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EGFR Tyrosine Kinase Inhibitor–Associated Interstitial Lung Disease During the Coronavirus Disease 2019 Pandemic

Open ArchivePublished:May 05, 2020DOI:https://doi.org/10.1016/j.jtho.2020.04.029
      To the Editor:
      EGFR tyrosine kinase inhibitor (TKI)–associated interstitial lung disease (ILD) and coronavirus disease 2019 (COVID-19) infection share similar clinical and imaging findings. How to distinguish between the two diseases is a crucial issue during the current COVID-19 pandemic.
      Lung cancer is the leading cause of death worldwide. TKIs targeting EGFR have been reported to improve progression-free survival in patients with NSCLC harboring sensitive EGFR mutations. The most serious adverse drug reaction in patients receiving EGFR TKIs is ILD, with an incidence in Japan of 1.6% to 4.3% and 0.3% to 1% worldwide.
      • Shah R.R.
      Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas.
      The median interval to onset is 1 to 2 months from the first dose, and the mortality rate can reach 13% to 50%.
      • Shah R.R.
      Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas.
      Chest computed tomography (CT) findings of EGFR TKI–associated ILD can be divided into the following four patterns
      • 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.
      : nonspecific areas with ground-glass opacity (GGO), multifocal areas of airspace consolidations, patchy distribution of GGO accompanied by interlobar septal thickening, and extensive bilateral GGO or airspace consolidations with traction bronchiectasis. The latter has the worst prognosis. Symptoms of EGFR TKI–associated ILD are nonspecific, with the most common being dyspnea (94.3%), fever (51.4%), and cough (20%); 5.7% of patients are asymptomatic.
      • Shah R.R.
      Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas.
      EGFR TKI–associated ILD is diagnosed essentially by the exclusion of other diseases. Early diagnosis, discontinuing EGFR TKIs, and starting high-dose steroid treatment as soon as possible are recommended.
      At the time of writing, 2,927,523 people have been confirmed to be affected with COVID-19 infection and 202,107 people have died worldwide, with a mortality rate of 6.9%. The median incubation period of severe acute respiratory syndrome coronavirus 2 is 5.1 days, with 97.5% of patients becoming symptomatic within 11.5 days. Chest radiograph (CXR) is most often used to detect lesions in patients with COVID-19 infection in most countries; however, only 33.3% to 69% of patients with COVID-19 infection have abnormalities on CXR.

      Wong HYF, Lam HYS, Fong AH, et al. Frequency and distribution of chest radiographic findings in COVID-19 positive patients [e-pub ahead of print]. Radiology. https://doi.org/10.1148/radiol.2020201160, accessed May 11, 2020.

      In addition, the severity on CXR peaks at 10 to 12 days from symptom onset. Chest CT for patients with COVID-19 infection is highly sensitive, and the cardinal hallmarks of COVID-19 on chest CT are bilateral distribution of GGO with or without consolidation in posterior and peripheral lungs, and the most common picture on chest CT includes GGO at 14% to 98%, consolidation at 2% to 64%, GGO with consolidation at 19% to 59%, and interlobular septum thickening at 1% to 75%.

      Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review [e-pub ahead of print]. Eur Radiol. https://doi.org/10.1007/s00330-020-06801-0, accessed May 11, 2020.

      The most common symptoms of patients with COVID-19 include fever (85%–90%), cough (65%–70%), fatigue (35%–40%), sputum production (30%–35%), shortness of breath (15%–20%), myalgia or arthralgia (10%–15%), headaches (10%–36%), sore throat (10%–15%), and chills (10%–12%).
      Taken together, it is very difficult to distinguish between COVID-19 infection and EGFR TKI–associated ILD with clinical and imaging presentations. For an early diagnosis, rapid tests for severe acute respiratory syndrome coronavirus 2 are necessary, such as reverse transcriptase-polymerase chain reaction, isothermal amplification assays, or serology tests to differentiate COVID-19 infection from EGFR TKI–associated ILD, especially in the first 1 to 2 months after starting EGFR TKI therapy. In addition, the standard treatment for EGFR TKI–associated ILD is to discontinue TKIs and start high-dose steroids immediately; however, high-dose steroid treatment has been reported to be harmful for patients with COVID-19 infection.
      • Russell C.D.
      • Millar J.E.
      • Baillie J.K.
      Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
      In Table 1, we summarize the differences between EGFR TKI–associated ILD and COVID-19 infection.
      Table 1The Differences Between EGFR TKI–Associated ILD and COVID-19 Infection
      GefitinibErlotinibAfatinibOsimertinibCOVID-19 Infection
      Incidence, (%)Overall 1.3
      • Shah R.R.
      Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas.


      Japan 1.6–4.3; non-Japanese 0.3–1
      1.1%–4.31.63.9
      Interval to onsetMedian time 24–42 d; majority within 4–8 wk.Median time 39 d; majority within 4 wk.Median time 26.5 d (in Japan)Median time 54 d (14–240 d)Median incubation period of 5.1 d, with 97.5% becoming symptomatic within 11.5 d
      Mortality13%–50%
      • Shah R.R.
      Tyrosine kinase inhibitor-induced interstitial lung disease: clinical features, diagnostic challenges, and therapeutic dilemmas.
      6.95% (to April 25, 2020)
      CXRNA33.3%–69% patients positive with COVID-19 had abnormalities on CXR

      Wong HYF, Lam HYS, Fong AH, et al. Frequency and distribution of chest radiographic findings in COVID-19 positive patients [e-pub ahead of print]. Radiology. https://doi.org/10.1148/radiol.2020201160, accessed May 11, 2020.



      47%–80% consolidation, 20%–38% GGO

      The severity of CXR peaked at 10–12 d from symptom onset.

      Wong HYF, Lam HYS, Fong AH, et al. Frequency and distribution of chest radiographic findings in COVID-19 positive patients [e-pub ahead of print]. Radiology. https://doi.org/10.1148/radiol.2020201160, accessed May 11, 2020.

      Chest CTIncludes four patterns as below
      • 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.


      A nonspecific area with GGO.

      A multifocal area of airspace consolidations.

      Patchy distribution of GGO accompanied by interlobar septal thickening.

      Extensive bilateral GGO or airspace consolidations with traction bronchiectasis.
      Bilateral distribution of GGO with or without consolidation in posterior and peripheral lungs was the cardinal hallmark of COVID-19.

      Included the following patterns

      Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review [e-pub ahead of print]. Eur Radiol. https://doi.org/10.1007/s00330-020-06801-0, accessed May 11, 2020.

      :

      GGOs 14%–98%; consolidation 2%–64%; GGO + consolidation 19%–59%; interlobular septum thickening 1%–75%; reticular pattern 1%–22%; crazy paving 5%–36%; air bronchogram 21%–80%; bronchial wall thickening 11%–23%; pleural thickening 32%; subpleural line 20%; nodules 3%–13%; reversed halo sign 2%–3%; pleural effusion or pericardial effusion 1%–8%; lymphadenopathy 4%–8%
      DiagnosisDiagnosis of EGFR TKI–associated interstitial pneumonitis is made essentially by exclusion of othersRT-PCR, isothermal amplification assays, serology tests
      SymptomsNonspecific, dyspnea 94.3%, fever 51.4%, cough 20%, asymptomatic 5.7%Fever 85%–90%, cough 65%–70%, fatigue 35%–40%, sputum production 30%–35%, shortness of breath 15%–20%, myalgia or arthralgia 10%–15%, headaches 10%–36%, sore throat 10%–15%, chills 10%–12%.
      TreatmentEarly detection, discontinue EGFR TKI, and start high-dose steroids as soon as possible.No FDA-approved drugs as yet.

      Steroids may be harmful
      • Russell C.D.
      • Millar J.E.
      • Baillie J.K.
      Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
      COVID-19, coronavirus disease 2019; CXR, chest radiograph; FDA, Food and Drug Administration; GGO, ground-glass opacity; ILD, interstitial lung disease; NA, not applicable; RT-PCR, reverse transcriptase-polymerase chain reaction; TKI, tyrosine kinase inhibitor.

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      1. Wong HYF, Lam HYS, Fong AH, et al. Frequency and distribution of chest radiographic findings in COVID-19 positive patients [e-pub ahead of print]. Radiology. https://doi.org/10.1148/radiol.2020201160, accessed May 11, 2020.

      2. Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review [e-pub ahead of print]. Eur Radiol. https://doi.org/10.1007/s00330-020-06801-0, accessed May 11, 2020.

        • Russell C.D.
        • Millar J.E.
        • Baillie J.K.
        Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
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