Abstract
Introduction
The increased use of computed tomography (CT) scans as a diagnostic tool has led to more incidental findings such as interstitial lung abnormalities (ILAs). The incidence of ILAs is estimated to be 13.1/1000 person-years. 1 ILAs may progress. ILA progression is associated with higher mortality. 2 Patients with ILAs are at higher risk of developing and dying from lung cancer. 3 We discuss about risk stratification, evaluation and uncertainties associated with ILAs.
Anti-MDA5 is a myositis-specific antibody (MSA) associated with dermatomyositis (DM). Anti-MDA5 DM is a heterogeneous condition. We highlight the known clinical phenotypes of anti-MDA5 DM. As we discover more about anti-MDA5, we highlight the importance of interpreting a laboratory result in the appropriate clinical context before a diagnosis and treatment decision is made.
Case report
A 72-year-old Chinese male 100 pack-year smoker presented with progressive exertional breathlessness over 2 months. He had unproductive cough and significant weight loss. He had no fever, haemoptysis, or chest pain. There were right sided crackles heard on chest auscultation. He had no palpable cervical lymph nodes or digital clubbing. On his chest radiograph (CXR) done on admission, there was a mass-like opacity seen at the aorto-pulmonary window with lower zone reticular opacities. (Figure 1) On a CXR done a year ago, these changes were not evident. A CT thorax confirmed the presence of a large spiculated mass at the aorto-pulmonary window, causing an abrupt truncation of the left upper lobe bronchus. There was left upper lobe atelectasis and enlarged mediastinal lymph nodes. Bilateral paraseptal emphysema was present predominantly in the upper lobes. Bilateral subpleural reticular opacities, traction bronchiolectasis and mild ground glass opacities (GGO) were present in a basal predominant distribution. (Figure 1) There were no pleural effusions, honeycombing, cysts, mosaic attenuation, predominant GGO, nodules or centrilobular nodules seen. On a CT abdomen done a year ago, our patient was noted to have bilateral airspace opacities in dependent areas of the lungs. These changes were perceived to be dependent atelectasis and were left alone. (a): A mass-like-opacity is seen at the aorto-pulmonary window. (black arrow) There are lower zone reticular opacities seen. (white arrow) (b): The lung mass at the aorto-pulmonary window appears to be inseparable from the mediastinum. (black arrow). The mass causes an abrupt truncation of the left upper lobe bronchus. There is an enlarged right hilar lymph node seen. (*) (c): There is upper lobe paraseptal emphysema seen. (black arrow) There are basal predominant subpleural reticular opacities with traction bronchiolectasis and mild ground glass opacities (GGO) seen. (white arrow) (d): There are bilateral basal predominant subpleural reticular opacities with traction bronchiolectasis and mild GGO seen. (white arrow).
We obtained a detailed history of his occupational, environmental and drug exposures. Our patient worked on a barge as a general worker for the past 25 years. His work involved the transport of sea sand. Prior to that, he was a renovation worker for 30 years. He did carpentry and was not involved in pipe fitting or insulation work. He did not use occupational respiratory protection. He did not do gardening and had no pets. He had no prolonged contact with birds and did not own a home humidifier. He did not take chronic medications or supplements. He did not have a history of aspiration or recurrent lung infections. He had no family history of lung diseases. Autoimmune serologies (antinuclear antibody (ANA), extractable nuclear antigen profile, rheumatoid factor, anti-cyclic citrullinated peptide and an extended myositis panel (EMP)) were done to evaluate for connective tissue disease (CTD). The autoimmune serologies came back positive for ANA (1: 320 homogeneous) and EMP (weakly positive anti-MDA5).
A rheumatology consult was obtained. He did not have periorbital heliotrope rash, V-sign, shawl sign, Gottron papules, Gottron sign, palmar papules, periungual erythema, Raynaud’s phenomenon, mechanic’s hands, skin ulcers, digital necrosis, calcinosis, arthralgia or arthritis, There was no muscle weakness detected. Serum creatine kinase was 86 U/L (reference range: 56–336 U/L). Serum aspartate aminotransferase was 28 U/L (reference range: 12–42 U/L). The patient declined electromyography.
The patient’s serial lung function tests results.
Legend: FEV1: Forced expiratory volume in the 1st second FVC: forced vital capacity RV: residual volume TLC: total lung capacity DLCOcor: corrected diffusing capacity of the lungs to carbon monoxide Va: alveolar volume KCO: carbon monoxide transfer coefficient L: L mM/min/kPa: milimoles/minute/kPa mM/min/kPa/L: milimoles/minute/kilopascals/litre Hb: haemoglobin g/dl: gram per decilitre LLN: lower limit of normal ULN: upper limit of normal.
Given his significant smoking history, the possibility of smoking-related ILDs was considered. The absence of widespread GGO made a diagnosis of desquamative interstitial pneumonitis less likely. We were unable to make a confident diagnosis of idiopathic pulmonary fibrosis (IPF) in the absence of honeycombing. We have classified his radiologic changes as subpleural fibrotic ILAs (SF-ILA) with a probable usual interstitial pneumonia (UIP) pattern. Patients with this pattern are more likely to develop IPF and have a higher risk of mortality. 5 In the absence of other clinical features of DM, the significance of MDA5 seropositivity is unclear. Our current diagnosis is extensive stage SCLC (ES-SCLC), chronic obstructive pulmonary disease (COPD) and SF-ILA with a probable UIP pattern and MDA5 seropositivity.
He was started on chemotherapy. The addition of immune checkpoint inhibitors (ICI) to first-line chemotherapy has led to improved survival for lung cancer patients.6,7 However, patients with ILAs, especially SF-ILA, are at higher risk of developing ICI-associated pneumonitis (IAP). 8 Our patient had poor pulmonary reserves and IAP might have been fatal. ICI was omitted. He received inhaled bronchodilators for COPD.
Our patient’s repeat CT thorax showed partial treatment response of SCLC to chemotherapy. His ILAs (Figure 2) remained stable. His serial PFTs showed improvement. (Table 1) Our patient had untreated COPD with airflow obstruction. This led to air-trapping and an increased residual volume, giving rise to pseudo-restriction. Untreated COPD resulted in uneven distribution of inspired gas to lung units with different time constants and resulted in reduced DLCO. The large lung mass and the presence of SF-ILA resulted in loss of lung units. All these factors contributed to reduced lung volumes and DLCO. The improvement in PFTs is explained by the reduction in size of the mass and relief of airflow obstruction with bronchodilatation. (a): There is upper lobe predominant paraseptal emphysema seen. (black arrow) There are basal predominant subpleural reticular opacities with traction bronchiolectasis and mild GGO seen. (white arrow) These changes are grossly stable compared to the initial CT thorax. There is a new left pleural effusion that has developed since the initial CT thorax. (*) There is left sided volume loss as suggested by the elevated left hemidiaphragm and left oblique fissure. (b): There is reduction in size of the left lung mass. (black arrow) There are subpleural reticular opacities with traction bronchiolectasis and mild GGO seen. (white arrow) These changes are grossly stable compared to the initial CT thorax. There is a new left pleural effusion that has developed since the initial CT thorax. (*).
Discussion
ILAs are defined as non-dependent lung abnormalities that affect more than 5% of any lung zone in patients not suspected to have underlying ILD. 9 ILAs include ground-glass or reticular abnormalities, non-emphysematous cysts, and fibrotic changes such as lung distortion, traction bronchiectasis or honeycombing. ILAs are classified based on location and the presence of fibrosis. Subpleural and/or fibrotic ILAs are more likely to progress and are associated with increased mortality.
Patients with ILAs should be evaluated within 3 to 12 months of diagnosis. 10 A clinical assessment is done to assess for symptoms and to identify exposures. PFTs are performed to detect physiologic impairment. Patients with ILAs noted on partial imaging of the thorax should undergo a high-resolution CT (HRCT) thorax. Manoeuvres such as prone positioning and inspiratory and expiratory scans help to exclude mimics. There remains significant inter-observer variability in the diagnosis and classification of ILAs. ILAs should be discussed at a multidisciplinary meeting. ILAs that fit a defined pattern of ILD should be managed accordingly. The utility of bronchoalveolar lavage and lung biopsy in the evaluation of ILAs is to exclude alternative diagnoses. There are no pathognomonic cellular analysis or histopathologic patterns associated with ILAs. These procedures have potential risks of morbidity and mortality and are currently not recommended as standard of care. A repeat HRCT thorax is suggested to be done at 12 to 24 months after the initial scan or earlier if ILA progression is suspected. The duration of and criteria for discharge from surveillance is uncertain.
Risk factors for ILAs have been identified. 10 Non-modifiable risk factors include older age, male gender and genetic predisposition (MUC5B promoter variant rs35705950). Modifiable risk factors include tobacco smoke and other inhalational exposures. Exposures that can potentially cause lung injury should be avoided. Tobacco abstinence and use of occupational respiratory protection is encouraged. No treatment options for progressive ILAs have been identified.
The definition and classification of ILAs requires validation. Criteria for defining ILA progression needs to be more precise and requires validation. To improve the sensitivity of risk stratification, we must understand the pathogenesis and natural history of ILAs better. It is uncertain if early intervention with conventional ILD treatment would modify the disease course of progressive ILAs.
Anti-MDA5 DM is a rare condition more commonly seen in Asians. Different phenotypes for anti-MDA5 DM have been identified. Phenotype 1 tend to be females who develop rapidly progressive ILD and mechanic’s hands and is associated with a high mortality. Phenotype 2 tend to be females who develop non-rapidly progressive ILD with skin and articular manifestations. Phenotype 3 tend to be males who present with ILD, musculo-cutaneous and vasculopathic manifestations. Phenotypes 2 and 3 are associated with a low mortality. 11 Our patient did not fit into these known phenotypes. Autoantibodies have been detected in cancer patients with no evidence of autoimmune disease. They are postulated to be related to tumour cell breakdown and antigen release. 12 Unlike other MSAs such as anti-nuclear matrix protein 2 (anti-NXP2) and anti-transcriptional intermediary factor-1γ (anti-TIF-1γ), the association between anti-MDA5 and cancer is less clear. 13 We continue to monitor our patient for the evolution of his condition.
Conclusion
Given our patient’s significant smoking history and the presence of ILAs, he is at higher risk of developing cancer. He is also at a higher risk of ILA progression and mortality. Patients like him should be referred early to a respiratory physician. As we discover more about anti-MDA5, we highlight the importance of interpreting a laboratory result in the appropriate clinical context before a diagnosis and treatment decision is made.
Footnotes
Declaration of conflicting interests
Funding
ORCID iDs
