Diagnostic value of Lung Function Test, Chest x-ray, and Pulmonary HR-CT in Detecting Interstitial Lung Disease at the Onset of Inammatory Rheumatic Diseases

Objectives: Interstitial lung disease (ILD) is a severe pulmonary complication in inammatory rheumatic diseases (IRD) and associated with a signicantly increased morbidity and mortality. Therefore, ILD screening in patients with IRD is essential. The objective of the present study was to determine the diagnostic value of pulmonary function tests (PFT), chest x-ray (CXR), and high-resolution computed tomography (HRCT) chest imaging in detecting ILD at the onset of IRD. Methods: The case-control study included 126 patients with new onset of IRD (patients with ILD: N = 63; control group: N = 63). If pathological ndings were observed in the screening tests (CXR or reduced carbon monoxide diffusion [DLCO] < 80 %), patients underwent a pulmonary HRCT. In addition, an immunological bronchioalveolar lavage (BAL) was performed in the ILD group as reference for the detection of ILD. Results: A reduced DLCO (< 80 %) showed a sensitivity of 83.6 % and specicity of 45.8 % compared to chest x-ray with 64.2 % and 73.6%, respectively, in detecting ILD. The combination of reduced DLCO and CXR revealed a sensitivity of 95.2 % and specicity of 38.7 %. The highest sensitivity (95.2 %) and specicity (77.4 %) was observed for the combination of reduced DLCO, chest x-ray, and pulmonary HRCT. Conclusion: At the beginning of the disease, IRD-patients with ILD show a reduced DLCO which could be a sensitive tool for ILD-screening in IRD at the onset of the disease. Only patients with pathological ndings in PFT and chest x-ray should undergo pulmonary HRCT. With this stepwise IRD-associated ILD screening approach, nearly 25 % of HRCT and therefore unnecessary radiation exposure can be avoided.


Introduction
Based on growing insights into immunopathological pathways, rheumatology has changed over the years from a discipline that focused mainly on joint diseases to a wide spectrum of in ammatory rheumatic diseases (IRD), encompassing in ammatory joint diseases, connective tissue diseases (CTD), myositis as well as vasculitis [1][2][3][4][5][6].
Many IRD present with complex clinical pictures, involving other tissues, of which the lungs are a frequent target of autoimmune-mediated injury (10% − 65% depending on the disease) [7][8][9][10][11][12]. In addition, lung involvement in IRD is associated with a signi cant morbidity and one of the leading cause of mortality in patients with systemic sclerosis (SSc) (10-year mortality rate of 31-71%) [13][14][15]. Among many diverse forms of IRD-associated lung involvements, most common is interstitial lung disease (ILD) which clinical manifestations and severity can vary from subclinical abnormality to dyspnoea, respiratory failure, and death [15][16][17].
Given the poor prognosis, effective screening to improve early diagnosis of IRD-patients with associated ILD is of paramount importance [15,16]. Currently, national and international guidelines recommend pulmonary high-resolution computer tomography (HRCT) based on the high sensitivity for detecting and monitoring lung involvement in patients with IRD [17][18][19][20][21]. In addition, immunological bronchoalveolar lavage (BAL) is a diagnostic cornerstone if ILD is suspected [18][19][20][21][22]. A surgical lung biopsy is not clinically necessary in most patients and only used in special circumstances and questions [18].
At the onset and diagnosis of IRD, an organ screening should be performed to detect lung involvement and other manifestations. However, despite the complex, multisystemic disease and risk of ILD with increased morbidity and mortality, only less than half of SSc-patients underwent a basic organ screening at the time of initial diagnosis, as shown in a survey with members of the Scleroderma Society of Canada [23]. According to various studies, 54 % to 65 % of patients with SSc or dermatomyositis presented with lung involvement at the onset of their disease [8,24]. Consequently, not every patient needs a pulmonary HRCT at initial diagnosis.
The aim of the study was to determine the diagnostic value of pulmonary function tests (PFT), chest xray, and HRCT of the lung for identifying patients with ILD at the onset of IRD. Nearly all participants underwent PFT including forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), total lung capacity (TLC), transfer factor of the lung for carbon monoxide (TLCO), and diffusing capacity for carbon monoxide (DLCO). DCLO < 80 % was considered as a reduced diffusing capacity.

Methods
An additional chest x-ray could be performed. Patients with at least one suspicious nding in PFT or chest x-ray underwent pulmonary HRCT. To exclude other causes of lung involvement, immunological BAL was performed in all patients who showed pathological ndings in the HRCT. ILD group (IRD-patients with newly diagnosed lung involvement) (see Table 1): Control group (IRD-patients without lung involvement) (see Table 1): In order to perform a comparison, 63 patients with newly diagnosed IRD without lung involvement acted as control group. These patients also underwent initial lung diagnostics with PFT, chest x-ray, and optional pulmonary HR-CT and immunological BAL in the Department of Rheumatology, University Hospital Jena/Germany. With this stepwise diagnostic approach and the absence of characteristic morphological changes, lLD-manifestations in these IRD-patients were excluded. Exclusion criteria were de ned as already known diagnosed IRD.

Statistical analysis
The data were documented in Microsoft Excel® (Microsoft Windows, Redmond Washington, USA). The statistically analysis was performed by IBM SPSS Statistics 25 (IBM SPSS Statistics, Chicago, Illinois, USA, for Windows). At the beginning, a case control matching was performed with the support of IBM SPSS Statistics 25. It was matched by gender, age, PFT, and chest x-ray. The tolerance/fuzz factor for age was 40.
In the following, a descriptive statistic was used to evaluate the data. The sensitivity and speci city were veri ed by crosstabs and receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) was used to summarize the diagnostic accuracy of the evaluated diagnostic test. According to Hosmer, a value of 0.5 suggest no discrimination by the test, 0.7 to 0.8 is acceptable, 0.8 to 0.9 is excellent and > 0,9 is considered outstanding [25]. Moreover, the following statistical tests were used to verify differences and to objectify correlations: t-test (t) and Pearson´s chi-squared test (χ 2 ) for independent samples. As correlations coe cients: Cramer´s-V (Cramer´s-V) as a measure of the strength of the relationship between more than two dichotomous characteristics. According to Cohen, for the correlation coe cient (Cramer´s-V): Small effect size 0.1 to < 0.3, medium effect size 0.3 to < 0.5, large effect size ≥ 0.5 [26]. A P < 0.05 was considered as statistical signi cant.

Results
Baseline characteristics (see Table 1): ). Cramer´s-V shows a medium effect size. Table 2 depicts the distribution of all included IRD diseases. Lung function test (see Table 3 and Fig. 1):  Chest x-ray (see Table 3 and Fig. 1): Chest x-ray revealed a sensitivity of 64.2 % speci city of 73.6 % in detecting ILD in IRD-patients. For IRDsubgroups, the sensitivity was 63.3 % for CTD-patients, 61.5 % for small vessel vasculitis, and 70.0 % for myositis with a speci city of 73.6 % for all three aetiologies.
Pulmonary HRCT and immunological BAL (see Tables 1 and  3): All ILD group-patients and 60.3 % in the control group underwent a HRCT of the lung. 17 patients (27.0 %) of the control group showed pathological ndings, resulting in a sensitivity and speci city of 100.0 % and 55.3 %.
If pathological ndings were observed on HRCT, patients were required to undergo an immunological BAL. In consideration of the immunological BAL, morphological changes in the control group in the pulmonary HRCT were mainly interpreted as post-in ammatory (scars) (N = 6; 9.5 %) or associated to smoking in the context of respiratory bronchiolitis interstitial lung disease (RB-ILD) (N = 7; 11.1 %).
Combination of chest x-ray and DLCO (see Table 4 and Fig. 1): Combination of chest x-ray, DLCO, and pulmonary HRCT (see Table 4): If the rst chest x-ray and DLCO (< 80 %) were combined and in the following pulmonary HR-CT was added (if ≥ 1 pathologic nding present), a sensitivity and speci city of 95.2 % and 77.4 % was achieved.
In total, with this stepwise approach 24.7 % of HRCT could be avoided, with a false negative rate of only 4.8 %.

Discussion
The aim of the present study was to determine the diagnostic value of PFT, chest x-ray, and pulmonary HRCT in detecting ILD in newly diagnosed patients with IRD.
Based on new therapeutic options (e. g. Nintedanib) for IRD-associated lung involvement in form of ILD as well as the increased mortality in patients with chronic systemic autoimmune diseases and pulmonary manifestations, evaluation of the lungs at the time of IRD-diagnosis is essential [27,28]. On the other hand, not all IRD patients show a lung involvement [7,29,30].

Chest x-ray
In our study, the sole use of chest x-ray yielded a low sensitivity (64.  [40]. This can be explained to a large extent by the different manifestations of these diseases [41]. HRCT and immunological BAL In our study, HRCT showed the highest sensitivity (100.0 %) with a speci city of 55.3 %. Thus, our results are consistent with the majority of studies, regarding HRCT generally as the gold standard for the diagnosis of ILD [8, 29,30,33,34,36,38]. In addition, the evidence-based European consensus statements for identi cation and management of ILD in SSc recommend that SSc-patients should be screened for ILD using HRCT, particularly if they are showing one or more risk factors [19]. However, it should be emphasized that HR-CT is highly sensitive in detecting pulmonary morphologic changes, but IRD-patients do not necessarily have ILD despite the presence of these changes. That is the reason why patients were partially excluded in some studies [33,34].
Only a few publications additionally focus on biopsy or immunological BAL to con rm the diagnosis of ILD [35,37,40]. Our present study demonstrated the utility of the immunological BAL. The HRCT shows a lack of speci city with 55.3 %, 17 patients showed morphological abnormalities in the pulmonary HRCT, but they were due to post-in ammatory changes (scars), smoker associated or other lung diseases. A immunological BAL could compensate this lack of speci city. Until now, comparable studies do not exist in the present literature for the assessment of the importance of the immunological BAL.

Combined examinations
As described in the literature before, also our study showed that a combination of several parameters of PFT did not increase speci city without a signi cant loss of sensitivity in detecting ILD [33,34].
We revealed a sensitivity and speci city to 93.7 % and 39.7 % if using a combination of PFT (DLCO < 80 %) and chest x-ray. Bernstein  or DLCO < 70 % [34]. With these algorithms, 40 % to 45 % of patients with ILD would be scored as false negatives. However, a screening algorithm in patients with newly diagnosed IRD should be highly sensitive (even accepting a poorer speci city), because it is already a pre-selected population with high risk of pulmonary involvement and high mortality over time.
A potential limitation of our study is the fact that we performed HRCT in IRD-patients with a DCLO < 80 %. Regarding the rules for the application of ionizing radiation, patients with a DLCO > 80 % underwent no pulmonary HRCT or only in justi ed individual cases. Consequently, the diagnostic value of the presented algorithm could be potentially overestimated, because an HCRT was not performed on every study participant.
Conclusion ILD in patients with in ammatory rheumatic diseases are associated with increased morbidity and mortality, whereas new effective treatment options are now available. Consequently, screening methods are crucial for early diagnosis of lung involvement.
DLCO combined with chest x-ray proved to be a potential screening tool for detecting lung manifestations in IRD-patients. Based on the high sensitivity of DLCO in combination with chest x-ray, all patients with a reduced DLCO (< 80 %) or/and a suspicious chest x-ray ndings should undergo pulmonary HRCT. To detect in ammatory activity in the lungs and to exclude other diseases for differential diagnosis, a immunological BAL should also be performed. With our stepwise approach algorithm, nearly 25 % of HRCT can be avoided. In addition, given the often impairing ILD-therapy with side effects, the diagnosis should not be made on the basis of HRCT alone. In ammatory rheumatic diseases were associated with interstitial lung disease, whereas the screening procedure at the onset of in ammatory rheumatic diseases is unclear Diffusing capacity for carbon monoxide (DLCO < 80 %) should be used to identify IRD-patients who require further lung imaging

Abbreviations
The combination of reduced DLCO (< 80 %), chest x-ray and pulmonary high-resolution computer tomography yielded the highest sensitivity and speci city in detecting of interstitial lung disease manifestation in the onset of in ammatory rheumatic diseases DLCO is a screening marker in in ammatory rheumatic diseases-associated interstitial lung disease Declarations