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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 58-68

Imaging in connective tissue disease-associated interstitial lung disease


1 Department of Radiology, University Hospitals of Leicester NHS Trust, Leicester, UK
2 Department of Radiology, Southend University Hospital, UK
3 Department of Rheumatology, Southend University Hospital, UK

Date of Submission18-Oct-2021
Date of Acceptance18-Nov-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Praveen P G. Rao
Department of Radiology, University Hospitals of Leicester NHS Trust, Leicester
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.332979

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  Abstract 


Interstitial lung disease (ILD) in rheumatic or connective tissue disease (CTD) is well recognized and presents both diagnostic and management challenges to rheumatologists. Imaging plays a central role in diagnosing and assessing treatment response. Chest radiography is easily available and is usually the first imaging modality but is neither sensitive nor specific. Lung ultrasound (LUS) is an emerging modality to detect the presence and assess the evolution of ILD. There are established correlations of B-lines and subpleural interlobular septal thickening in ILD. LUS could be a useful tool in the early screening of younger patients at risk of ILD and in minimizing cumulative radiation exposure. High-resolution computed tomography (HRCT) remains the modality of choice in characterization, assessment of disease severity/progression, and response to therapy. Interpretation of HRCT in ILD is often challenging, but an emphasis on pattern recognition in the clinical context should lead to prompt diagnosis and management. The most common ILD pattern in rheumatic disease is nonspecific interstitial pneumonitis followed by usual interstitial pneumonitis. Other less common but well-recognized patterns are organizing pneumonia, lymphocytic interstitial pneumonitis, diffuse alveolar damage, and disease-modifying antirheumatic drug-related pneumonitis. A systematic approach with a focus on the dominant pattern, zonal distribution, and additional specific features such as necrobiotic nodules (rheumatoid arthritis) and dilated esophagus (systemic sclerosis) should, in a majority of the cases, lead to the right diagnosis. Comparison with any prior imaging and follow-up imaging aids diagnostic confidence and can prognosticate disease outcome. This article aims at describing the established CTD-ILD patterns and diseases with a pictorial review and emphasizes on emerging LUS technique.

Keywords: B-lines, connective tissue disease-interstitial lung disease, diffuse alveolar damage, nonspecific interstitial pneumonitis, organizing pneumonia, usual interstitial pneumonitis


How to cite this article:
G. Rao PP, Joshi K, Liyanage S, Dalili D, Koduri G. Imaging in connective tissue disease-associated interstitial lung disease. Indian J Rheumatol 2021;16, Suppl S1:58-68

How to cite this URL:
G. Rao PP, Joshi K, Liyanage S, Dalili D, Koduri G. Imaging in connective tissue disease-associated interstitial lung disease. Indian J Rheumatol [serial online] 2021 [cited 2022 May 28];16, Suppl S1:58-68. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/5/58/332979




  Introduction Top


Interstitial lung disease (ILD) in rheumatic or connective tissue disease (CTD) is one of the most severe and distressing respiratory complications with relatively high mortality. Although well recognized, CTD-ILD represents a challenge to rheumatologists in terms of early recognition, initiation or cessation of drugs, prognostic stratification, and disease outcomes. Disease-modifying antirheumatic drugs (DMARDs) and biological agents to treat rheumatic and autoimmune diseases can incite ILD[1],[2],[3] and may present an additional management dilemma. Imaging plays an important role in diagnosing and assessing the treatment response.

Chest radiograph (CXR) is usually the initial imaging modality as it is ubiquitous, inexpensive and confers a much lower ionizing radiation dose compared to thoracic high-resolution computed tomography (HRCT). CXR lacks sensitivity and specificity in the accurate detection of ILD.[4] However, it plays an important role in the diagnostic workup of ILD, especially before initiation of DMARDs, for an initial evaluation in symptomatic patients, and during follow-up [Figure 1]a and [Figure 1]b. CXR is also helpful in the detection of associated non-ILD features, such as acromioclavicular joint erosion or pleural effusion in a patient with rheumatoid arthritis (RA).
Figure 1: Chest radiograph of a 78-year-old male presenting with progressive breathlessness and diffuse bilateral pulmonary infiltrates (a) has a wide range of differential diagnoses. Additional subsequent history indicated the recent commencement of methotrexate for rheumatoid arthritis, a presumed diagnosis of methotrexate pneumonitis was made in the absence of clinical and biochemical markers of infection. Six weeks after drug cessation, the radiograph demonstrates near-complete resolution (b)

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HRCT is the gold standard imaging modality for diagnosis, characterization, assessment of disease severity/progression, and response to therapy in ILD.[5] [Figure 2]a and [Figure 2]b. HRCT provides a detailed morphologic depiction of the lung involved, even before any alteration of diffusion capacity of lungs for carbon monoxide (DLCO) is seen. After a diagnosis of CTD-ILD is established, yearly HRCT in the first 3 years should be considered to monitor the rate of disease progression.
Figure 2: Representative CT image Figure (a and b) of a 60-year-old female with anti-centromere and anti-Ro-positive interstitial lung disease demonstrating organizing pneumonia and limited ground-glass opacities (curved arrows), most obvious in the right middle lobe (arrow). Six months after steroids, follow-up CT at the same level shows good treatment response

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  High-Resolution Computed Tomography Patterns of Interstitial Lung Disease Top


Interpretation of HRCT patterns of ILD is often challenging even to the experienced. Even in the best of the specialist centers worldwide, about 30% of ILD cannot be accurately characterized before biopsy despite specialist multidisciplinary discussion.[6] In addition, ILD may overlap with and indeed coexist with atypical infections [Figure 3]a, heart failure, pulmonary hemorrhages [Figure 3]b, drug-induced ILD (DI-ILD) [Figure 3]c, and occasionally with lung cancer. Skillful HRCT interpretation requires a good understanding of detailed lung anatomy and architecture [Figure 4]a, understanding the correlative disease pathophysiology and histological processes [Figure 4]b in the context of clinical presentation and inflammatory/autoimmune markers.
Figure 3: CT chest of a 29-year-old male with no medical history presenting with acute breathlessness requiring high flow oxygen, CT chest (a) demonstrates bilateral nodules of varied sizes on a background of diffuse ground-glass opacities (GGO). Note absence of traction bronchiectasis. CRP was only mildly raised. He was treated for a probable autoimmune disease, but the final diagnosis was an atypical viral infection (not COVID). A 54-year-old female presenting for the first time with a relatively short onset of breathlessness, representative CT chest (b) shows diffuse bilateral GGO distinctly sparing the subpleural lung. Subsequent investigations revealed high antineutrophil cytoplasmic antibody titers, consistent with eosinophilic granulomatosis with polyangiitis-related diffuse pulmonary hemorrhage. A 78-year-old male presented with progressive breathlessness (for CXR, refer to Figure 1a). Representative CT (c) shows diffuse GGO and interstitial thickening on a background of emphysema. He was recently started on methotrexate for rheumatoid arthritis, the temporal and causal factors point to methotrexate pneumonitis

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Figure 4: Secondary pulmonary lobule schematically represented in Figure a. Representative correlative computed tomography image (b) at the right posterior lung base demonstrates abnormal interlobular smooth thickening (thin arrow) indicating interstitial edema or lymphatic obstruction and central tree-in-bud nodularity (curved arrow) indicating impacted secretion or infection in the terminal bronchiole and acini which is typically but not exclusively seen in tuberculosis

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  Common High-Resolution Computed Tomography Terminologies, Description, and Associations Top


Certain imaging and pathological descriptions imply key features that are likely to indicate certain histopathological processes. It is outside the remit of this article to enlist and describe all the features. CTD-ILD-relevant HRCT terms/descriptions are listed in [Table 1] with representative imaging.
Table 1: Relevant high-resolution computed tomography terms to describe the findings in connective tissue disease-interstitial lung disease

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  Practical approach to Interstitial Lung Disease: Useful High-Resolution Computed Tomography Diagnostic tips Top


  1. Interpret HRCT in the clinical context and autoimmune assay where possible.
  2. Avoid generalized impressions, instead identify the dominant pattern (s), and use algorithms.
  3. CTD-ILD can be chronic and/or dynamic, review any previous relevant imaging for any subtle or early clues. Some CT-ILD are based on exclusions and occasionally will require repeated serial scans for a disease pattern to manifest.
  4. Distribution or concentration of lung patterns favors particular diseases, e.g., typical usual interstitial pneumonitis (UIP) pattern is dominant at the lung bases with obvious honeycombing [Figure 10], and co-existing lung nodules that may cavitate (necrobiotic nodules), [Figure 12]a and [Figure 12]b should suggest RA.
  5. Often, there is an overlap of different patterns with wide differential diagnoses. Concentrating on the key distinctive, most relevant and typical patterns will help in narrowing the differential diagnoses. For example, the presence of striking mosaic lung attenuation/air trapping on a background of upper and mid-zone established fibrotic lungs strongly suggests chronic hypersensitivity pneumonitis-related ILD and should prompt clinicians to interrogate for an exposure history or incriminating/inciting inhalation etiology such as keeping birds or DI-ILD.
  6. Dilated main pulmonary trunk (MPA) >32 mm [Figure 13]a and/or reversal of aortopulmonary ratio may suggest pulmonary hypertension, and in ILD, it indicates worse prognosis, particularly in systemic sclerosis (SSc).
Figure 5: Traction bronchiectasis at right lung base is a hallmark of established interstitial lung disease (ILD). It implies tractional bronchial dilation due to adjacent parenchymal distortion secondary to fibrotic process. Traction bronchiectasis is usually associated with some loss of lung volume in the context of ILD is irreversible. However, in the context of acute infection or acute respiratory distress syndrome, traction bronchiectasis is potentially reversible. More obvious traction bronchiectasis (curved arrow) in a patient with scleroderma (note dilated fluid filed distal esophagus, bold arrow). Also note subpleural reticulations at both the lung bases (arrow)

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Figure 6: (a) Subpleural lines (arrow) without traction bronchiectasis in the right lower lobe usually suggests nonspecific interstitial pneumonitis (NSIP). Note parenchymal distortion and traction bronchiolectasis (anteriorly) in the same lobe in a 39-year-old male with known sarcoidosis. Central and peripheral ground-glass opacities (GGO) in the left upper lobe with subtle subpleural reticulations (*) are also more suggestive of NSIP pattern than pulmonary sarcoidosis-related fibrosis. (b) Subpleural cysts/reticulations anteriorly in both upper lobes with no appreciable GGO and presence of early honeycombing (bold arrow) posteriorly in the right lower lobe in a 60-year-old male with rheumatoid arthritis and usual interstitial pneumonitis pattern interstitial lung disease

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Figure 7: Diffuse bilateral centrilobular micronodular pattern (a) in a 69-year-old female has a wide D/D including tuberculosis, metastasis, and smoking-related interstitial lung disease (respiratory bronchiolitis interstitial lung disease). Note single cyst in the left upper lobe (curved arrow). Open-lung biopsy surprisingly confirmed Langerhans cell histiocytosis. Subtle bilateral patchy perilymphatic predominant central fine nodular pattern (b) is consistent with sarcoidosis. This 42-year-old male had bilateral hilar and mediastinal lymphadenopathy (not shown)

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Figure 8: Representative axial images (a and b) of a 66-year-old female with known Sjogren's syndrome demonstrating bilateral multiple thin-walled perivascular cysts (arrows) and multiple nodules (bold arrows) on a background of ground-glass opacities. Several nodules significantly progressed to lung masses, were eventually confirmed to be lymphomatous deposits

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Figure 9: Honeycombing in two different patients with rheumatoid arthritis. Honeycombing can occur in any lobe but predominantly occurs at the bases. Honeycombing can be symmetrical (typical usual interstitial pneumonitis pattern) or asymmetrical. It usually represents late stages of fibrosis. Macro-honeycombing (palisades of cyst 0.5 mm to 2 cm, arrows) seen in the right base (a and b) is considered to be worse in prognosis than micro-honeycombing (<0.5 mm, curved arrow) which is best appreciated in the left lung base (b). Note small bilateral dependent pleural effusions (*)

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Figure 10: Representative coronal computed tomography [Figure 10] image of a 60-year-old male with progressive usual interstitial pneumonitis pattern of interstitial fibrosis. Note the clear bi-basal dominant fibrosis and honeycombing (arrow). The presence of increased ground-glass opacities (curved arrow) is a little unusual and is likely to represent active pneumonitis/inflammation at the time of presentation

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Figure 11: A 77-year-old female with known rheumatoid arthritis presenting with new-onset severe breathlessness. Representative axial computed tomography images demonstrate diffuse basally dominant patchy ground-glass opacities and mosaic lung attenuation (arrows) with relative sparing of lung apices. Also note multiple bilateral traction bronchiectasis and bronchiolectasis, indicating early organizing phase of diffuse alveolar damage. She had a recent chest infection treated with antibiotics. This was treated as acute interstitial pneumonitis, secondary to possible chest infection

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Figure 12: Representative axial computed tomography images (a and b) of a 75-year-old male with rheumatoid arthritis demonstrate bronchiectasis, traction bronchiectasis (curved arrows), and multiple bilateral peripheral solid/cavitating rheumatoid necrobiotic nodules (arrows)

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Figure 13: Representative axial and coronal computed tomography images (a and b) of a 60-year-old female with progressive systemic sclerosis and established nonspecific interstitial pneumonitis pattern of interstitial fibrosis characterized by subpleural lines (arrows), ground-glass opacities (bold arrows), and traction bronchiolectasis. The main pulmonary artery is dilated at 35 mm which suggests pulmonary hypertension and indicates worse prognosis

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  Common Patterns in Rheumatological Disease Top


The most common ILD patterns in CTD-ILD are nonspecific interstitial pneumonitis (NSIP) and usual interstitial pneumoniatis. Less common but well-recognized patterns are organizing pneumonia and pneumonitis which can also be secondary to DMARDs.

Nonspecific interstitial pneumonitis

Nonspecific interstitial pneumonitis is the most common pattern of ILD seen in CTDs. It can occur in nearly all collagen/connective tissue disorders with thoracic manifestations. The common presenting symptoms with NSIP are dyspnea, cough, and fatigue which progressively worsen over several months. There is no gender predilection or correlation with smoking.[7] Histologically, the disease process is characterized by temporally and spatially homogeneous inflammation and fibrosis. NSIP can be subdivided into cellular or fibrotic subtypes. In the milder cellular NSIP subtype, the inflammation occurs without a major fibrotic component. It may subsequently improve or resolve spontaneously or with treatment. Whereas, in fibrotic NSIP, the fibrotic element is the main underlying feature, and is unlikely to respond to treatment and has a worse prognosis.[8]

Initial CXR may be normal in NSIP. With progression, lower zone predominant reticular and ground-glass opacities (GGO) develop in a bilaterally symmetrical pattern with both central and peripheral distributions. In the cellular subtype, the GGOs are the predominant feature. With fibrotic NSIP, reticular opacities representing fibrosis can be seen with resultant traction bronchiectasis[9] and no to minimal honeycombing may be seen in addition to GGO. The imaging abnormalities seen in NSIP persist in a majority of the patients. The GGO may improve with time, but the reticular abnormalities/fibrosis persist and can progress to a more UIP-like pattern over time.[10] Fibrotic NSIP cannot be sometimes reliably differentiated from UIP and may require an open-lung biopsy to confirm. Curvilinear sparing of the immediate subpleural lung parenchyma and positive autoimmune screen favour NSIP over UIP [Figure 6]a and [Figure 13]a.

Usual interstitial pneumonitis

Although UIP can occur with several CTDs, it is most strongly associated with RA. Clinical features of UIP include gradual onset of dyspnea and cough. UIP is seen more commonly in men, with smoking and recurrent micro-aspirations being the other risk factors.[7] The histologic appearance of UIP is characterized by basally dominant patchy interstitial fibrosis and honeycombing interspersed with normal lung parenchyma.[8]

As with NSIP, the initial CXRs may be normal. As the disease progresses, peripheral reticular opacities are seen in the lower zones with progressive reduction of the lung volumes.[11] On CT, there are subpleural reticular opacities with honeycombing which demonstrate an apicobasal gradient. The presence of basal dominant honeycombing strongly favors a typical UIP pattern. The fibrotic process results in loss of normal pulmonary architecture and traction bronchiectasis [Figure 9]a and [Figure 9]b. GGOs may be present, but they are not the predominant finding as in NSIP.[12] Longitudinal studies have shown that the extent of disease generally worsens over months or years[10] [Figure 14]a and [Figure 14]b.
Figure 14: Representative matched axial computed tomography (CT) images (a and b) of a 60-year-old male demonstrating the marked progression of usual interstitial pneumonitis pattern interstitial fibrosis over a 5-year interval. He presented with severe shortness of breath. On the latest CT (b), in addition to marked progressive honeycombing (arrow) and traction bronchiectasis, there is loss of lung volumes. The diffuse ground-glass opacities is likely to represent active inflammation

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Organizing pneumonia

Organizing pneumonia (OP) is also known as cryptogenic organizing pneumonia (COP) or broncho-obliterative organizing pneumonia (BOOP). Dermatomyositis/polymyositis (DM/PM) and RA are commonly associated with OP patterns, although it may also be seen with progressive systemic sclerosis (PSS), systemic lupus erythematous (SLE), and mixed connective tissue disorder (MCTD). Immunosuppressive treatments including biological agents (e.g., rituximab and tocilizumab) have been implicated to induce OP pattern ILD.[1] Patients with OP develop subacute onset of cough, dyspnea, and even fever. Like NSIP, there is no gender predilection or association with smoking.[7] The key histologic feature of OP is polyps of granulation tissue that develop in the distal airway and alveoli.[13]

In OP, CXR demonstrates multifocal, usually, bilateral airspace opacities which can be migratory on serial studies. The fleeting pattern can occur with or without treatment.[14] On CT, the abnormalities vary from patchy solid to ground-glass consolidation of variable sizes, generally in a peripheral or peribronchial distribution [Figure 15]a and [Figure 15]b. Air bronchograms and mild cylindrical bronchiectasis are commonly present.[15] Perilobular opacities/consolidations and the reversed halo sign [also called atoll sign, [Figure 15]c], where a region of GGO is surrounded by a rim of consolidation, may be seen.[7]
Figure 15: Representative axial images (a and b) of a 47-year-old female with mixed connective tissue disease. Computed tomography 4 months apart demonstrates rapidly progressive fibrosing organizing pneumonia, consistent with the underlying connective tissue disease phenotype, with possible contribution from recent infection as a trigger. The focal peribronchial ground-glass opacities in the right lower lobe has progressed to bilateral patchy peribronchial and perilobular (arrow) central and peripheral consolidations. (c) Reversed halo sign or atoll sign (curved arrow) in a different patient with mixed connective tissue disease-related organizing pneumonia

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OP normally responds well to the cessation of the incriminating factors if known, or to corticosteroid therapy. Relapses may occur when treatment is stopped. The consolidative areas can gradually evolve into a more ground-glass type consolidation with areas of reticulations giving a more NSIP-like pattern.[16]

Lymphocytic interstitial pneumonitis

Idiopathic lymphocytic interstitial pneumonitis (LIP) is rare. It is classically associated with Sjogren's syndrome but may be seen with RA or SLE. LIP occurs more commonly in women and presents with gradually progressive cough and dyspnea. On histology, there is diffuse infiltration of the interstitium by lymphocytes, plasma cells, and histiocytes resulting in widening of the alveolar septa. Reactive lymphoid follicles develop in the distribution of pulmonary lymphatics.[7]

CXR features of LIP can be nonspecific. Basal predominant reticular or reticulonodular opacities, with or without alveolar GGO, may be present. The characteristic CT finding in LIP is that of thin-walled perivascular cysts on a background of solid/ground-glass nodules [Figure 8]a and [Figure 8]b. Other associated findings include ill-defined centrilobular nodules, thickening of the bronchovascular bundle, and interlobular septa.[17]

In most cases, the GGOs improve. The cysts, however, remain and can progress to honeycombing.[18] Patients with LIP are at risk of lymphoma.

Diffuse alveolar damage

Systemic lupus erythematosus and DM/PM may rarely present with acute respiratory symptoms secondary to diffuse alveolar damage (DAD). DAD is characterized by an early exudative phase with noncardiogenic pulmonary edema, hyaline membranes, and inflammation, followed by a chronic organizing phase with alveolar septal fibrosis and type II pneumocyte hyperplasia.[19] Acute interstitial pneumonia (AIP) is DAD of unknown cause and can occur acutely in preexisting ILDs. The histological pattern is indistinguishable from that of acute respiratory distress syndrome.[20],[21]

Patchy bilateral airspace opacities with air bronchograms are seen on CXR. In the early phase, CT demonstrates extensive geographic ground glassing [Figure 11]a and solid consolidation with focal lobular sparing. Most often, there is a basilar predilection. In the chronic phase, there are bronchovascular distortion, tractional changes, and honeycombing.[7] DAD has a relatively poor prognosis. CT findings in long-term follow-up of survivors are reticular opacities with parenchymal distortion in the anterior distribution with areas of hypoattenuation and lung cysts.[22]


  Systematic Approach to Interstitial Lung Disease- Associated with Connective Tissue Diseases Top


When evaluating the HRCT in a patient with CTD-ILD, an attempt must be made to identify the predominant feature on the scan.


  Reticular Opacities Top


If reticular opacities are present, i.e., a fibrosing type of ILD, the main diagnoses to consider are UIP and NSIP. A clear apicobasal gradient and honeycombing strongly favor UIP [Figure 9]a, [Figure 9]b and [Figure 10]. If the patient has underlying RA UIP pattern of fibrosis, is most common, but there may be other associated chest findings such as pleural effusion or thickening, rheumatoid nodules, or bronchiectasis. With NSIP, although lower zone predominant, a clear apicobasal gradient is not usually seen. NSIP is typically associated with more GGO, and the presence of a dilated/patulous esophagus should suggest SSc [Figure 16]a and [Figure 16]b. Nodules, cysts, mosaic lung attenuation, and honeycombing are uncommon in NSIP. In clinical practice, however, distinguishing between the two entities can be difficult, particularly between fibrosing NSIP and UIP. However, this distinction is prognostically important as 5-year and 10-year survival rates for idiopathic UIP are 43% and 15%, respectively.[23] At the other end of the spectrum, idiopathic cellular NSIP and DIP have a survival rate of nearly 100%.[24],[25]
Figure 16: Representative axial computed tomography images (a and b) at the lung bases demonstrate nonspecific patchy diffuse ground-glass opacities and early tractional bronchiolectasis, suggestive of nonspecific interstitial pneumonitis pattern. The presence of dilated/patulous esophagus should alert progressive systemic sclerosis as the etiology

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  Ground-Glass Opacities Top


Ground-glass opacities are most commonly seen in NSIP. GGOs in a peribronchial or perilobular distribution with areas of consolidation, possibly with a reversed halo sign [Figure 15]c, favour OP. Clinically, OP has a more subacute onset compared to NSIP or UIP. Serial imaging may show the fleeting nature of the opacities. Diffuse or patchy widespread bilateral GGOs with acute onset of symptoms may be due to DAD. GGOs are also a feature of LIP where they are lower zone predominant. The presence of thin-walled perivascular cysts [Figure 8]a and [Figure 8]b, particularly in a patient with Sjogren's syndrome, should help in making this diagnosis.

GGOs in atypical infection (viral, e.g., influenza) tend to be upper zone dominant and patchy and may be associated with more focal small centrilobular nodules, but typically, traction bronchiectasis is absent [Figure 3]a. Inflammatory GGOs in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, e.g., eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA), tend to be more conglomerate or diffuse and peripheral, usually in the mid and lower zones. They may initially present with diffuse GGO or pulmonary hemorrhage [Figure 3]b but over 1–10 years mostly develop a typical UIP pattern fibrosis with limited mild GGO.[26]


  Ultrasound in the Evaluation of Interstitial Lung Disease Top


Although HRCT detects both early and subclinical lung changes; its routine use is limited by high costs and radiation exposure, especially in disease evaluation and monitoring of chronic conditions. The equivalent radiation dose for an average chest HRCT is 2 millisievert, which corresponds to the radiological exposure of 50 CXRs.[27] Therefore, there is a need for an accurate, nonionizing diagnostic tool for ILD detection. Generally, patients with a very early diagnosis of ILD are young or middle-aged, and any efforts to avoid their exposure to ionizing radiation are prudent. In fact, in many fields of medicine, there is a large interest in reducing radiation exposure in the management of chronic diseases.[28] The ability to identify the first signs of ILD with a high sensitivity could make lung ultrasound (LUS) application crucial in the management of patients, particularly young patients who require frequent serial imaging to assess the natural history of the disease.

LUS has proven useful in the assessment of ILD through identification of frequency of B-lines, irregularities in the pleural lining and subpleural alterations.[29] Studies have established correlations between the appearance of B-lines and subpleural thickening of interlobular septa in ILD and alveolar edema.[30],[31],[32]

B-line artifacts (BLA) (also known as comet-tails) are vertical hyperechoic reverberations appearing as bright projecting lines that originate from the pleural line and extend to the bottom of the ultrasound screen.[33] They do not fade and appear to move in tandem with the sliding lung during respiration.[34] While B-lines can be normal variants, they would have to occur in smaller numbers (<5) and be seen in the lower lung to be deemed as nonpathological.

As B-lines are artifacts caused by physiological changes in aeration of the lung parenchyma and increase in lung density,[35],[36],[37] ultrasound machine variations such as probe type, probe frequency, and harmonics can affect B-line assessment. Various studies have explored a range of ultrasound frequencies [as demonstrated in [Table 2]], however, a consensus has been made that convex[38] or micro-convex[29] probes with an intermediate frequency of 3–5 MHz are the best options for detecting B-lines in LUS. While high-frequency linear probes may provide greater detail of pleural and subpleural changes, the penetrative depth provided at these frequencies would not be enough to verify if an artifact is a true B-line and, therefore, lower frequency probes are preferable when investigating BLA.[39],[40] Furthermore, the studies detailed in [Table 2] had differing cutoff points at which the number of B-lines would be classed as pathological and how many intercostal spaces should be imaged. This is still a topic for debate, as it can result in over- or under-calling ILD diagnosis on ultrasound. Most commonly 5 lines and 10 lines are chosen as cutoff points and between 8 and 72 intercostal areas are imaged.
Table 2: Lung ultrasound studies in various connective tissue diseases

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Lung ultrasound has been explored a lot in the last decade. The evidence so far demonstrates that LUS is superior to conventional CXR for detecting ILD, considering its very high negative predictive value.[30] Previous studies found a significant correlation between Warrick HRCT-score and B-lines in CTD. The studies are detailed in [Table 2].[39],[41],[42],[43],[45],[46],[47],[48],[49],[50],[51],[52],[53]

Rheumatoid arthritis studies

Two studies evaluated sonographic B-lines and compared them with HRCT, and one of the studies demonstrated a negative predictive value of 95%, a positive predictive value of 52%, sensitivity of 74%, and specificity of 88%.[39] Another study showed an even better sensitivity of 92% and specificity of 56% compared to HRCT.[41]

Lung Ultrasound in connective tissue disease-associated interstitial lung disease

There are several studies in CTD including systemic sclerosis, Sjogren's syndrome, and anti-synthetase syndrome. In comparison to healthy controls, more frequent pleural, subpleural, and B-lines were found in CTD. A positive correlation of sonographic B-lines with HRCT Warrick score was found in these studies, with LUS sensitivity ranging from 78% to 100% and specificity ranging from 89% to 99% in detecting ILD.[42] Another study evaluated whether LUS is reliable in the screening of ILD. The presence of B-lines on LUS examination correlated with ILD at HRCT, providing a sensitivity and negative predictive value of 100% in both established SSc and very early SSc.[43] The meta-analysis supported these data showing that the number of B-lines had a good correlation with the HRCT fibrosis pattern and good diagnostic accuracy in terms of sensitivity (91.5%) and specificity (81.3%).[44]

Since LUS is a noninvasive and nonionizing modality, rheumatologists have attempted to use it to assess the presence of CTD-ILD. A literature review has shown that the number of B-lines had a good correlation with the HRCT fibrosis pattern with good diagnostic accuracy and sensitivity,[44] expanding the armamentarium for diagnosis and follow-up of CTD-ILD. However, the appropriate place of LUS in the diagnostic or follow-up algorithm of ILD patients has not been identified. Thus, the opportunity to use LUS as a referral model in clinical practice is conceivable but theoretical at present. LUS could potentially be placed as the first pulmonary imaging technique in subjects with suspected ILD.

Compared to LUS, CXR showed lower sensitivity but higher specificity, suggesting that LUS and CXR have complementary uses. CXR permits a panoramic view of the thoracic surface, the detection of abnormalities of the inner portion of the lung (perihilar area), and the identification of lung nodules/masses. In the clinical setting, the combined use of LUS and CXR might be an effective approach to identify patients needing further investigation by HRCT, and assigning asymptomatic patients with negative LUS and CXR to follow-up.

Most studies included small cohorts of patients, therefore, there is no standardized approach for LUS examination in ILD. LUS is a good diagnostic technique for its repeatability, low cost, and low risk. There are no data available yet for the role of LUS in the follow-up and hence future studies are required to evaluate the role of LUS in the follow-up of ILD. If these data are confirmed in a large cohort of patients, LUS may become a useful screening technique for the early detection of ILD and would also guide the timing of HRCT.


  Ultrasound for Interstitial Lung Disease Top


Case study 1

Normal HRCT shows the well-defined smooth curvilinear pleural interface. Corroborative LUS image demonstrates smooth pleura (arrows) with no B lines [Figure 17].
Figure 17: Normal high-resolution computed tomography, note the well-defined smooth curvilinear pleural interface. Bottom LUS image demonstrates corroborative smooth pleura (arrows) with no B-lines

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Case study 2

Mild ILD – A 74-year-old man was diagnosed with RA in 2019. He was started on hydroxychloroquine given the low disease activity, but his arthritis got worse after 18 months which required treatment escalation. He had a CXR before the initiation of methotrexate, which showed possible early ILD changes. Therefore, he had a further HRCT for confirmation of pattern and severity of ILD [Figure 18].
Figure 18: (a) Curvilinear low-frequency probe showing multiple discrete B-lines (arrows) in the right lung base. (b) Linear high-frequency probe showing a thickened irregular fragmented pleural line (arrow). High-resolution computed tomography showing early subpleural interstitial and subpleural ground-glass changes mainly in the nondependent right lung base. * Right hemidiaphragm

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Case study 3

Moderate ILD – A 52-year-old female was diagnosed with Jo1-positive myositis in 2009 which was well controlled on azathioprine. She developed ILD in 2012 which had been progressing gradually. She participated in the RECITAL trial in 2019 (rituximab vs. cyclophosphamide) which stabilized her ILD [Figure 19].
Figure 19: High-frequency lung ultrasound shows irregular thickened pleural line and multiple coalescing B-lines “white lung.” High-resolution computed tomography showing extensive interstitial and ground-glass changes in both the lung bases but predominantly on the right with traction dilation of the bronchioles

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Case study 4

Severe ILD – A 65-year-old male presented in 2019 with shortness of breath. He was found to have pulmonary fibrosis with positive ANA and anti-Smith antibodies [Figure 20].
Figure 20: AQ15 - High frequency LUS shows multiple coalescing B-lines ‘white lung’ the area between the yellow arrows (a) and irregular thickened pleural line indicated by the bold arrow (b)

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To conclude, imaging is crucial in the management of ILD in rheumatic diseases, for diagnosis, prognosticating, for assessing response to treatment, and ruling out other causes. The findings on imaging should always be interpreted in the background of the clinical setting and serological findings. As of now, HRCT chest is the modality of choice for ILD; CXR is used for initial screening and LUS may help in detecting early ILD in young individuals.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20]
 
 
    Tables

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