The Fleischner Society published a position paper on the role of chest computed tomography (CT) diagnosis of drug-related pneumonitis (DRP) in patients treated with molecular targeting therapies and immune checkpoint inhibitors. The paper, which was published in a recent edition of CHEST, provides key insights into the imaging patterns useful for diagnosing DRP and predicting corresponding prognosis.

Agents Linked to DRP

An international, multidisciplinary panel of the Fleischner Society, including experts in lung cancer, interstitial lung disease, and radiology, described key molecular targeting agents and immunotherapies associated with DRP in this position paper. According to the literature, DRP has been reported in patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy, including gefitinib. A cited meta-analysis has indicated that the overall incidence of DRP among patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKI therapy is 1.12% for all grades.


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Patients with DRP are also frequently treated with mTOR (mechanistic target of rapamycin) inhibitors, such as everolimus and temsirolimus, often for the purpose of renal cell carcinoma. Previous management guidance suggests that asymptomatic patients with mTOR-induced pneumonitis as well as radiologic changes only can continue taking their mTOR inhibitor therapy without adjustments in dose at the discretion of the treating physician. Patients should be aware of signs of worsening, however, which may lead to modifications in treatment with mTOR inhibitors.

Anaplastic lymphoma kinase inhibitors for the treatment of NSCLC have been reportedly associated with severe acute pneumonitis. A meta-analysis cited in the Fleischner Society position paper suggests the overall incidence of pneumonitis in patients with advanced NSCLC treated with anaplastic lymphoma kinase inhibitors is 2.14% for all grades.

B-cell-depleting monoclonal antibody rituximab has also been associated with DRP. Additionally, the position paper notes that several immunotherapy agents have been associated with DRP. Immune checkpoint inhibitors associated with DRP, according to the literature, include ipilimumab, nivolumab, pembrolizumab, atezolizumab, and durvalumab.

Imaging Features

The Fleischner Society panel noted that DRP is mostly diagnosed on routine CT scans for follow-up cancer management. A CT pattern of DRP described in the paper includes radiologic non-specific interstitial pneumonia pattern, which features diffuse or patchy areas of ground-glass opacity. Typically, there is a peripheral and lower lung zone predominance in this pattern. Abnormalities are often bilateral and symmetric with predominantly lower-lung and peripheral involvement.

Radiologic organizing pneumonia pattern is another imaging feature in DRP and is characterized by areas of consolidation typically found in peripheral or peribronchovascular distribution. This pattern appears to occur in patients who are treated with immunotherapy, EGFR-TKIs, mTOR inhibitors, and anaplastic lymphoma kinase inhibitors.

In contrast, a radiologic hypersensitivity pneumonitis pattern generally occurs following treatment with gefitinib or erlotinib, mTOR inhibitors, and immune checkpoint inhibitors. This pattern features small, poorly defined centrilobular nodules either with or without widespread areas of lobular areas or ground-glass opacity.

A radiologic diffuse alveolar damage (DAD) pattern also features bilateral areas of ground-glass opacity as well as “dependent airspace consolidation with traction bronchiectasis” on chest CT, which increases with disease evolution. The radiologic DAD pattern may occur in patients treated with EGFR-TKIs, immune checkpoint inhibitors, or anaplastic lymphoma kinase inhibitors. In many cases, this pattern is associated with serious clinical outcomes.

The panel also described the radiologic simple pulmonary eosinophilia pattern as a “simple pulmonary eosinophilia pattern” featuring “nonsegmental consolidation or ground-glass opacity that can be unilateral or bilateral.” Prognosis associated with this pattern on CT is generally excellent, with spontaneous resolution commonly observed within 4 weeks.

Diagnostic Criteria Proposal

Based on previously proposed diagnostic criteria for DRP as well as the challenges associated with stopping and restarting a drug in some settings, the Fleischner Society panel provides the following diagnostic criteria for DRP:

  • Newly identified pulmonary parenchymal opacities on CT/chest radiography (bilateral nonsegmental distribution common)
  • Temporal association of presentation with start of systemic treatment
  • Exclusion of other possible/likely causes

Management

In terms of management, the panel emphasized the importance of early diagnosis and prompt cessation of the offending agent. A multidisciplinary approach to care could rely on discussions from clinicians, pathologists, and radiologists. The panel also pointed to the use of glucocorticoids as a common method for resolving lung injury, particularly in severe cases of DRP. Patients with severe DRP often require hospitalization, at least for initial treatment and subsequent monitoring. Other supportive management measures include the use of supplemental oxygen as well as noninvasive and/or invasive mechanical ventilator support.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Johkoh T, Lee KS, Nishino M, et al. Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: a position paper from the Fleischner Society. CHEST. Published online January 9, 2021. doi:10.1016/j.chest.2020.11.027