utility of VLLs in secondary IPs needs to be investigated further. Third, the present study was retrospective in nature, with limited clinical information. The existence of respiratory symptoms, dyspnea, or abnormal respiratory sounds on auscultation may increase the diagnostic ability in combination with VLLs. The clinical utility of VLLs thus needs to be validated in a prospective, observational study in a real-world setting.  were semi-quantitatively evaluated as follows: grade 0 (0%), grade 1 (< 25%), grade 2 (25-50%), grade 3 (50-75%), and grade 4 (> 75%). The white, grey, and black boxes in the images represent grade 1, 2, and ≥ 3 for reticular pattern, respectively, or grade 0, 1, and ≥ 2 for honeycombing and ground-glass opacity, respectively.

Conclusions
Patients with IIPs, including those with mild IIPs, had decreased VLLs, especially lVLL, on chest X-ray. The measurements of lVLL, tVLL, and l/uVLL ratio demonstrated high diagnostic accuracies for the detection of IIPs. This simple method may aid the early detection of IIPs by non-respiratory practitioners and physicians in areas with poor access to CT examinations.

Methods
Study design. This retrospective observational study was conducted in accordance with the ethical stand- The inclusion criteria were as follows: chest X-ray and spirometry performed within 1 week of each other, and clinically stable disease with no worsening for at least 4 weeks before spirometry and chest X-ray. If multiple data were available for the same patient, the earliest data from the initial diagnosis of IIP were evaluated. The exclusion criteria were as follows: patients with pleuroparenchymal fibroelastosis, characterized by upper-lobe-dominant fibrosis 28 ; patients with anatomical chest abnormalities, abnormal chest shadows without IIP (e.g. lung cancer, pleural effusion, or pneumothorax), or a history of chest surgery; patients with missing data for either chest X-ray or spirometry within 1 week; and patients with clinically unstable disease within 4 weeks (e.g. pneumonia or acute exacerbation). Clinically stable Exploratory and validation cohorts. A total of 280 consecutive patients with IIPs and 400 control subjects were evaluated. The patients with IIPs were randomly allocated to the exploratory or validation cohort (Fig. 1). Control subjects were selected for each cohort by propensity score-matching using age, sex, and BMI. Each cohort finally included 140 patients with IIPs and 140 control subjects. The two cohorts were merged into a total cohort for final analysis.
Secondary interstitial pneumonia cohorts. A total of 240 consecutive patients with secondary IPs, including connective tissue diseases, sarcoidosis, hypersensitivity pneumonia, and pneumoconiosis, were evaluated as the secondary IP cohort.
Evaluation of chest X-rays and computed tomography. Lung volume loss was evaluated by measuring uVLL, lVLL, and tVLL in the right lung on chest X-rays taken in the upright position and at maximum inspiration ( Fig. 2A-C). The data were adjusted for body height [VLLs (mm/m) = unadjusted VLLs (mm)/body height (m)]. The l/u VLL ratio was also calculated. The right (instead of the left) lung was evaluated to eliminate the possible effect of cardiac shadow. VLLs were evaluated by two independent investigators and the results are expressed as a mean of the two estimates. The extent of the reticular pattern, honeycombing, and GGO on chest CT images were semi-quantitatively evaluated as follows: grade 0 (0%), grade 1 (< 25%), grade 2 (25-50%), grade 3 (50-75%), and grade 4 (> 75%) 29 . The definitions of reticular pattern, honeycombing, and GGO were according to the Fleishner Society criteria 30 . The %LAA on chest CT images was calculated using image-analyzing software (SYNAPSE VINCENT; Fuji Film, Tokyo, Japan).

Statistical analyses.
The randomization of patients with IIPs was stratified by sex and %predicted FVC.
One-to-one propensity score-matching was performed using age, sex, and BMI as co-variables. Continuous variables were compared by Wilcoxon's rank sum test and categorical variables by Fisher's exact test. The predictive values of VLLs for the diagnosis of IIPs were evaluated by multivariate logistic regression analysis. The cut-off values of VLLs for the diagnosis of IIPs were estimated by ROC analysis and determined using Youden's index (maximum value of [sensitivity + specificity − 1]). The correlations between VLLs and clinical factors were evaluated by Pearson's correlation analysis. The correlations of VLLs with the increased extent of lung abnormalities in the patients with IIPs were evaluated by the Jonckheere-Terpstra test. The inter-observer reproducibility was evaluated by intraclass correlation analyses. A p value < 0.05 (two-sided) was considered significant. All statistical analyses were carried out using JMP v13.0.0 (SAS Institute Japan, Tokyo, Japan), except The Jonckheere-Terpstra test was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).

Data availability
All data generated or analyzed during this study are included in this published article and Supplementary Information file.