|Ahead of print publication
Descriptive study of the role of ultrasound in the evaluation of patients with interstitial lung disease associated with autoimmune connective tissue disorders
Varghese Koshy1, Kiran Patel2, Deep Yadav3, Puneet Saxena4, RA George5, Vandana Gangadharan5, George Koshy6
1 Department of Rheumatology & Clinical Immunology, Command Hospital Central Command, Lucknow, Uttar Pradesh, India
2 Department of Radiology, M H Shillong, Shillong, Meghalaya, India
3 Department of Radiology, C H Air Force, Bengaluru, Karnataka, India
4 Department of Pulmonary Medicine, Army Hospital (Research & Refferal), New Delhi, India
5 Department of Pathology, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India
6 Department of Community Medicine, INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
|Date of Submission||26-Jul-2021|
|Date of Acceptance||16-Oct-2021|
|Date of Web Publication||21-Apr-2022|
Department of Rheumatology and Clinical Immunology, Command Hospital Central Command, Lucknow - 226 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background and Aim: High-resolution computed tomography (HRCT) of the chest has been the conventionally accepted modality of radiological investigation utilized in the evaluation and management of interstitial lung diseases (ILDs). The aim of this study was to compare the utilization of lung ultrasound (LUS) as a radiological modality versus HRCT scan of the chest, in the diagnosis of cases of ILD in autoimmune connective tissue disease (AICTD) patients at a tertiary care center in Northern India.
Methods: In this descriptive study, 42 consecutive diagnosed cases of AICTD with clinical risk of ILD were included, between July 2016 and March 2019, attending the rheumatology outpatient department of CH WC. They were assessed with lung ultrasonography and HRCT chest. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LUS were estimated considering HRCT as the reference method.
Results: Of these 42 patients, 30 (71.4%) had abnormal LUS findings. HRCT findings suggestive of ILD were seen in 31 (73.8%). Considering HRCT as gold standard, LUS resulted in 01 false-positive and 02 false-negative results. Sensitivity and specificity of LUS with respect to HRCT were 93.55% and 90.91%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of LUS were calculated at 89.38% and 94.51%, respectively. In 91.6% (11/12) patients with nonspecific interstitial pneumonitis pattern on HRCT, B-lines were found to be numerous and compact (<3 mm distance between B lines). On the other hand, compact B lines were seen in only 21.1% (4/19) cases showing HRCT patterns suggestive of usual interstitial pneumonitis (UIP)/likely UIP, with a significant difference between the two (P = 0.0002).
Conclusions: LUS is as nearly sensitive and specific as HRCT chest in the detection of ILD and has the distinct advantage of being without radiation exposure.
Keywords: Autoimmune connective tissue disease, interstitial lung disease, lung ultrasound, nonspecific interstitial pneumonitis, usual interstitial pneumonitis
|How to cite this URL:|
Koshy V, Patel K, Yadav D, Saxena P, George R A, Gangadharan V, Koshy G. Descriptive study of the role of ultrasound in the evaluation of patients with interstitial lung disease associated with autoimmune connective tissue disorders. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 1]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=343635
| Introduction|| |
Interstitial lung diseases (ILD), also known as diffuse parenchymal lung diseases (DPLDs), are a varied group of more than 200 lung disorders involving the interstitium, i.e., tissue and space around the alveoli.,
An autoimmune-mediated chronic inflammation in the pulmonary interstitium may result in ILDs.
The good sensitivity and negative predictive values (NPV) of lung ultrasound (LUS) postulate this technique as a useful tool for the screening of ILD and for the optimization of the indications of high-resolution computed tomography (HRCT) in rheumatic diseases.
Although chest radiograph offers significant advantages for diagnosing ILDs including ease of performance, wide availability, low radiation dose and low cost, multiple studies have shown low sensitivity., Currently, HRCT is considered the gold standard for the diagnosis of DPLD and to assess the extent and the pattern of pulmonary involvement., Subpleural reticular pattern, patchy ground-glass opacities, nodular pattern, and honeycombing are the common HRCT signs of ILDs.
In resource challenged regions, ultrasound may emerge as an economically and clinically viable tool for the early diagnosis of ILD. This cross-sectional study was performed to compare the findings of LUS with HRCT, in patients of autoimmune connective tissue diseases (AICTDs) who are at risk of ILD and to study the association between LUS finding and the HRCT classification of ILD.
| Methods|| |
A total of 42 consecutive diagnosed cases of AICTD with clinical risk of ILD were included in the study.
Following history and clinical examination, the patients with AICTD, who were clinically suspected to be at risk for ILD were subjected to LUS and HRCT imaging of the chest. LUS and HRCT chest were done on the same day, with LUS being performed and reported prior to HRCT. LUS was performed and reported upon by two radiologists (DY or RG with 10-and 24-year experience, respectively). Ultrasound was done on GE HEALTHCARE LOGIQ P5 machine equipped using 4 MHz convex and 8–12 MHz linear probes. The patient was scanned in a sitting or supine position with arms raised above head, using the intercostal spaces as acoustic windows.
None of the patients had been diagnosed with ILD in the past. Informed consent was obtained from all the patients participating in the study. All the patients would have had to undergo HRCT evaluation of the chest based on clinical grounds, even if they had not been part of the study. All patients who were established to have ILD were also routinely subjected to two dimensional (2D) Echocardiography, especially with a view point to evaluate for pulmonary artery hypertension and patients with echocardiographic evidence of underlying heart disease were excluded from the study.
- Patients above 18 years of age, with preexisting autoimmune connective tissue disorders presenting as clinically suspected case of ILD.
- Patients <18 years of age
- Patients who had been diagnosed or had radiological evidence of ILD in the past
- Images that were difficult to interpret due to obesity, image quality, or positioning were excluded from the study
- Patients with 2D Echocardiographic findings suggestive of Left Ventricular failure, Underlying Coronary Artery Disease and Valvular heart disease
- Patients who were diagnosed with COPD in the past
- Contraindication to HRCT, e.g., pregnancy.
For patients who met eligibility criteria, LUS evaluation was performed and reported prior to reviewing the patient's HRCT of chest or other imaging. Following a modification of a previously described protocol of Lichtenstein et al., LUS was performed according to basic eight region sonographic technique according to Volpicelli et al. Linear probe of 8–12 Mhz and convex probe of 4 MHz were used for lung examination. Each hemithorax was divided into four areas: 2 anterior and 2 lateral. The anterior chest wall was delineated from the parasternal to the anterior axillary line and was divided into upper and lower halves (from the clavicle to the fourth-fifth intercostal space and from the fourth-fifth space to the diaphragm). The lateral area was delineated from the anterior to the posterior axillary line and was divided into upper and basal halves. Longitudinal and transversal scans were performed on the anterior and lateral aspects [Figure 1].
|Figure 1: Eight zone lung ultrasound examination. PSL: Parasternal line, AAL: Anterior Axillary line, PAL: Posterior axillary line|
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Presence of the following signs were considered for ultrasound pleuro-pulmonary findings of ILD: (1) a positive region was defined by the presence of three or more B-lines in a longitudinal plane between two ribs, i.e., in a single frozen frame; (2) a positive scan is defined by the presence of two or more positive regions bilaterally; and (3) pleural line abnormalities defined as thickenings greater than 2 mm.
ILD was defined as at least three B lines in a single-frozen frame in two or more lung fields [Figure 2] & [Figure 3].
| Results|| |
In all, 42 connective tissue disease (CTD) patients with clinical suspicion of ILD were evaluated by LUS followed by HRCT chest [Table 1].
|Table 1: Distribution of study participants based on demographic characteristics (n=42)|
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Of these 42 patients, 30 (71.4%) had abnormal LUS findings [Table 2].
|Table 2: Distribution of study participants based on presence of USG findings (n=42)|
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HRCT findings suggestive of ILD were seen in 31 (73.8%) [Table 3].
|Table 3: Distribution of study participants based on HRCT diagnosis (n=42)|
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Considering HRCT as gold standard, LUS resulted in 01 false-positive and 02 false-negative results. Sensitivity and specificity of LUS with respect to HRCT were 93.55% and 90.91%, respectively. Assuming a prevalence of 45% for CTD-associated ILD, positive and NPVs of LUS were calculated at 89.38% and 94.51%, respectively [Table 4].
Compact B lines were seen in only 21.1% (4/19) cases showing HRCT patterns suggestive of UIP/likely UIP [Figure 4]a & [Figure 4]b. On the other hand, in 91.6% (11/12) patients with NSIP pattern on HRCT, B-lines were found to be numerous and compact (<3 mm distance between B lines) [Figure 5]a & [Figure 5]b, with a significant difference between the two (P=0.0002) [Table 5].
|Figure 4: (a) Ultrasound pattern positive for usual interstitial pneumonitis pattern of Interstitial lung diseases. (b) Corresponding high-resolution computed tomography of the chest is positive for usual interstitial pneumonitis pattern of interstitial lung diseases|
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|Figure 5: (a) Known patient of systemic lupus erythematosus: Ultrasonography chest positive for interstitial lung diseases. (b) Corresponding high-resolution computed tomography chest positive for nonspecific interstitial pneumonitis pattern of ILD (Interstitial Lung disease)|
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|Table 5: Associaton between HRCT diagnosis and reduced distance between two B lines (<3mm) (n=30)|
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Means and proportions were calculated for the continuous and categorical data, respectively. Statistical difference in proportions was tested using the Chi-square test, and difference in means was tested using independent sample t-test. P < 0.05 was considered statistically significant. Data were entered in MS Excel 2013 and analyzed using the SPSS software version 21.0 for Windows package (SPSS Science, Chicago, IL, USA). Sensitivity, specificity, PPV, and NPV of LUS were estimated considering HRCT as reference method.
| Discussion|| |
ILD occurs in 18%−50% of patients who are suffering from CTD and is a cause of significant morbidity and resultant mortality.
However, depending on the epidemiologic study used, the overall incidence of CTD-ILD is estimated to be 15%, about 10%–90% of patients with CTDs will have lung involvement in their lifetimes.
The frequency of ILD had been reported to be 45% in systemic sclerosis (SSc), 20%–30% in rheumatoid arthritis (RA), 20%–50% in polymyositis/dermatomyositis (DM), up to 25% in Stevens − Johnson syndrome, and 2%–8% in systemic lupus erythematosus (SLE).
Due to progressive and irreversible course of CTD-related ILD (CTD-ILD), early diagnosis is crucial.,,
Conventionally, ultrasound has not been considered for the evaluation of lungs, because air prevents the progression of the ultrasound beam. Although this is true in a normal, aerated lung, but if there is increase in fluid/tissue in the interstitium or loss of air in alveoli, it opens the pulmonary acoustic window.
In normal lung, ultrasound waves are completely reflected by air. Thus, the only sonographically detectable structure in a normally aerated lung is the pleura, visualized as a hyperechoic horizontal line. The dynamic horizontal movement caused by pleural line moving with respiration is called “lung sliding.” In addition, reverberation artifacts, in form of hyperechoic, horizontal lines at regular intervals and parallel to the pleural line are known as “A-lines.” Lung sliding and A-lines represent normal or excessive aeration of the peripheral alveolar spaces.
Lung diseases that increase interstitial and alveolar fluids cause specific sonographic artifacts., The air content in the lung decreases and the acoustic mismatch between the lung and the surrounding tissues is lowered.,
This phenomenon results in the ultrasound beam getting reflected as “B-lines.” B Lines are defined as discrete, well-defined, laser-like, vertical, hyperechoic reverberation artifacts that arise from the pleural line, extend to the bottom of the screen without fading, and move synchronously with lung sliding.
The division of the chest into eight zones in our study was performed according to international consensus statement published by Volpicelli.
In their prospective study on 58 consecutive patients, Barskova T et al. evaluated the role of B-lines on LUS for the early detection of ILD in systemic sclerosis. With HRCT, ILD was detected in 88% of the systemic sclerosis population and in 41% of the very early systemic sclerosis population. A significant difference in the number of B-lines was found in patients with and without ILD on HRCT (57 ± 53 vs. 9 ± 9; P < 0.0001), with a concordance rate of 83%. LUS demonstrated a sensitivity and NPV of 100% for the detection of ILD in both systemic sclerosis and very early systemic sclerosis.
Cogliati et al. performed LUS on 39 RA patients undergoing lung HRCT for clinical suspicion of DPLD with sensitivity and specificity for LUS being calculated 92% and 56%, respectively.
CTD being a disease of predominantly young and middle ages, in our study, relatively young patients (<60 years) accounted for 30 (71.5%) cases. Thirty were female and 12 were male. RA was the most common CTDs with 27 cases (64%) while systemic sclerosis accounted for 10 cases (23%), SLE accounted for 4 cases (9%), and DM accounted for 1 case (2%).
In our study, sensitivity and specificity of LUS with respect to HRCT are 93.55% and 90.91%, respectively. Positive and negative predictive values are dependent on the disease prevalence. In line with the known prevalence rates, we presumed that approximately 45% patients of AICTD would suffer from AICTD-ILD. The calculated positive and negative predictive values of LUS were 89.38% and 94.51%, respectively.
Strengths of the study
Lung ultrasonography (USG) study was always performed before HRCT on all the patients to reduce observer bias. Second, in our study, we included patients with range of AICTDs; thus, our tests of diagnostic accuracy measures should also apply to similar spectra of AICTDs. Third, we performed sonography and HRCT for a single patient on the same day to minimize the effects of temporal changes in clinical condition on the analysis. Fourth, our study demonstrated the feasibility of performing LUS in the sitting or supine position. Furthermore, both linear and convex array probes were used in this study instead of the micro convex probe used in many other studies. This was chosen based on an assessment that the two probes most likely to be found in a resource-limited setting where a microconvex probe is rarely available.
Limitations of the study
This was a small, single-center study. Second, we did not test interobserver effects by performing a secondary analysis of ultrasound characteristics using an independent ultrasound-trained physician to classify the images. Third, although we treated each assessment as independent, we did not confirm whether intra and interindividual correlation altered our findings. Fourth, additional patients were excluded from the analysis if the duration of time between their LUS and HRCT was too long. These restrictions resulted in a small population for final analyses. Fifth, our study has selection bias, as our analyses may be biased toward known ILD patients. Furthermore, HRCT is a suboptimal gold standard when compared to histopathological diagnosis. Finally, our study is a single-center observational study, in contrast to the multi-center studies.
| Conclusions|| |
Our results demonstrate that LUS represents a useful tool for early diagnosis of ILD in known patients of autoimmune CTDs. It has many advantages over HRCT and PFT; it is a bedside procedure widely available, easily performed, inexpensive, requires no ionizing radiation and is therefore readily and largely accepted by the patient. In addition, it can reasonably differentiate between NSIP and UIP pattern.
Our study suggests ultrasound alternative diagnostic tool which is available in resource-limited settings and can be easily used in office/outpatient department settings for the detection of ILD.
- LUS can be utilized as screening imaging modality for suspected cases of ILD (not for diagnosis)
- Patients with a positive screening LUS must undergo HRCT to confirm and classify ILD
- In future studies, a lung USG scoring system can be devised based on density of B-lines and number of areas involved to increase the diagnostic accuracy
- A prospective study with larger sample size is recommended to follow the patients up with serial ultrasounds and spirometry with HRCT as required to study the evolution of ILD pathology on LUS, and also to see if any correlation of the severity of NSIP can be achieved with the number of “B” Lines on LUS.
Ethical clearance obtained from IEC Name of IEC-COMMAND HOSPITAL WESTERN COMMAND IEC Date of Approval-31 October 2016 IEC Number-CHWC 04–31/10/ 16
Taken from individual patients
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract (first of two parts). N Engl J Med 1984;310:154-66.
Pande JN. Respiratory Medicine in the Tropics. Oxford: Oxford University Press; 2001.
Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994;150:967-72.
Vicente-Rabaneda EF, Bong DA, Castañeda S, Möller I. Use of ultrasound to diagnose and monitor interstitial lung disease in rheumatic diseases. Clin Rheumatol 2021;40:3547-64.
Epler GR, McLoud TC, Gaensler EA, Mikus JP, Carrington CB. Normal chest roentgenograms in chronic diffuse infiltrative lung disease. N Engl J Med 1978;298:934-9.
Padley SP, Hansell DM, Flower CD, Jennings P. Comparative accuracy of high resolution computed tomography and chest radiography in the diagnosis of chronic diffuse infiltrative lung disease. Clin Radiol 1991;44:222-6.
Launay D, Remy-Jardin M, Michon-Pasturel U, Mastora I, Hachulla E, Lambert M, et al.
High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 2006;33:1789-801.
Desai SR, Veeraraghavan S, Hansell DM, Nikolakopolou A, Goh NS, Nicholson AG, et al.
CT features of lung disease in patients with systemic sclerosis: Comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology 2004;232:560-7.
Strickland B, Strickland NH. The value of high definition, narrow section computed tomography in fibrosing alveolitis. Clin Radiol 1988;39:589-94.
Volpicelli G. Lung Sonography. Journal of Ultrasound in Medicine. 2013;32:165-71.
Kundu S, Mitra S, Ganguly J, Mukherjee S, Ray S, Mitra R. Spectrum of diffuse parenchymal lung diseases with special reference to idiopathic pulmonary fibrosis and connective tissue disease: An eastern India experience. Lung India 2014;31:354-60.
] [Full text]
Koo SM, Uh ST. Treatment of connective tissue disease-associated interstitial lung disease: The pulmonologist's point of view. Korean J Intern Med 2017;32:600-10.
Castelino FV, Varga J. Interstitial lung disease in connective tissue diseases: Evolving concepts of pathogenesis and management. Arthritis Res Ther 2010;12:213.
Assayag D, Ryerson CJ. Determining respiratory impairment in connective tissue disease-associated interstitial lung disease. Rheum Dis Clin North Am 2015;41:213-23.
Keir GJ, Maher TM, Ming D, Abdullah R, de Lauretis A, Wickremasinghe M, et al.
Rituximab in severe, treatment- refractory interstitial lung disease. Respirology 2014;19:353-9.
Mathai SC, Danoff SK. Management of interstitial lung disease associated with connective tissue disease. BMJ. 2016;h6819.
Ziskin MC, Thickman DI, Goldenberg NJ, Lapayowker MS, Becker JM. The comet tail artifact. J Ultrasound Med 1982;1:1-7.
Piette E, Daoust R, Denault A. Basic concepts in the use of thoracic and lung ultrasound. Curr Opin Anaesthesiol 2013;26:20-30.
Soldati G, Copetti R, Sher S. Sonographic interstitial syndrome: The sound of lung water. J Ultrasound Med 2009;28:163-74.
Barskova T, Gargani L, Guiducci S, Randone SB, Bruni C, Carnesecchi G, et al.
Lung ultrasound for the screening of interstitial lung disease in very early systemic sclerosis. Ann Rheum Dis. 2013;72:390-5.
Cogliati C, Antivalle M, Torzillo D, Birocchi S, Norsa A, Bianco R, et al.
Standard and pocket-size lung ultrasound devices can detect interstitial lung disease in rheumatoid arthritis patients. Rheumatology (Oxford) 2014;53:1497-503.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]