br Methods br Results br Discussion A



A B-line is a discrete, laser-like, vertical, hyper-echoic image that arises from the pleural line, extends to the bottom of the screen without fading and moves synchronously with respiration. It is formed by the reflection of the ultrasound beam from thickened subpleural interlobular septa (Lichtenstein et al. 1997). In patients with ILD, the subpleural interlobular septa are thickened by deposition of collagen and fibrous tissues. During LUS tests, the great impedance gradient between the thickened septa and air in the lung causes reflection of ultrasound beams, creating diffuse B-lines all over the lung surface (Hasan and Makhlouf 2014). The presence of B-lines at LUS examination correlates with ILD at HRCT (Gargani et al. 2009; Moazedi-Fuerst et al. 2014; Tardella et al. 2012).
In the present study, we found that all patients had diffuse B-lines on both sides of the lung. Likewise, pleural line irregularity and Am-lines are also useful LUS signs in the detection of ILD (Buda et al. 2016; Moazedi-Fuerst et al. 2015; Pinal-Fernandez et al. 2015; Sperandeo et al. 2009). We employed a semiquantitative method to comprehensively evaluate the severity of ILD and degree of pulmonary fibrosis, taking into account the B-lines, Pleural lines and Am-lines as described by Buda et al. (2016).
Moreover, our study found that patients with ILD complicated by PH had reduced RV function and higher lung ultrasound scores. With respect to pathophysiology, the cardiac and pulmonary systems are closely related. The ILD pathologic process goes through four stages (Wilkins and Lascola 2015): (i) the initial insult, which causes parenchymal injury and alveolitis; (ii) a proliferative phase characterized by cellular and parenchymal alterations in the tissues of the lung; (iii) development of interstitial fibrosis; and (iv) end-stage irreparable fibrosis of the lung.
These pathologic changes appear as a gradual increase in the number of B-lines and irregular pleural lines in the lung ultrasound. The structural changes that occur in the lung lead to hypoxic vasoconstriction, generation of vasoactive compounds (such as endothelin-1), acute and chronic changes in pulmonary vascular resistance and vascular anatomy and, eventually, development of pulmonary BAY 87-2243 (Jarman et al. 2014).
With the increased SPAP, RV structure and function will gradually be harmed by the increased afterload (Haddad et al. 2008). Therefore, traditional Echo and 2-D speckle tracking Echo analysis reveal increased SPAP and reduced RV function. This also explains the finding that LUS scores are correlated with SPAP and RV parameters. Nevertheless, except for SPAP, the correlation between LUS scores and RV parameters was weak. In addition to elevated SPAP, systemic inflammation and endothelial dysfunction may also lead to early right ventricular dysfunction (Aihara et al. 2013). Moreover, only some of the patients with PH progressed to right ventricular dysfunction at the time of examination. In a study of the effects of age, sex and obesity on RV volume and systolic function, it was reported that women had higher RV ejection fraction and there were no differences in RV ejection fraction across age categories (Foppa et al. 2016). In our study, there were fewer females in the ILDPH group (33.3%) than in the ILDNPH group (45%). This may also lead to a weaker correlation between ILD LUS scores and RV function.
In addition to a strong correlation between ILD LUS scores and SPAP, we found that a cutoff value (>16 points) predicted PH (SPAP >36 mm Hg). It was recently reported that number of B-lines >4 predicted elevated SPAP (>30 mm Hg) (Zheng et al. 2015). In comparison to our semiquantitative LUS scoring method, Zheng et al. evaluated only the number of B-lines. Similar to our results, Wangkaew et al. (2014), in a study of systemic sclerosis-associated ILD, found that there was a good correlation between HRCT scores and SPAP. In ILD patients, cross-sectional area of the pulmonary vascular bed, hypoxia vasoconstriction and pulmonary vascular remodeling have been found to affect PH (Caminati et al. 2013; Jarman et al. 2014; Nadrous et al. 2005; Nathan et al. 2008). Pulmonary fibrosis directly leads to change in the former two. On the other hand, generation of vasoactive compounds, downregulation of a fraction of endothelial cell genes and upregulation of the phospholipase A2 gene may play an important role in the ILD-PH pulmonary vascular remodeling (Gagermeier et al. 2005). However, pulmonary vasculopathy always leads to severe SPAP (Seeger et al. 2013; Steen 2005). In our study, most of the ILDPH patients developed mild PH; the mean SPAP of ILDPH was 52.5 mm Hg. Thus, in our study, the development of PH was presumably due to the decrease in cross-sectional area of the pulmonary vascular bed and hypoxia vasoconstriction. This further explains why for the good correlation found between ILD LUS scores and SPAP, the correlation coefficient was not particularly high (r = 0.735). Based on the preceding, it is not surprising to find that ILD LUS scores >16 points predicted elevated SPAP. LUS scores >16 points also indicate moderate or severe pulmonary fibrosis with histopathological features of thickened interstitia and honeycombing (Buda et al. 2016). With the extent of alveolar damage and abnormal incorporation of connective tissue and ongoing inflammation in this phase of ILD, pulmonary artery vasoconstriction might play an important role in the appearance of PH. However, the cutoff value of our study was obtained in a relatively small population; a multicenter study with a large population is necessary for further validation.