The Importance of Recognizing Interstitial Lung Disease in the Clinical Setting, and the Impact of EGFR Tyrosine Kinase Inhibitors During the Pandemic

Web Exclusives —April 2, 2021


Lung Cancer

Coronavirus disease 2019 (COVID-19) infection and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-associated interstitial lung disease (ILD) have overlapping clinical presentations and may look similar in imaging studies. Particularly because lung cancer is already a leading cause of death globally, differentiating between the 2 conditions has been critical during the COVID-19 pandemic.

In patients with non–small-cell lung cancer harboring sensitive EGFR mutations, TKIs targeting EGFR have been reported to increase progression-free survival. In patients receiving EGFR-TKIs, ILD is the most serious adverse drug reaction, and there is a disproportionate incidence reported in Japan ranging from 1.6% to 4.3%, compared with worldwide rates of 0.3% to 1%.1 The median interval to onset varies, and the mortality rate is in the range of 20% to 50%.1 There are 4 patterns of chest computed tomography (CT) findings into which EGFR-TKI–associated ILD can be divided2: nonspecific areas with ground-glass attenuations, multifocal areas of airspace consolidations, patchy distribution of ground-glass attenuation accompanied by interlobar septal thickening, and extensive bilateral ground-glass attenuation or airspace consolidations with traction bronchiectasis, which has the worst prognosis.2

In the clinical setting, there are nonspecific signs and symptoms of EGFR-TKI–associated ILD. In the vast majority of these cases, ILD presents as dyspnea (94.3%). Additionally, approximately half of patients present with fever (51.4%) and fewer with cough (20%). However, 5.7% of patients have no obvious clinical signs and appear asymptomatic.1

Clinicians systematically exclude other disease diagnoses to eventually diagnose EGFR-TKI–associated ILD. Aggressive management is recommended through early diagnosis, discontinuation of EGFR-TKIs, and initiation of high-dose steroid treatment.

At the time when Chih-Jen Yang, MD, PhD, and colleagues published a letter to the editor in the Journal of Thoracic Oncology, they noted that nearly 3 million people had been confirmed to be infected with COVID-19 and associated deaths had reached more than 200,000 people worldwide, with a mortality rate of 6.9%. For severe acute respiratory syndrome coronavirus 2, the median incubation period is 5.1 days, with the vast majority of patients (97.5%) becoming symptomatic within 11.5 days. In most countries, the most often used tool to detect lesions in patients with COVID-19 is chest radiograph; however, irregularities in chest radiograph are only found in one-third to two-thirds of patients with COVID-19 infection.3 Results of chest radiography frequently peak at 10 to 12 days from symptom onset and show bilateral lower zone consolidation.

Chest CT scans have been proven to have a high level of sensitivity for COVID-19, with cardinal signals being bilateral distribution of ground-glass opacities with or without consolidation in posterior and peripheral lung regions. The most common finding revealed on chest CT included ground-glass opacities, appearing in 14% to 98% of patients; multifocal, segmental consolidation occurring in 2% to 64%; ground-glass opacities with consolidation ranging from 19% to 59%; and interlobular septum thickening ranging from 1% to 75%.4

The clinical signs of COVID-19 vary, but the most common symptoms include chills (10%-12%), cough (65%-70%), fatigue (35%-40%), fever (85%-90%), headaches (10%-36%), myalgia or arthralgia (10%-15%), shortness of breath (15%-20%), sore throat (10%-15%), and sputum production (30%-35%).

Differentiating between COVID-19 infection and EGFR-TKI–associated ILD is challenging based on clinical signs and imaging presentations, highlighting the critical importance of rapid tests for severe acute respiratory syndrome coronavirus 2, as well as reverse transcriptase-polymerase chain reaction, isothermal amplification assays, or serology tests to distinguish COVID-19 infection from EGFR-TKI–associated ILD.

This highlights that it is critical to have a clear diagnosis, based on the required treatment algorithm for each condition. EGFR-TKI–associated ILD is routinely treated by ceasing treatment with TKIs and initiating high-dose steroid therapy immediately; yet high-dose steroid treatment may be risky for COVID-19 patients, and they could be harmed with such treatment.5 Based on evidence to date, no clear rationale exists to expect that corticosteroids would provide benefit to patients with COVID-19, and corticosteroid treatment outside clinical trials might be injurious.

Healthcare providers need to be aware of the overlapping symptomatology, and the high degree of clinical sensitivity required to improve treatment selection and outcomes.


Chang HL, Chen YH, Taiwan HC, Yang CJ. EGFR tyrosine kinase inhibitor-associated interstitial lung disease during the coronavirus disease 2019 pandemic. J Thorac Oncol. 2020;15:e129-e131.


  1. Shah RR. Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas. Drug Saf. 2016;39:1073-1091.
  2. Endo M, Johkoh T, Kimura K, Yamamoto N. Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer. 2006;52:135-140.
  3. Wong HYF, Lam HYS, Fong AH, et al. Frequency and distribution of chest radiographic findings in patients positive for COVID-19. Radiology. 2020;296:E72-E78.
  4. Ye Z, Zhang Y, Wang Y, et al. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review. Eur Radiol. 2020;30:4381-4389
  5. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395:473-475.
Related Articles
American Cancer Society Cancer Action Network Releases Recommendations to Increase Cancer Biomarker Testing
Web Exclusives
The American Cancer Society Cancer Action Network has published data that demonstrate there are multiple barriers to biomarker testing access and released recommendations that address these barriers.
Sotorasib Demonstrates Efficacy in CodeBreaK 100 Phase 2 Study Results
Web Exclusives
Sotorasib has shown promising antitumor activity in phase 2 of a clinical trial of patients with heavily treated advanced NSCLC.
Results of an International Study Identify Barriers to Molecular Testing in NSCLC
Web Exclusives
Recently released survey responses identified multiple barriers to, and dissatisfaction with, the current state of molecular testing in lung cancer.
Last modified: April 2, 2021

Subscribe to the Journal of Oncology Navigation & Survivorship®

To sign up for our print publication or e-newsletter, please enter your contact information below.

  • First Name *
    Last Name *
    Profession or Role
    Primary Specialty or Disease State
  • Please enter your mailing address.

    Address Line 2
    Zip Code