Assessment of transthoracic sonography in patients with interstitial lung diseases

Aim: This study was designed to recognize the sonographic features of interstitial lung diseases (ILD). Furthermore, the possible correlations of these features with the functional and radiological parameters of the disease were assessed. Patients and methods: Forty-two patients with ILD were included; each patient underwent spirometry, Multi Detector CT chest (MDCT) and transthoracic sonography (TS). Fifteen healthy volunteers were also studied as controls. Results: The sonographic features among ILD patients were B lines in 73.8% , abolished lung sliding in 23.8%, irregular and thickened pleura in 47.6%and 35.7% respectively and subpleural lesions in 38.1%.Increasing distance between the B lines was negatively correlated with both of Forced Vital Capacity % predicted , ground glass opacities and positively correlated with reticular opacities patterns on MDCT chest. Conclusion: TS can be used as an additional imaging method for assessment of ILD and as a marker to estimate the severity of disease.


Introduction
Chest ultrasonography has many uses, both diagnostic and interventional. It is used in the diagnosis of diseases of the pleural space, such as pleural effusion, pleural thickening, pleural masses, and pneumothorax. It is also used in the diagnosis of diseases caused by lung parenchymal lesions, such as pneumonia, lung abscesses, neoplasms, pulmonary embolism, and arteriovenous malformations [1].
Interstitial lung disease (ILD) refers to a group of disorders that are characterized by varying combinations of inflammation and fibrosis involving the space between the epithelial and endothelial basement membranes [2].
High-resolution computed tomography (HRCT) should be considered the gold standard technique for the diagnosis of ILD, and many other noninvasive and invasive procedures concur in clinical practice to define and characterize ILD, such as chest radiography, laboratory and serological tests (e.g. angiotensinconverting enzyme and antinuclear antibodies), pulmonary function tests, bronchoscopy with bronchoalveolar lavage, and transbronchial lung biopsy [3].
However, some studies have demonstrated that transthoracic sonography (TS), as a consequence of its well-known advantages (absence of radiation exposure, ready availability, and cost-effectiveness), can play a complementary role in the diagnosis of ILD, especially when chest radiography or HRCT is not readily available or undesirable − for instance during pregnancy [4]. Moreover, TS can be useful in monitoring the course of the disease in patients with confirmed ILD (thus avoiding unnecessary overload of radiation exposure).
One study found that lung ultrasound can be used as a simple screening method for detection of ILD in very early systemic sclerosis [5].

Aim
This study was conducted to evaluate the TS features in patients with ILDs. Moreover, the possible correlations of sonographic findings with functional and radiological parameters of ILDs were assessed.

Patients and methods
This study was conducted in Minia University Hospital during the period from October 2014 to September 2015 on 42 patients with ILDs. The study protocol was approved by the Ethics Committee of the Faculty of Medicine, Minia University, and informed consent was obtained from all patients.
Diagnosis was based on the presence of dyspnea, cough, and other chest symptoms. Physical examination revealed inspiratory rales and clubbing in some cases with restrictive ventilatory defect on pulmonary function tests (PFTs) [6] on using ZAN 300 (Biomedica, Germany).
Results were obtained for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), ratio of FEV 1 / FVC (FEV 1 /FVC%), forced expiratory flow at 25-75% of vital capacity, and peak expiratory flow. Values were obtained while the patient exerted his or her maximum effort to avoid any expected error in diagnosis. The absolute values and the percentages of spirometric parameters predicted from the participant's age, sex, and height were calculated. Eight patients were excluded (four due to obesity and four due to inability to undergo pulmonary function tests).
Multidetector computed tomography (MDCT) of the chest without contrast using GE bright speed 16 detector/slice (General Electric, Germany) was performed on all patients. Computed tomography (CT) patterns were recorded as reticular changes, ground glass, nodules, honey combing, mosaic, and traction bronchiectasis. Any abnormalities on MDCT of the chest in the form of areas of consolidation and pleural effusions were also evaluated.
Twelve cases were diagnosed as idiopathic pulmonary fibrosis (based on exclusion of other known causes of ILDs and usual interstitial pneumonia pattern on HRCT in the form of basilar, subpleural reticular opacities, and honeycombing with or without traction bronchiectasis) [8]. Ten cases had hypersensitivity pneumonitis (based on the history of exposure to organic agents and HRCT findings of ground-glass opacity, centrilobular nodules, mosaic areas, and traction bronchiectasis in chronic cases) [9]. The HRCT of eight cases was consistent with nonspecific interstitial pneumonia in the form of ground-glass opacities with or without areas of consolidation, and reticular changes sparing subpleural areas [10]. Five cases had sarcoidosis stage II&#x2013;IV (based on peripheral lymph node biopsy) and seven cases had lymphangitis carcinomatosis (four cases due to bronchogenic carcinoma and three cases secondary to hematologic malignancies).

Transthoracic sonography
It was performed on all patients using Philips ClearVue 350 (USA) using both 2.5-5 MHz convex probe and 7.5-10 MHz linear probe for lung and pleural examinations. Patients were investigated in the supine or sitting position with their arms raised above heads to widen the intercostal space. Lung ultrasonography was performed in a series of scan lines along the chest wall with the transducer oriented either perpendicular or transverse to the chest wall. It was done using grayscale (B-mode), time-motion (M-mode), and color Doppler. TS was performed blindly with no knowledge of the clinical and radiological findings.
The following were assessed [11]: Presence or absence of lung sliding (the 'to-and-fro' dynamic movement of the lung during respiration that was visible at the pleural line).
Artifact type: A lines=anterior predominant bilateral A lines (horizontal hyperechoic lines below and parallel to the pleural line and associated with lung sliding).
B lines=anterior predominant bilateral B lines (vertical hyperechoic lines arising from the pleural line that spreads all the way to the edge of the screen without fading) erasing A lines and moving with lung sliding. It is also called 'comet tails' artifact. The distance between each of two adjacent B lines close to the pleural line was measured and expressed in milliliters; B3 and B7 means that the distance between two B lines was 3 and 7 mm, respectively [12].
AB lines=anterior predominant B lines at one side, and predominant A lines at the other side [13].
O line (non-A, non-B) defined as absence of any visible artifact, either horizontal or vertical, arising from the pleural line [14].
Assessment of pleura as regards pleural thickness, pleural surface (either smooth, irregular or interrupted), and presence of pleural effusion.
Pleural thickenings are defined as focal or diffuse echogenic lesions arising from the visceral or parietal pleura that are greater than 3 mm in width with or without an irregular pleural surface [15].
Pleural effusion was seen as a homogeneous, anechoic space between the parietal and visceral pleura [15]. Subpleural parenchymal findings as hyoechoic or isoechoic lesions were also recorded. The echogenicity of pleural fibrosis or thickening varies. It may be hypoechoic, which makes distinction from small pleural effusion problematic. A finding that favors fibrosis is absent respiratory movement of the lung pleural interface and the findings on color Doppler. Pleural fluid provides a color Doppler signal as small reflectors within the fluid move. Color signal from pleural fibrosis is generally absent [16].
The study also included 15 healthy volunteers as controls matched in age and sex with the studied patients. They had no history of previous respiratory diseases and their chest radiographs were normal. Pulmonary function tests and thoracic sonography were performed for them.

Statistical analysis
Data entry and analysis was performed using SPSS Inc. (Chicago, Illinois, USA), version 19 (Statistical Package for Social Science). Data were presented as number, percentage, mean, and SD. The χ 2 -test was used to compare between qualitative variables. Differences were considered statistically significant when P values were less than 0.05. Bivariate correlation using Spearman's test was used. Table 1 shows descriptive and clinical data among patients of ILD and controls. Table 2 shows PFTs and MDCT findings among the studied participants. Regarding pleural abnormalities, thickened pleura and pleural effusion were significantly higher among patients than among controls (35.7 vs. 0%, P=0.002, 33.3 vs. 0%, P=0.001 respectively). The subpleural parenchymal lesions were significantly higher in ILD patients compared with controls (38.1 vs.0%, P=0.007). Their sizes ranged from 15 to 20 mm. Ten of these lesions were hypoechoic and six were isoechoic (Figs 1-3).

Results
Regarding the correlation between B-line distance and pulmonary function tests, it was found that increasing B-line distance had a significant negative correlation with FVC% predicted only (r=−0.46, P=0.003) with no correlations with FEV 1 or FEV 1 /FVC (Fig. 4). Figure 5 shows that there was a significant positive correlation between increasing B-line distance and the reticular pattern on MDCT (r=0.51, P=0.004). In contrast, there was a significant negative correlation between B-line distance and ground-glass opacity (r=−0.41, P=0.02) (Fig. 6).
Considering the correlation of other sonographic findings of ILD with functional and radiological Data are presented as n (%). parameters of the disease, Table 4 shows that abolishing lung sliding is positively correlated with the reticular changes on MDCT, with no other correlations.

Discussion
The present study was designed to detect the sonographic features in patients with ILDs. On analyzing our findings, we found that the most predominant artifact type among patients with ILD was B lines (73.8%), followed by O lines (9%), A lines and AB lines (7.1% for each). Thirty-three and 47.6% of the studied patients had thickened and interrupted or irregular pleura, respectively. Abolished lung sliding was present in 23.8% of ILD patients (Table 3). A previous study of the sonographic lung surface in 12 patients with pulmonary sarcoidosis revealed that all patients had a rough, irregular pleural surface accompanied by an increase in comet tail artifacts [17].
Gargani et al. [18] found that 51% of systemic sclerosis patients had B lines as a hallmark of interstitial pulmonary fibrosis.
Under normal nonedematous or fibrotic conditions, bilateral B lines or comet tails are absent because no acoustic mismatch occurs as the ultrasound beam passes through the subpleural space [19]. Thus, none of the controls had bilateral B lines.  B lines are generated by the reflection of the ultrasound beam from thickened subpleural interlobular septa. In patients with heart failure, interlobular septa are thickened by water, and in pulmonary fibrosis, interstitial lobular septa are thickened by collagen tissue accumulation [20].
Histologically the interlobular septa are 7 mm apart when they reach the subpleural space, and this is roughly the distance between the origins of individual comet tails at the pleural line [21].
TS can detect ILD if the interstitium of the peripheral lung is involved [22]. The typical TS findings associated with pulmonary fibrosis include [23] the following: fragmentation and irregular thickening of the pleural line, especially in the lower lobes (findings that are independent of the severity of the disease); attenuation of the physiological gliding sign, which is related to the stage of the disease; immobility of the diaphragm, which is best visualized on a scan of the right chest when the patient is in the supine position (end-stage disease); and multiple reverberation artifacts (advanced stage).
All these abnormalities can be detected in both lungs, which is a reflection of the diffuse nature of the fibrotic process [22].
Subpleural parenchymal alterations in patients with ILD are visible in TS and comprise a broad    spectrum of pathologic changes, such as granuloma, pulmonary nodules, and pulmonary metastasis [4].
Reissig and Kroegel [4] found that one-third of ILD patients had subpleural alterations, of whom 85.7% had sarcoidosis, 66.7% had lymphangitis carcinomatosis, and 40% had silicosis. These alterations may represent granuloma in sarcoidosis and silicosis and tumor growth in lymphangitis carcinomatosis.
However, subpleural alterations and multiple comet tail artifacts are nonspecific. They may also occur in patients with chronic obstructive lung disease, bronchiolitis obliterans-organizing pneumonia, and pulmonary alveolar proteinosis, as well as after pneumonia and pulmonary embolism. It may be suggested that the number of comet tail artifacts is smaller and the affected area is more localized in these conditions [4]. In the current study, these abnormalities were detected on both sides of the lung, reflecting the diffuse fibrosing process and corresponding to the findings on MDCT as 16 cases had subpleural lesions on sonar and 19 cases had subpleural lesions on MDCT.
TS is the most sensitive technique, allowing very small amounts of pleural fluids of about 3-5 ml to be detected [24]. Pleural effusion may accompany ILD as well as a variety of other disorders, including heart failure, carcinoma, pneumonia, and pulmonary embolism, and thus is not specific. Among the 42 studied patients, 14 patients (33.3%) had pleural effusion ( Table 3); five of them had lymphangitis carcinomatosis, six had areas of consolidation at the side of effusion, and three cases had nonspecific interstitial pneumonia, whereas MDCT detected 12 cases of pleural effusions.
The second aim of the current study was to detect the possible correlation of sonographic findings with the functional and radiological pattern of ILD. It was found that there was a significant negative correlation between B-line distance detected sonographically and FVC% predicted (r=−0.46, P=0.03) (Fig. 4). This was in agreement with the findings of Gargani et al. [18] and Hasan et al. [25], who found that B lines inversely correlated with FVC, total lung capacity (TLC), and diffusion capacity of the lung for carbon monoxide (DLCO), as narrow distances between B lines (B3) represent early alveolar wall affection and little pulmonary function impairment, whereas wide distances between B lines (B7) indicate thickened septa and marked impairment in lung function.
In the current study, the reticular pattern on HRCT had a highly significant positive correlation with B-line distance (r=0.51, P=0.004) (Fig. 5) and a significant negative correlation between ground-glass opacity and Correlation between forced vital capacity (FVC%) predicted and Bline distance in patients of interstitial lung disease (ILD).

Figure 5
Correlation between reticular pattern on multidetector computed tomography (MDCT) and B-line distance in patients with interstitial lung disease (ILD).

Figure 6
Correlation between ground-glass opacities (GGO) and B-line distance in patients with interstitial lung disease (ILD).
B-line distance (r=−0.41, P=0.02) (Fig. 6). This was in agreement with the findings of Hasan et al. [25] and Assayag et al. [26] who found that the distance between each two adjacent B lines positively correlated with the degree of interstitial affection on using the Warick scoring system on HRCT.
It was found that abolished lung sliding only had a highly significant positive correlation with reticular opacities on MDCT (r=0.45, P=0.001) ( Table 4). This could be attributed to the fact that fibrosis affects the visceral pleura, which is followed by restriction of lung ventilation and expansion, which impairs lung sliding.
Pinal-Fernandez et al. [27] found that pleural irregularities were correlated with HRCT and pulmonary function test parameters in patients with systemic sclerosis and in those with antisynthetase syndrome, whereas in our study we found no correlation between pleural irregularities with pulmonary function tests and MDCT findings ( Table 4).
The present study had some limitations; one of them was that diffusion capacity of the lung for carbon monoxide and total lung capacity were not measured. Second, the sonographic findings according to the thoracic area examined in the patients are not mentioned. Lastly, we did not compare chest radiographic findings with sonographic findings among patients with ILD.

Conclusion
TS is a cost-effective noninvasive modality that requires neither ionizing radiation nor a contrast medium.
These advantages render it a complementary method for diagnosis of ILDs especially in situations where chest CT is not available or is contraindicated.
Bilateral B lines in combination with a thickened, irregular pleura and subpleural lesions are strongly suggestive of the presence of ILD. Increasing B-line distance can be used as a surrogate marker of pulmonary function deterioration and for the presence of fibrosis on chest CT.
Additional studies including a higher number of patients are needed to verify our results and to provide information on the feasibility of TS for early detection of ILD especially among patients with a high risk for developing ILDs.