REVIEWS AND COMMENTARY • STATEMENTS AND GUIDELINES

Chest CT Diagnosis and Clinical Management ofDrug-related Pneumonitis in Patients Receiving
Molecular Targeting Agents and Immune Checkpoint
Inhibitors: A Position Paper from the Fleischner Society
Takeshi Johkoh, MD, PhD* • Kyung Soo Lee, MD, PhD* • Mizuki Nishino, MD, MPH •William D. Travis, MD • Jay H. Ryu, MD • Ho Yun Lee, MD, PhD • Christopher J. Ryerson, MD, MAS •Tomás Franquet, MD, PhD • Alexander A. Bankier, MD, PhD • Kevin K. Brown, MD • Jin Mo Goo, MD, PhD •Hans-Ulrich Kauczor, MD • David A. Lynch, MB • Andrew G. Nicholson, MD • Luca Richeldi, MD, PhD •Cornelia M. Schaefer-Prokop, MD, PhD • Johny Verschakelen, MD, PhD • Suhail Raoof, MD •Geoffrey D. Rubin, MD, MBA • Charles Powell, MD • Yoshikazu Inoue, MD, PhD • Hiroto Hatabu, MD, PhD
From the Department of Radiology, Kansai Rosai Hospital, Amagasaki, Japan (T.J.); Department of Radiology, Samsung Medical Center (K.S.L., H.Y.L.) and Department
of Health Sciences and Technology, SAIHST (H.Y.L.), Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea; Department
of Imaging, Dana-Farber Cancer Institute, Boston, Mass (M.N.); Department of Radiology (M.N.) and Center for Pulmonary Functional Imaging (H.H.), Brigham and
Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY (W.D.T.); Division of
Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minn (J.H.R.); Department of Medicine, University of British Columbia and Centre for Heart Lung
Innovation, St. Paul’s Hospital, Vancouver, Canada (C.J.R.); Department of Radiology, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain (T.F.);
Department of Radiology, University of Massachusetts Medical Center, Worcester, Mass (A.A.B.); Departments of Medicine (K.K.B.) and Radiology (D.A.L.), National
Jewish Health, Denver, Colo; Department of Radiology, Seoul National University College of Medicine, Seoul, Korea (J.M.G.); Diagnostic and Interventional Radiology, University Hospital Heidelberg, Translational Lung Research Center Heidelberg, member of the German Center of Lung Research, Heidelberg, Germany (H.U.K.);
Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, England(A.G.N.); Complex Operative Unit of Pneumology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy (L.R.);
Department of Radiology, Meander Medical Center, Amersfoort, the Netherlands (C.M.S.P.); Department of Radiology, University Hospitals Leuven, Leuven, Belgium(J.V.); Division of Pulmonary and Critical Care Medicine, Lenox Hill Hospital, Northwell Health System, New York, NY (S.R.); Department of Radiology, Duke University School of Medicine, Durham, NC (G.D.R.); Department of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY(C.P.); and Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan (Y.I.). Received August 14, 2020; revision
requested September 22; final revision received October 6; accepted November 5. Address correspondence to K.S.L. (e-mail: kyungs.lee@samsung.com).
*T.J. and K.S.L. contributed equally to this work.
Conflicts of interest are listed at the end of this article.
Radiology 2021; 00:1–17﻿ • https://doi.org/10.1148/radiol.2021203427• Content codes:

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by
excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important.
The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death.
Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic
pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary
eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronicinterstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatmentof a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along withsupportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, andtrial sponsors, among others.
This article is a simultaneous joint publication in Radiology and CHEST. The articles are identical except for stylistic changes in keeping with each journal’s style.
Either version may be used in citing this article.
Published under a CC BY 4.0 license.
Online supplemental material is available for this article.

R

ecent advances in cancer biology have opened a newera of molecular targeting therapy, including tyrosine
kinase inhibitors (TKIs) targeting epidermal growth factor
receptor (EGFR) that have a significant treatment advantage over cytotoxic agents for the treatment of advanced
non–small cell lung cancer (NSCLC) (1,2). More recently,
an entirely new group of drugs has been shown to be beneficial to patients with advanced-stage cancer (3–6). This
includes immune checkpoint inhibitors (ICIs) that prolong survival and improve quality of life in patients withadvanced-stage cancers including NSCLCs (7). In a U.S.
cross-sectional study (8), patients with cancer eligible for

ICIs increased from 1.54% in 2011 to 43.63% in 2018;
patients’ response to ICIs was 0.14% in 2011 and increased to 12.46% in 2018.
Since the first report from Japan of severe acute lunginjury in patients with NSCLC treated with gefitinib (9),pneumonitis associated with molecular targeting agentshas attracted considerable attention. More recently, ICIs
such as nivolumab and pembrolizumab have demonstrated to be associated with toxicities often termed immune-related adverse effects, including pneumonitis as oneof the clinically significant and potentially life-threatening toxicities (10–12). The availability of serial chest CT

This copy is for personal use only. To order printed copies, contact reprints@rsna.org

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

Abbreviations
DAD = diffuse alveolar damage, DRP = drug-related pneumonitis,
EGFR = epidermal growth factor receptor, HP = hypersensitivity pneumonitis, ICI = immune checkpoint inhibitor, ILD = interstitial lungdisease, NSCLC = non–small cell lung cancer, NSIP = nonspecific interstitial pneumonia, OP = organizing pneumonia, PD-1 = programmed
cell death protein 1, PD-L1 = programmed death ligand 1, TKI = tyrosine kinase inhibitor

Summary
Increasing use of molecular targeting agents and immune checkpoint
inhibitors has increased the frequency and broadened the spectrum oflung toxicity, particularly in patients with cancer. In this position paper from the Fleischner Society, the authors provide diagnostic criteria and management recommendations of drug-related pneumonitis
for radiologists, clinicians, clinical trialists, and trial sponsors.

Essentials
The CT patterns in drug-related pneumonitis (DRP) reflect acute(diffuse alveolar damage) interstitial pneumonia and transient(simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial
pneumonia).
n The diagnostic criteria include newly identified pulmonary parenchymal opacities at imaging, temporal association of presentation
with the initiation of a systemic therapeutic agent, and the exclusion of other likely causes.
n Management of DRP consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures
including supplemental oxygen and intensive care.
nscans during cancer treatment allows detailed evaluations ofboth presymptomatic and symptomatic drug-related pneumonitis (DRP) and characterization of its radiologic manifestations in patients with different cancer types treated with different agents.
The reports on pneumonitis among patients with NSCLC
receiving EGFR-targeted TKIs, or EGFR-TKIs, included acutefatal events (13–23). Moreover, the recent introduction of novel
molecular targeting agents such as third-generation EGFR-TKIs,
newer anaplastic lymphoma kinase inhibitors, BRAF inhibitors,
antibody-drug conjugates, and use of ICI combination regimens
has brought new challenges to DRP (24). Despite many reportson this topic, there is limited published guidance on the evaluation and treatment of patients with DRP secondary to treatment
with ICIs.
In this position paper from the Fleischner Society, we identified specific questions for diagnosis and management of DRP
in patients receiving molecular targeting agents and ICIs. We
conducted a systematic search to identify supporting evidence
on these topics that had been published since the introductionof EGFR-TKIs in 2003. Based on the review of the literature
combined with expert opinions, this position paper provides a
description of radiologic patterns; a set of proposed diagnostic
criteria; and management recommendations for DRP, which will
be of value in improving the understanding of the pathophysiology, prognosis, and management of this diverse group of conditions. We believe that this position paper will be of interest to adiverse group of health care providers and clinical researchers.

2

Methodology and Literature Search
The international multidisciplinary panel included 19 experts
in interstitial lung diseases (ILDs) and lung cancer (10 radiologists, seven pulmonologists, and two pathologists). All were
Fleischner Society members, working with two expert medical
librarians who were nonmembers.
The panel developed key questions believed to be important
for the diagnosis and management of DRP based on their clinical experience in the diagnosis and management of pneumonitis.
In brief, coleaders drafted provisional questions. After discussion
by all members of the writing committee, the questions were finalized. Likewise, answer paragraphs for each key question weredrafted by key writing members, which were circulated, revised,and approved by all committee members.
The PubMed literature search strategy is shown in Appendix
E1 (online) (search date: June 1, 2020). Combined free-text keywords and controlled vocabulary terms were used. The filters forthe search were applied, and the filters included Humans [species], English [language], and journal articles [article types]. The
number of search results totaled 926 items not including abstract
only or editorial only. With the 926 items at hand, the key writing members wrote sections in their charges in consideration of
the given questions. The cited items included 106 original articles and seven reviews. During circulation, review, proofreading,and revision processes among the writing committee members,
we added eight case report references. We included 121 references consisting mainly of original articles (n = 106), relevant
reviews (n = 7), and case reports (n = 8), with relevant citations
provided to the writing committee for incorporation into theevidence summary where appropriate.

Clinical Features of DRP
The incidence of DRP varies widely among published studies.
A recent population-based study from France (25) estimatedan incidence of 1.2 per 100 000 per year and a prevalence of
2.6 per 100 000. DRP accounts for 2.5%–5% of prevalent
cases of ILD (25–27). Cancer drugs (eg, bleomycin) are themost common cause of DRP, followed by drugs for autoimmune diseases (eg, methotrexate), amiodarone, and antibiotics (eg, nitrofurantoin), based on a recent systematic review(27). Additionally, awareness of the incidence and risk factorsof pneumonitis related to specific anticancer agents is increasing in importance.
DRP can manifest as a variety of clinical syndromes of lunginjury (27–31). The onset of illness may be acute, insidious, andsometimes delayed with a long latent period (eg, beyond 10
years in some cases of carmustine-induced pulmonary fibrosis)
after completion of drug treatment (27,28). The clinical symptoms are generally nonspecific, including dyspnea, cough, malaise, and low-grade fever. Some patients may be asymptomaticeven in the presence of diffuse pulmonary opacities. Lung auscultation often reveals crackles but may be normal. It is difficult
to clinically distinguish DRP from lung disease of other causessuch as infections, pulmonary hemorrhage, pulmonary edema,
radiation-induced pneumonitis, and metastases. In addition,
evaluation for cardiovascular etiologies including heart failure,radiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et alpulmonary embolism, pulmonary veno-occlusive disease, andother forms of pulmonary hypertension needs to be consideredin this setting. The clinical suspicion for DRP arises from thetemporal relationship between drug exposure and the onset ofclinical presentation (27,28). In most patients, the diagnosis of
DRP is unlikely to be made with certainty even after extensive
clinical evaluation, including lung biopsy.
The increasing use of molecular targeting agents and ICIs
has broadened the spectrum of lung toxicity encountered clinically, especially in patients with cancer. This is exemplified byimmune-related adverse effects in patients treated with ICIs,
which manifest as a wide array of organ toxicities, including
pneumonitis (11,32,33). These toxicities are thought to be theresult of general immunologic activation, including autoimmune response.
The severity of symptoms associated with DRP may range
from mild to life-threatening with rapid progression to death.
The Common Terminology Criteria for Adverse Events published by the National Cancer Institute of the National Institutesof Health provides standardized definitions for grading the severity of organ toxicity (34). The grades for pneumonitis include
grade 1 (asymptomatic), grade 2 (symptomatic), grade 3 (severe
symptoms), grade 4 (life-threatening respiratory compromise),and grade 5 (death related to adverse event).
Laboratory tests such as serologic testing and microbial cultures may help to establish infectious or other etiologies for pulmonary infiltrates but are not useful in specifically diagnosing
DRP (12,27–29,35,36). Similarly, pulmonary function testing
commonly demonstrates a restrictive pattern (reduced forced vital capacity and/or total lung capacity) along with a reduced diffusion capacity, which is the typical pattern seen in ILD. Whenpresent, it is helpful in assessing the degree of pulmonary impairment, but it does not contribute to confirming the diagnosis of
DRP (27–29).
When Should Chest CT Be Performed to Confirm the
Diagnosis in Patients Suspected of Having DRP?
In patients receiving drugs potentially causing pulmonary
toxicity, chest CT (and particularly thin-section CT; section
thickness of 2.0–2.5 mm or less) plays an important role inevaluating the appearance, the progression, and the resolutionof pulmonary abnormalities (37). CT should be performed as
early as possible when DRP is suspected and in the presenceof a positive temporal relationship between drug exposure andsymptom onset. CT may allow early detection of the DRP
while it is still at a reversible stage, or it may help to identify
findings indicating other etiologies that can explain the symptoms of the patients (38). CT is also essential to evaluate thepresence of other common causes (eg, community-acquired orhealth care–associated pneumonia) for the nonspecific clinicalmanifestations of DRP.
Should Lung Biopsy Be Performed to Confirm the Diagnosis
in Patients Suspected of Having DRP?
Whether lung biopsy should be performed in patients suspected of having DRP depends on the clinical context, alternative diagnoses being considered, benefit-risk analysis, and exRadiology: Volume 00: Number 0— 2021 n radiology.rsna.org

pected outcomes for the individual patient. These issues need
to be discussed with the patient in a shared decision-making
process that incorporates the individual patient’s values andpreferences.
An adequate lung biopsy performed with bronchoscopic(forceps or cryobiopsy) or surgical approach (preferably, videoassisted thoracoscopic biopsy) can demonstrate the histopathologic pattern of lung injury (eg, nonspecific interstitial pneumonia [NSIP], organizing pneumonia [OP], or diffuse alveolar
damage [DAD]) in patients suspected of having DRP. However,the features seen on lung biopsy are unlikely to confirm the diagnosis of DRP because these histopathologic patterns are nonspecific and can be seen with other causes, including infections.
A biopsy may sometimes be useful to exclude recurrent malignancy, given that tumors can manifest as diffuse lung infiltrationand mimic ILD.
Bronchoscopic cryobiopsy yields larger samples of lung tissue
but is associated with a higher rate of bleeding and pneumothorax compared with forceps biopsy (39). Overall in-hospital mortality after surgical lung biopsy for ILD in the United States wasfound to be 6.4% in a recent analysis of a national data set (40).
The in-hospital mortality rate was 1.7% for elective operations
compared with 16.0% for nonelective operations. Possible needfor surgical lung biopsy should be entertained early rather thanlate in the clinical course because severe respiratory dysfunction
and dependence on mechanical ventilation increase the mortality rate associated with surgical lung biopsy (41).
More often, bronchoscopy with bronchoalveolar lavage isperformed to exclude infections (including opportunistic, mycobacterial, and viral), alveolar hemorrhage, or metastatic and/or lymphangitic spread (cancer cells). However, bronchoalveolar
lavage fluid–derived differential cell count is often overlapping
and nonspecific (27,28,42,43). Nonetheless, bronchoalveolar
lavage may yield specimens diagnostic of infection (eg, Pneumocystis) or malignancy and bronchoalveolar lavage fluid–derived
differential cell counts may provide diagnostic clues (eg, eosinophilia) as to the underlying pathologic process.
When Should Suspected Offending Drugs Be Stopped in
Patients Suspected of Having DRP?
Discontinuation of the suspected drug is advisable for patientswith severe or progressive lung disease (eg, with worsening
to grade 2 or 3 [Common Terminology Criteria for Adverse
Events]) for which DRP is deemed a possible or likely causeof the clinical presentation, while additional studies are being
performed for diagnostic clarification. Improvement following cessation of drug administration without glucocorticoid
therapy would strongly support the diagnosis of DRP in theabsence of other more likely explanations emerging from thediagnostic work-up (27,43).
It may be appropriate to closely monitor patients while
continuing therapy when the lung injury is not severe or progressive, particularly asymptomatic patients with isolated radiologic changes (grade 1 pneumonitis), as discussed in thefollowing sections regarding specific agents including mechanistic target of rapamycin, or mTOR, inhibitor and thirdgeneration EGFR-TKIs (32). It is important to acknowledge
3

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

the life-threatening nature of the malignancies treated with the
implicated drugs, the benefits of the therapy, and the uncertainties regarding the impact of medication discontinuationin this setting. Thus, it is appropriate for clinicians to discussthese issues at a multidisciplinary conference (see later section
on Multidisciplinary Diagnosis of DRP) and with patients toreach a shared decision regarding preferred course of action.
Additionally, major clinical guidelines based on the consensus
of multidisciplinary and multiorganizational panels are available for specific entities such as ICI-related pneumonitis, andshould be considered for patient treatment in specific clinicalsettings when relevant (44–47).
Does Improvement with Glucocorticoid Therapy Confirm the
Diagnosis of DRP?
Clinical improvement subsequent to glucocorticoid therapy
does not definitively confirm the diagnosis of DRP because
other inflammatory processes that are not drug related (eg,radiation pneumonitis) may also respond to glucocorticoid
therapy. In addition, improvement may merely be coincidental
and due to a self-limited event (eg, aspiration pneumonia) withspontaneous recovery. Nonetheless, glucocorticoid therapy iscommonly used in the management of patients suspected ofhaving DRP, especially if the lung injury is severe or progressive, and response to glucocorticoid therapy would supporta diagnosis of DRP (vs progression of underlying cancer, forexample) in the absence of a better alternative explanation(27,45,48,49). Improvement with glucocorticoid therapy may
also obviate invasive diagnostic maneuvers such as bronchoscopic or surgical lung biopsy.
Should Rechallenge with a Suspected Drug Be Performed to
Confirm the Diagnosis of DRP?
It is rarely appropriate to rechallenge with the suspected drug
to confirm the diagnosis, especially when the lung toxicity has
been severe or if there were substantial residual abnormalities
at chest imaging (45,50). An exception may be consideredwhen lung toxicity has been mild and transient, particularly ifalternative cancer therapies are unlikely to be effective.
What Prognostic Factors Should Be Considered in Patientswith DRP?
Prognostic factors in patients with DRP include acute onset,
severity of lung toxicity (eg, hypoxemia), response to treatment(eg, drug withdrawal), older age, current or prior smoking history, preexisting lung disease, other comorbidities, and thestatus of the underlying cancer (27,35). There are no scoring
schemes currently available that integrate these factors into apredictive model. The prognosis associated with DRP also varies depending on the specific drug and the type of underlying
cancer. There are emerging reports of beneficial effects fromdrug-related toxicities on tumor response to therapy, especiallyin those who are treated with newer molecular targeting cancer
therapy or ICIs (51,52). This interesting possibility should befurther investigated in a disease-specific and therapy-specificmanner (53).

4Imaging Features of DRP
Most DRP is diagnosed on routine follow-up CT scans formonitoring in patients with cancer; specific protocol-basedscans targeted to depict DRP are not obtained. In addition,
given the unique nature (eg, nature of diagnostic exclusion,
symptomless cases, and wide differential diagnoses, etc) of theentity, defining the specific protocol for CT study is difficultand impractical. Thinner-section (2.0–2.5 mm or less in section thickness) and contiguous CT scans are recommended
usually with intravenous contrast agent injection. For thoroughimage analysis, not only transverse but also coronal reformatted images are needed. Follow-up chest CT is useful to assess
the changes of DRP findings and response to DRP treatment(36,54). However, the details of follow-up scans including timeintervals depend on the clinical context (severity of symptoms
and clinical follow-up course, etc).
The CT features of DRP associated with systemic therapeutic
agents should be systematically described, including distribution
and patterns of parenchymal abnormalities and presence of individual features including ground-glass opacities, airspace consolidation, reticular opacities, centrilobular nodules, interlobular
septal thickening, honeycombing, and traction bronchiectasis.
Each drug can be associated with multiple injury patterns at
CT (Fig 1) (55), which are typically not specific. In most situations, clinicians rely on the temporal relationships between theadministration of drugs and the onset of symptoms, along withthe exclusion of other potential causes of lung injury, particularly
infections and metastatic diseases (28).
What Are the CT Patterns of DRP?
DRPs have various histologic patterns and diverse CT findings(31,56,57). Although CT and histologic patterns coincide in
only half of patients with DRP (57), the CT pattern reflects
the extent and distribution of lung abnormalities and helps topredict changes in terms of prognostication. Some of the commonly described patterns include interstitial pneumonia either
as NSIP, OP, DAD, hypersensitivity pneumonitis (HP), andsimple pulmonary eosinophilia (Table 1) (58–61). Often, imaging demonstrates more than one pattern (Fig 1); in this casethe dominant pattern is typically reported. Other drug-related
lung diseases such as granulomatous pneumonitis, vasculitis,
alveolar proteinosis, constrictive (obliterative) bronchiolitis,
and veno-occlusive disease are uncommon (32,59) and demonstrate diverse CT features; thus, they are difficult to classify into one of the aforementioned common CT patterns.
The DRP CT patterns are nonspecific for either drug reaction
in general or the reaction to a particular drug. Consequently,
the diagnosis of DRP is based on a combination of clinical,
radiologic, and histologic (when necessary) findings in a patient who has received a drug known or suspected to cause theabnormalities.
Radiologic NSIP pattern.—NSIP pattern consists of patchy
or diffuse areas of ground-glass opacity (58,59), typically with
peripheral and lower lung zone predominance. With progression, evidence of fibrosis including reticulation, traction

radiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al

Figure 1: Images show gefitinib-related pneumonitis with different CT patterns in two different patients with lung cancer. (a, b) Lung window
images of CT scans obtained at levels of right inferior pulmonary vein (a) and liver dome (b), respectively, show several areas of parenchymal
consolidation or poorly defined nodules (arrows) in right lung. Lesions showed migration and waxing and waning in extent for 3 months and thendisappeared (not shown here), features compatible with simple pulmonary eosinophilia pattern. Patient was a 53-year-old woman with lung adenocarcinoma, positive for missense mutation in exon 21. (c, d) CT scans obtained at levels of right middle lobar bronchus (c) and basal trunk (d), respectively, demonstrate parenchymal opacity in both lungs along bronchovascular bundles (thick arrows) or subpleural lungs (arrowheads), featurescompatible with organizing pneumonia pattern. Also note primary lung cancer (open arrows) in right middle lobe and hilar and subcarinal lymph
node enlargement (thin arrows). Patient was a 46-year-old man and had non-small cell lung cancer on biopsy, positive for none of the epidermal
growth factor receptor mutations.

Table 1: Radiologic Patterns of Drug-related Pneumonitis at Chest CT

Pattern

Imaging Manifestations at Chest CT

NSIP (see Fig 2)

Starting from patchy areas of GGO, progression to irregular reticular opacities,
architectural distortion, and traction bronchiectasis, with or without associated areasof consolidation; bilateral and symmetric, with predominant lower-lung involvement
Multifocal patchy alveolar opacities typically with peribronchovascular and/or peripheral
distribution; may demonstrate reversed halo sign
Poorly defined small centrilobular nodules, bilateral GGO, large or lobular areas ofdecreased attenuation and vascularity (mosaic attenuation)
Extensive bilateral areas of GGO and dependent airspace consolidation in exudative phase;
traction bronchiectasis and decreased lung volumes in organizing and fibrotic phases
Nonsegmental consolidation or GGO, unilateral or bilateral; transient and migratory;
spontaneous resolution within 4 weeks is common

OP (see Figs 1c, 1d, 3, and 4)
HP (see Fig 5)
DAD (AIP/ARDS pattern) (see Fig 6)
Simple PEo (see Figs 1a, 1b, and 7)

Note.—AIP = acute interstitial pneumonia, ARDS = acute respiratory distress syndrome, DAD = diffuse alveolar damage, GGO = groundglass opacity, HP = hypersensitivity pneumonitis, NSIP = nonspecific interstitial pneumonia, OP = organizing pneumonia, PEo = pulmonary eosinophilia.

bronchiectasis, and occasionally honeycombing are identified(Table 1). In some patients, fibrosis is predominantly peribronRadiology: Volume 00: Number 0— 2021 n radiology.rsna.org

chovascular in distribution (Fig 2) (62). The abnormalities areusually bilateral and symmetric, with predominant lower-lung5Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

Figure 2: Images show gefitinib-related pneumonitis leading to pulmonary fibrosis in a 72-year-old woman with advanced-stage lung adenocarcinoma. (a) Lung window image of CT scan obtained at level of rightinferior pulmonary vein shows primary lung cancer (arrows) in right lower
lobe and lung-to-lung metastases (arrowheads) in both lungs. (b, c) Lung
window images of CT scans obtained at levels of lower lobar bronchi (b)and liver dome (c), respectively, depict pulmonary fibrosis with groundglass opacity plus reticulation in both lungs mainly along bronchovascularbundles. Also note traction bronchiectasis (arrows), signs of intralobular fibrosis. Cystic lesions (arrowheads) may have been caused by check-valve
mechanism (tumor necrosis and bronchiolar dilatation and air filling) wheremetastatic tumors were present. Primary tumor (open arrows) is still present
in right lower lobe.

and peripheral involvement (58,63). A NSIP pattern has beenreported in patients undergoing treatment with gefitinib or erlotinib (Table 2) (16).
Radiologic OP pattern.—Radiologic OP pattern is characterized by areas of consolidation often in a predominantly peripheral or peribronchovascular distribution (Table 1) (56,59,64).
Radiologic OP pattern may occur in patients treated with ICIs
(Fig 3), EGFR-TKIs (Fig 1), mTOR inhibitors (Fig 4), andanaplastic lymphoma kinase inhibitors (Table 2) (56,58,65).
Radiologic HP pattern.—HP pattern shows small, poorly
defined centrilobular nodules with or without widespreadareas of ground-glass opacity or lobular areas of decreased
attenuation and vascularity (Fig 5). Radiologic HP pattern
may occur after treatment with gefitinib or erlotinib (66),mTOR inhibitors, and ICIs (Table 2) (54,65).
Radiologic DAD pattern.—DAD pattern demonstrates extensive bilateral areas of ground-glass opacity and dependent airspace consolidation with traction bronchiectasis atchest CT with their proportion depending on disease phases(exudative, organizing, and fibrotic) (67). The extent ofground-glass opacity and traction bronchiectasis increases
as the disease evolves (68). This pattern has been reported inpatients treated with EGFR-TKIs, anaplastic lymphoma kinase inhibitors, and ICIs (Fig 6) (12,58,69). This radiologic

6

pattern is often associated with serious clinical outcome
from pneumonitis, thus requiring awareness of this pattern
among radiologists (Table 2) (32).
Radiologic simple pulmonary eosinophilia pattern.—Simple pulmonary eosinophilia pattern demonstrates nonsegmental consolidation or ground-glass opacity that can beunilateral or bilateral. The lung abnormalities are usuallytransient and migratory, and the prognosis is excellent;
spontaneous resolution within 4 weeks is common (Figs 1,
7) (70,71). The pulmonary eosinophilia pattern is seen in
osimertinib therapy (72).
CT Characteristics Associated with Specific Classes ofCancer TherapyWith the recent rapid advances of cancer therapy, pneumonitis related to novel agents have been increasingly described,
along with their CT patterns. Many studies, as described in thefollowing sections, applied the concept of CT pattern–based
approach similar to the one described above, indicating a widespread use and applicability of this approach. It should also
be noted that the concept and approach to DRP continue to
evolve, as more novel agents are translated into the clinical settings and provide newer sets of challenges for the diagnosis,
monitoring, and treatment.
Molecular Target Agents
EGFR-TKI Therapy.—In 2003, four cases of severe DAD pattern in patients treated with gefitinib were reported; amongradiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al
Table 2: Incidence and Patterns of Drug-related Pneumonitis Caused by Molecular Targeting Agents and Immune Checkpoint
Inhibitors

Incidence: All-Grade
Pneumonitis (%)

Drug

Incidence: High-Grade(Grade 3–4) Pneumonitis (%)

EGFR inhibitors*

Erlotinib
Gefitinib
Afatinib†
Osimertinib‡
ALK inhibitors*
Alectinib
Brigatinib
Ceritinib
Crizotinib
PD-1 inhibitors║
Nivolumab
Pembrrolizumab
PD-L1 inhibitors**
Atezolizumab
Durvalumab
AvelumabRadiologic Patterns
OP, DAD (AIP/ARDS),
HP, NSIP, PEo†

Overall: 1.12 (0.79, 1.58)
Japan: 4.77 (3.84, 5.91)
Non-Japan: 0.55 (0.32, 0.92)
3.01 (1.85, 4.85)

Overall: 0.61 (0.40, 0.93)
Japan: 2.49 (1.77, 3.50)
Non-Japan: 0.37 (0.21, 0.64)
0.56 (0.18, 1.73)
OP, DAD (AIP/ARDS)§

Overall: 2.14 (1.37, 3.34)
Japan: 6.25 (3.97, 9.70)
Non-Japan: 1.14 (0.33, 3.92)…

Overall: 1.33 (0.80, 2.21)
Japan: 3.31 (1.66, 6.47)
Non-Japan: 0.39 (0.03, 5.19)…

Monotherapy: 2.7 (1.9, 3.6)
Monotherapy: 0.8 (0.4, 1.2)
Combination therapy: 6.6 (4.7, 8.7)# Combination therapy: 1.7 (0.8, 2.9)#
OP, DAD (AIP/ARDS),
HP, NSIP
1.3 (0.8, 1.9)…
…

0.4 (0, 0.8)††…
…

Note.—Modified from reference 24. Data in parentheses are 95% CIs. Drug-related pneumonitis from mechanistic target of rapamycin inhibitors, CD20 antibodies, and ipilimumab were not tabulated owing to lack of robust meta-analysis data. AIP = acute interstitial
pneumonia, ALK = anaplastic lymphoma kinase, ARDS = acute respiratory distress syndrome, DAD = diffuse alveolar damage, EGFR =epidermal growth factor receptor mutation, HP = hypersensitivity pneumonitis, NSCLC = non–small cell lung cancer, NSIP = nonspecificinterstitial pneumonia, OP = organizing pneumonia, PD-1 = programmed cell protein death 1, PD-L1 = programmed death ligand 1, PeO= pulmonary eosinophilia. Source.—References 54, 58, 73, 84, 85, 89, 90, 120.
* Incidence rates are meta-analyses of trials of NSCLC treated with single-agent therapy.
†
Incidence is among patients treated with EGFR inhibitors without prior exposure to EGFR-directed therapy.
‡
Data include patients who received osimertinib after previous treatment with conventional EGFR inhibitors. Overall incidence of pneumonitis was 4% in a recent phase 3 first-line treatment of osimertinib for EGFR-mutant NSCLC.
§
In addition to these common patterns, “pulmonary edema–like shadows” characterized by bilateral ground-glass appearance, thickeningof the interlobular septa and the bronchovascular bundles distributed predominantly in the side of the pulmonary hilum, and occasional
bilateral pleural effusion have been described in ALK-related pneumonitis.
║
Incidence rates are based on the meta-analyses of PD-1 inhibitor trials for melanoma, NSCLC, and renal cell carcinomas.
#
Incidence rates are based on the meta-analyses of combination therapy regimens of PD-1 inhibitor, combined with ipilimumab or peptide
vaccines, for patients with melanoma.
** Incidence rates are based on the meta-analyses of single-agent PD-L1 inhibitor trials for NSCLC.
††
The study addressed only grade 3–4 pneumonitis.

four patients, two recovered with steroids and two died due tothe DRP (9). In a recent report of a meta-analysis (73) of 153
trials worldwide including 15 713 patients with NSCLC and
EGFR-TKI therapy, the overall incidence of DRP was 1.12%
for all grades, 0.61% for high-grade pneumonitis, and 0.20%
for grade 5 pneumonitis. When the incidence of pneumonitis
was compared among the multiple factors including EGFRTKI agents, treatment lines, EGFR mutation status, trial
phases, and countries in the meta-analyses, significantly higher
incidence rates were noted among Japanese studies comparedwith non-Japanese studies for all grades (4.77% vs 0.55%;
P , .001), high grade (2.49% vs 0.37%; P , .001), and grade
5 pneumonitis (1.00% vs 0.18%; P , .001) (Table 2). Thesefindings provide further support to a previous Japanese study

Radiology: Volume 00: Number 0— 2021 n radiology.rsna.org(74) reporting clinically significant effects of pneumonitis related to EGFR-TKIs. Serum proteomic markers and genetic
polymorphisms have been studied as candidates to explain thehigher incidence of pneumonitis in Japanese patients compared with others; however, no conclusive results have beenobtained (73,75–77). Genetic and environmental factors that
contribute to the development of EGFR-TKI pneumonitis remain to be understood.
NSIP (Fig 2), OP (Fig 1), DAD (Fig 6), and HP (Fig 5)
patterns have been reported with EGRF-TKIs. Poor prognosis is expected when there is a short interval between the initiation of the targeting therapy and the onset of pneumonitis,
when the CT findings are represented by a DAD pattern, andwhen there is preexisting ILD (58). Severe and potentially fatal7

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

Figure 3: Images show pembrolizumab-related pneumonitis with organizing pneumonia pattern in a 68-year-old man with lung adenocarcinoma. (a, b) Lung window images of CT scans obtained at levels of aortic arch (a) and liver dome (b), respectively, show patchy
parenchymal consolidation, ground-glass opacity, and nodules in both lungs. Also note right hilar nodal enlargement (N) and tumor pleuralseeding (arrowheads). Patient received right upper lobectomy and following adjuvant concurrent chemotherapy-radiation therapy 3 years
before current CT examination. Pembrolizumab was given 14 days prior to this CT examination. (c, d) Follow-up CT scans obtained 1.5
months after and at similar levels to a and b, respectively, demonstrate much decreased extent and attenuation of lung lesions. Patient underwent tapering of corticosteroid intake.

pneumonitis in patients treated with ICIs plus EGFR-TKIs has
been recently reported (56,78).
Emerging observations indicate that a milder form of lungreaction to EGFR-TKIs may manifest at imaging only withoutclinical symptoms, especially in the setting of the newer EGFRTKI treatments. A novel type of drug-related pulmonary phenomenon called transient asymptomatic pulmonary opacities has
been described in up to 20% of patients with NSCLC treatedwith the third-generation EGFR-TKI osimertinib (Fig 8)(72,79). Transient asymptomatic pulmonary opacities are described as localized pulmonary opacities mostly with radiologic
simple pulmonary eosinophilia pattern, which resolves without any treatment during continued osimertinib therapy with a
median 6-week duration (Figs 1, 8). Interestingly, patients
who developed this apparent grade 1 pneumonitis had longer
progression-free survival and overall survival compared withpatients without transient asymptomatic pulmonary opacities,
indicating the potential association between drug-related phenomena and treatment benefits.
mTOR inhibitors.—DRP is frequently seen in patients with
mTOR inhibitors, including temsirolimus and everolimus.
Temsirolimus has been approved for treatment of renal cell
8

carcinoma (56). In a retrospective study of 22 patients, eight(36%) developed DRP with areas of ground-glass opacity andconsolidation (80). In 178 patients with advanced renal cell carcinoma, 52 patients (29%) developed DRP (81). In 46 patientswith metastatic renal cell carcinoma (21 with temsirolimus and25 with everolimus), CT evidence of pneumonitis was seen in
14 patients (30%). Stable disease by using Response Evaluation
Criteria in Solid Tumors criteria was achieved in 12 (86%) of 14
patients who developed radiologic pneumonitis compared with
14 (44%) of 32 without pneumonitis (P , .01) (53).
In 66 patients with advanced neuroendocrine tumors who
were treated with everolimus, DRP was reported in 14 (21%)
patients (OP pattern in eight, NSIP pattern in five, and HP
pattern in one) (Fig 4) (65). In 40 patients with Waldenstrom
macroglobulinemia being treated with everolimus, 23 (58%) patients developed DRP, with a radiologic OP pattern in 16 andNSIP pattern in seven (82).
According to the management guideline by Albiges et al (83),asymptomatic patients with mTOR pneumonitis and radiologicchanges only (grade 1) may continue mTOR inhibitor therapy
without dose adjustment at the treating physician’s discretion.
However, patients should be informed of any signs of worsening
to look out for, which would require contacting their physician.
radiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al

Figure 4: Images show everolimus (mechanistic target of rapamycin)–related pneumonitis with organizing pneumonia pattern ina 68-year-old woman with breast cancer lung metastasis. (a) Lung
window of CT scan obtained at level of liver dome shows metastatic
lung nodule from breast cancer. (b) Lung window image obtained
at level of 15 mm inferior to a and 2.5 months after everolimus use
demonstrates parenchymal opacity composed of ground-glass opacity
and consolidation (arrows) in bilateral lower lung zones. (c) Coronal
reformatted image depicts same opacity in lower lung zones.

Anaplastic lymphoma kinase inhibitors.—Severe acute pneumonitis in patients receiving crizotinib therapy for advanced
NSCLC has been reported (69). In the recent meta-analysis(84) of 18 trials with 2261 patients with anaplastic lymphoma
kinase inhibitor monotherapy and advanced NSCLC, the overall incidence of pneumonitis was 2.14% for all grades, 1.33%
for high-grade pneumonitis (grade 3 or above), and 0.22% for
grade 5 pneumonitis. Similar to the EGFR-TKI study, Japanesecohorts showed a higher incidence of anaplastic lymphoma kinase–inhibitor pneumonitis for all grades (6.25% vs 1.14%; P, .001) and grade 3 and above pneumonitis (3.31% vs 0.39%;
P , .001), compared with non-Japanese cohorts from multiple countries other than Japan (Table 2) (84). In postmarketing surveillance of crizotinib therapy in Japan, the incidence ofpneumonitis associated with crizotinib therapy was 5.8% for all
grades, and 3.5% for grade 3 or greater pneumonitis. In 27% of
patients with pneumonitis, CT findings were suggestive of thepresence of DAD. Age 55 years or older, Eastern Cooperative
Oncology Group performance status between 2 and 4, smoking
history, previous or concomitant ILD, and comorbid pleural effusion were noted as significant risk factors for crizotinib-related
pneumonitis (85).
Radiology: Volume 00: Number 0— 2021 n radiology.rsna.org

CD20 antibody.—Rituximab, a B-cell–depleting monoclonal
antibody, has been reported to cause pulmonary toxicity. In asystematic review of 21 clinical trials and 40 case reports and/or series, 121 patients were reported to have DRP. The mostcommon indication for the drug therapy was diffuse large Bcell lymphoma. The DRP occurred more frequently in malepatients and most commonly in the 5th and 6th decades of life.
Rituximab-related pneumonitis was fatal in 18 (15%) of 121
cases and showed DAD pattern at CT (86).
ICI Therapy
The U.S. Food and Drug Administration has approved agentsincluding ipilimumab (cytotoxic T-lymphocyte–associatedprotein 4 inhibitor), nivolumab, and pembrolizumab (programmed cell death protein 1 [PD-1] inhibitors), as well as
atezolizumab and durvalumab (programmed death ligand 1[PD-L1] inhibitors) to treat different types of advanced cancer(87). In this setting, ICI therapy is associated with a varietyof immune-related adverse effects that can affect any organ(6,56). The initial reports have described a spectrum of radiologic patterns of interstitial pneumonias and clinical courses(Table 2) (12,35,36,88).
9

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

Figure 5: Images show docetaxel-related pneumonitis with hypersensitivity pneumonitis pattern in a 62-year-old woman with breast cancer. (a, b) Lung window of CT
scans obtained at levels of great vessels (a) and cardiac ventricle (b), respectively, show patchy and wide areas of ground-glass opacity and some small nodular lesions(arrowheads in b) in both lungs. Also note area of lobular hypoattenuation (open arrow in b) in left lower lobe. Patient had been undergoing docetaxel chemotherapy afterright mastectomy and sentinel lymph node dissection. (c, d) Coronal images also demonstrate areas of ground-glass opacity, small nodules (arrowheads), and lobular
areas (open arrow) of mosaic perfusion in both lungs. (e) Transverse and (f) coronal-reformatted CT images obtained at similar levels to and 6 months after a and c, respectively, and with discontinuation of docetaxel therapy, show disappeared lung lesions.

Figure 6: Images show erlotinib-related pneumonitis with diffuse alveolar damage pattern in a 40-year-old man with an advanced-stage lungadenocarcinoma. (a, b) Lung window images of CT scans obtained at levels of aortic arch (a) and cardiac ventricles (b), respectively, and after
erlotinib therapy, depict diffuse ground-glass opacity in entire right lung, features compatible with diffuse alveolar damage. Also note masses (arrows)
in left lung, lung-to-lung metastatic nodules (arrowheads) in both lungs, and a large amount of pericardial effusion (open arrows).

In a meta-analysis (89) including 4496 patients from 20 single-tumor-type trials of PD-1 inhibitor including 12 melanoma
studies, five NSCLC studies, and three renal cell carcinoma studies, the overall incidence of pneumonitis during PD-1 inhibitor
monotherapy was 2.7% (95% CI: 1.9, 3.6) for all grades and 0.8%
(95% CI: 0.4, 1.2) for grade 3 or higher pneumonitis. The incidence of PD-1–related pneumonitis was higher in patients with
NSCLC or renal cell carcinoma compared with that in patientswith melanoma, and during combination therapy compared with10

monotherapy. In another meta-analysis (90) of 19 clinical trials of
PD-1 inhibitors and PD-L1 inhibitors as single-agent therapy in
NSCLC, the incidence was higher in patients treated with PD-1
inhibitors compared with those treated with PD-L1 inhibitors(3.6% vs 1.3%, respectively; P = .001), providing valuable insightfor optimal clinical selection of these agents given the overlapping
approved indications of PD-1 and PD-L1 inhibitors. A subanalysis
of patients with NSCLC treated with pembrolizumab in the phase
I KEYNOTE-001 trial demonstrated that the overall incidence ofradiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al

Figure 7: Images show osimertinib-related pneumonitis with simple pulmonary eosinophilia pattern in a 60-year-old man with lung adenocarcinoma. (a) Lung window image obtained at level of distal main bronchi shows multifocal opacity (arrows) in right upper lobe and superior segmentof left lower lobe during osimertinib therapy. (b) CT scan obtained at similar level to and 2 months after a demonstrates that opacity lesions in both
lungs have disappeared completely. Patient did not undergo any therapy for opacity lesions.

pneumonitis was 3.8%. A higher incidence was noted in patientswith a history of asthma or chronic obstructive pulmonary disease(5.3%) and in those with a history of thoracic radiation (6.0%)(6,91). A retrospective study enrolling 1826 patients with cancer reported 64 (3.5%) cases of ICI-related pneumonitis, whichmore commonly occurred in men and former or current smokers, with a median age of 59 years. In this series, 66% of patientswith pneumonitis had grade 2 or 3, 9% had grade 4, and 9% had
grade 5 (fatal) pneumonitis. An earlier onset was noted in lungcancer versus melanoma (median of 2.1 months vs 5.2 months;
P = .02). OP (23%) was the most common pattern followed by
HP pattern (16%) (87,92). Moreover, in a recent meta-analysis
of fatal toxicities related to ICIs, DRP was identified as the mostcommon toxicity leading to PD-1/PD-L1–related mortality, accounting for 35% of all deaths (88,93). In a study of 20 patientswith DRP among 170 patients with melanoma, lung cancer, andlymphoma treated with PD-1 inhibitors, OP pattern (Fig 3) was
found in 13 patients and was the most common pattern, followed
by NSIP pattern in three, HP pattern in two, and DAD pattern(acute respiratory distress syndrome/acute respiratory distress syndrome pattern in the study referring to the American Thoracic
Society/European Respiratory Society classification of idiopathic
interstitial pneumonias) in two patients (54). The CT patterns
were associated with the toxicity grades of pneumonitis as definedby Common Terminology Criteria for Adverse Events; DAD
pattern had the highest grades, followed by OP pattern, whereas
NSIP and HP patterns had lower grades, indicating the utility of
CT pattern–based approach in assessing the severity of ICI-related
pneumonitis (54). Seventeen patients received corticosteroid therapy, and three also received infliximab treatment. Seven patientswere retreated, of whom two developed DRPs again. One patientdemonstrated pneumonitis flare-up on tapering of corticosteroid
intake without retreatment with ICI or any other agents, further
indicating the complex nature of the entity and importance of imaging follow-up of these patients (54).

Pathologic Analysis
Lung biopsy may be indicated in patients in whom the clinicaland radiologic picture do not clearly point to a specific pattern
Radiology: Volume 00: Number 0— 2021 n radiology.rsna.org

of lung injury or in whom the differential diagnosis raises theconsideration of markedly different therapeutic strategies (eg,drug toxicity vs infection or malignancy).
What Histologic Characteristics Should Be Documented inLung Biopsies Performed for DRP?
Lung biopsies should be evaluated for patterns of interstitial pneumonia by using criteria within the American Thoracic Society/
European Respiratory Society International Multidisciplinary
Classification of the Idiopathic Interstitial Pneumonias (94,95)
including cellular and fibrotic NSIP, usual interstitial pneumonia, OP (including acute fibrinous subtype), lymphoid interstitial
pneumonia and DAD, as well as bronchocentric inflammatorychanges (including hypersensitivity pneumonia) and noncaseating granulomas (96). Diffuse malignant infiltration, mimicking
or coexisting with ILD, should be ruled out. In addition, depending on the morphologic features and the clinical setting, infectious
agents such as bacteria, fungi, mycobacteria, or viral agents should
be searched for by using special stains where indicated.
What Histologic Features Are Most Suggestive of DRP?
Although any of the above histologic patterns can be seen in
DRP, there is a more frequent overlap of patterns, coexistenttissue eosinophilia, chronic interstitial inflammation, lymphoid aggregates, and pleuritis compared with idiopathic cases
showing similar histologic patterns. However, these same features are not specific because they are also seen in connective
tissue disease–related lung disease.
There are limited published data on the pathologic featuresof pulmonary toxicity in ICIs and targeting molecular therapies;
hence, most of the cases are diagnosed based on clinical andCT features only. Nonetheless, the main pathologic features described include cellular and/or fibrosing interstitial pneumonia,
OP, HP, DAD, and pulmonary eosinophilia (35,54).
What Information Is Available from Bronchoalveolar Lavage
Fluid Analysis?
Infectious organisms can be identified with bronchoalveolar
lavage fluid cultures (27). In 12 (46%) of 26 patients with11

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

shown to be effective in otherdisciplines (99). Multidisciplinary diagnosis is particularly
important in patients suspected of having DRP because
there is no individual featurethat is required or sufficientfor the diagnosis of DRP. The
multidisciplinary diagnosis approach typically involves clinicians, radiologists, and pathologists (if biopsy is performed)
and can be used in clinical settings and trials with centralized
review of adverse events. Because DRP is often observed in
more acute or subacute clinicalsettings, the actual consultations among subspecialties may
happen as informal and formal
Figure 8: Images show osimertinib-related transient asymptomatic pulmonary opacities in a 65-year-old woman with
communication by using telelung adenocarcinoma. (a) Lung window image of CT scan obtained at level of left main bronchus shows focal opacity
phone or virtual conference. In
areas (arrows) in left upper lobe during osimertinib therapy. (b) CT scan obtained at similar level to and 2 months after
more chronic or difficult cases,
a demonstrates that opacities seen at CT scan (a) have disappeared nearly completely without any therapy for opacity
lesions.
it may be discussed formally ata multidisciplinary diagnosis
everolimus treatment and initial diagnosis of DRP, bronchoalconference. It is important that multidisciplinary discussion
veolar lavage fluid cultures enabled a diagnosis of Pneumocystis
shall happen in the clinical context of the need for clinicaljirovecii pneumonia (97). Cell count of bronchoalveolar lavage
management of the patients suspected of having DRP.
fluid in DRP may disclose raised lymphocyte, neutrophil, andeosinophil numbers. Particularly in pulmonary eosinophilia
Description of Central Review for the Multidisciplinary
pattern, cell count helps to make a diagnosis of the disease by
Diagnosis of DRP
documenting eosinophilia. However, the cell count is not speTo determine the accurate incidence of DRP in clinical trials
cific, because similar results could be seen in other inflammaand postmarketing surveillance, the cases diagnosed by eachtory and infectious conditions (27,28,42,43).
physician in primary investigation site should be evaluated byusing a process of central review (100,101) to achieve uniform
Proposal for Diagnostic Criteria
criteria through accurate and consistent data. The strategy at
Camus et al (98) proposed the following diagnostic criteria forthe time of the review should be based on a multidisciplinary
DRP: (a) exposure to the causative drug, (b) development of
diagnosis approach, involving a multidisciplinary team consistpulmonary infiltrates, (c) meticulous exclusion of all other posing of at least one chest physician, one oncologist, one chest
sible causes, (d) dechallenge producing measurable improveradiologist, and (if a biopsy is available) one pathologist. Morement in symptoms and imaging, and (e) rechallenge causing
over, it is essential to use a mutually agreed diagnostic checklist
worsening. However, some patients do not have improvement(refer to Appendix E2 [online] for record of multidisciplinary
with dechallenge, and rechallenge is often impossible in many
discussion and Appendix E3 [online] for objective evaluation
clinical settings, thus making these criteria impractical in manyof chest CT and ILD) consistently throughout an individual
patients.
study or cohort. At first, each radiologist and chest physician
Therefore, we propose the following criteria: (a) newly idenshould independently evaluate the case, followed by the subsetified pulmonary parenchymal opacities at CT or chest radiogquent multidisciplinary discussion among the experts to reachraphy, commonly in a bilateral nonsegmental distribution; (b)a consensus.
temporal association of presentation with the initiation of a systemic therapeutic agent; and (c) exclusion of other likely causes
Management(Table 3) (see also Figs E1–E5 [online]).
Pharmacovigilance, or drug safety monitoring, plays animportant role in identifying, understanding, and preventProposed Method for Central Review
ing adverse drug reactions. The World Health Organization
Program for International Drug Monitoring (VigiAccess)Introduction of Multidisciplinary Diagnosis
provides an international forum for collaboration in pharThe process of multidisciplinary diagnosis is by means of intermacovigilance, collecting data from real-world settings. All
active multidisciplinary discussion, an approach that has been
drug-related adverse effects should be declared to the phar12radiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al
Table 3: Clinical, Pathologic, and Radiologic Features of DRP Compared with Pneumonia, Diffuse Alveolar Hemorrhage, Pulmonary Edema, Radiation Pneumonitis, and Pulmonary Metastases

Variable

Clinical Features

DRP

OP, DAD, cellular and fibrotic
Temporal relationshipAsymptomatic to
NSIP, granulomatous
between drug exposure
acutely progressiveinterstitial pneumonia,
and onset of disease;dyspnea, andPEo, and lymphoid
cough with or with- improvement with druginterstitial pneumonia
cessationout feverFilling of alveolar spaces
Fever, chill,
Varying disease patterns
by exudate of edema fluid
productive cough,depending on patients’and neutrophil (lobar);
myalgia, headache
immune status;
patchy peribronchiolar
immunocompetent versus
inflammation with lessimmunocompromised
abundant edema formation
status; positive microbiology(bronchopneumonia); andculture or polymerase chainmononuclear inflammatory
reaction test; improvement
cell infiltrate in alveolar
with antibiotic treatment
septa and interstitial
tissue surrounding small
parenchymal vessels(interstitial pneumonia)
Intraalveolar hemorrhage,
Injury to alveolar-capillary
Hemoptysis
hemosiderin-laden
microcirculation (eg,(two-thirds ofmacrophages in alveolar
microscopic polyangiitis),patients), anemia
spaces and interstitium, andcirculating autoantibody
and diffuse opacity
occasional focal or diffuse(eg, ANCA), coagulation
at imaging
areas of capillaritis
disorders
Expansion of connective
Dyspnea, cough,Hydrostatic (cardiac or
tissue space aroundfrothy sputum
renal failure) andconducting airways,(sometimes)
permeability edema
accompanying vessels, and(DAD)
interlobular septa (hydrostaticedema); alveolar space andinterstitial edema; hyaline
membrane formation andproliferation of type II cells

Pneumonia(see Fig E1[online])Diffuse alveolar
hemorrhage(see Fig E2[online])Pulmonaryedema(see Fig E3[online])Radiation
pneumonitis(see Fig E4[online])Dyspnea, dry cough,chest pain with orwithout fever(low grade)

Progressively
Pulmonaryworsening
lymphangitic
dyspnea, coughcarcinomatosis(see Fig E5[online])Relevant Factors

Temporal relationship toradiation exposure(3–12 weeks after
irradiation)

Most commonly withgastric, breast, lung,and pancreas cancers

Pathologic Features

Radiologic Features
Various interstitial pneumonia
patterns including OP,
DAD, NSIP, HP, and PEo
Lobar pneumonia,
bronchopneumonia, andinterstitial pneumonia
patterns; atypical
pneumonia (septic emboli,
abscess, and chronic
pneumonia such as
actinomycosis or chronic
necrotizing pulmonary
aspergillosis)

Bilateral patchy opacities
in middle and lower lungzones on chest radiographs;
diffuse or geographic
ground-glass opacities/
consolidation at CT
Hazy opacities, Kerley lines,
batwing appearance inhydrostatic edema; patchy
and widespread areas ofparenchymal opacities inpermeability edema andtheir evolutional change;
pleural effusion (morefrequently in hydrostaticedema)
Opacities within radiation
portal or roughly withinarea of high-dose radiation;
ground-glass opacity andOP pattern away fromradiation portal

Airspace and interstitial edema,proceeding to poorly definedconsolidation, DAD andtype II cell hyperplasia;
evolutional changes toradiation fibrosis; HP or
OP pattern away fromradiation portal can occur
Thickening of bronchovascular Linear or reticulonodular
lesions on chest radiographs;
bundles and septae, related
ground-glass opacities;
to proliferation of neoplastic
septal thickening (smoothcells, interstitial inflammation
or nodular), bilateraland fibrosis (desmoplastic
asymmetric or unilateral;
reaction) and lymphatic
pleural effusion at CT
dilatation by edema or
tumor section (mucin)

Note.—ANCA = antinuclear cytoplasmic antibody, DAD = diffuse alveolar damage, DRP = drug-related pneumonitis, HP = hypersensitivity pneumonitis, NSIP = nonspecific interstitial pneumonia, OP = organizing pneumonia, PEo = pulmonary eosinophilia. Source.—Reference 121.

Radiology: Volume 00: Number 0— 2021 n radiology.rsna.org

13

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis

macovigilance program, which is the cornerstone of the alert
system. With clinicians’ reports on adverse drug reactions,the incorporation of clinical and pharmacologic information
could help to avoid the unnecessary exposure to adverse drug
reactions (102,103).
In general, delayed diagnosis of DRP is associated withhigher severity of lung injury and less reversibility, resulting inresidual lung damage (ie, fibrosis) (27,48). Thus, early diagnosis and cessation (except some drugs; refer to previous sections
regarding specific agents) of the offending drug intake promote
optimal outcomes in patients with DRP. In addition, glucocorticoids are commonly administered to facilitate the resolutionof lung injury, particularly for those severely affected (National
Cancer Institute grade 3–4 pneumonitis) as assessed by symptoms, gas exchange derangements, and radiologic abnormalities(27,35,45,48). These patients usually require hospitalization for
their initial treatment and monitoring (35,45). Supportive measures, including supplemental oxygen and noninvasive or invasive mechanical ventilator support, may be needed.
For the management of ICI-related pneumonitis, the National Comprehensive Cancer Network, American Societyof Clinical Oncology, Society for Immunotherapy of Cancer,
and European Society for Medical Oncology guidelines (45–47,104,105) recommend discontinuing ICI therapy for any
grade of pneumonitis and recommend treating grade 2 pneumonitis with corticosteroids. Permanent discontinuation of ICIs issuggested for grade 3–4 pneumonitis by all guidelines. For those
without improvement on corticosteroids after 48 hours, infliximab, mycophenolate mofetil, or intravenous immunoglobulin
may be used (45–47,104,105).
Is Preexisting ILD a Risk Factor for DRP and Does Preexisting
ILD Lead to Worse Outcomes in Patients with DRP?
Preexisting ILD is a risk factor for the development of DRP(27,28,48). Multiple studies on the incidence of lung toxicity
associated with antineoplastic agents have demonstrated that
preexisting ILD is associated with a higher likelihood of DRP,
sometimes described as an acute exacerbation of preexisting ILD(28,74,80,106–112). For example, the odds ratio for developing
DRP in patients with lung cancer treated with chemotherapy
or gefitinib ranges from 4.8 to 25.3 (depending on the severityof ILD) in patients with preexisting ILD compared with those
without preexisting ILD (74). A recent systematic review (113) on
DRP found that preexisting ILD is an independent risk factor for
DRP with a wide spectrum of therapeutic agents. However, someuncertainty remains on whether preexisting ILD is a risk factor
for the development of ICI-associated pneumonitis in particular,largely due to the exclusion of patients with preexisting ILDs fromclinical trials of ICIs. Recent studies have suggested preexisting fibrotic changes at CT are associated with an increased risk of antiPD-1–related pneumonitis in patients with NSCLC (114,115).
Several studies demonstrated worse outcome related to
DRP among patients with preexisting ILD compared withthose without (74,109,110,112,116–119). For example, Kudoh et al (110) reported the odds ratio for fatal outcomesfrom DRP related to chemotherapy or gefitinib therapy to be
2.27 for patients with preexisting ILD compared with those
14

without ILD. Furthermore, greater CT extent of preexisting
ILD portended higher risk of fatal outcome.
Does Glucocorticoid Therapy Improve Clinical Outcome inPatients with DRP?
Glucocorticoid therapy is often used in patients with DRP toameliorate and to expedite the recovery of lung injury (27,45,48).
This strategy is commonly used when DRP is moderate to severe
and of acute or fulminant onset. However, this practice is based on
retrospective studies and expert opinion because no clinical trial
has been performed to prove the efficacy of glucocorticoid therapy
in the treatment of patients with DRP (113).

Conclusion
This position paper of the Fleischner Society summarizes simplified diagnostic criteria, CT pattern approach, and management
recommendation of drug-related pneumonitis (DRP) in theemerging era of molecular targeting agents and cancer immunotherapy, by using a multidisciplinary approach. The diagnosis
and management of DRP will continue to evolve with the advancement of treatments, and a radiologic pattern approach withmultidisciplinary diagnosis will remain crucially important forthe optimal treatment of the patients.
Acknowledgments: We are grateful for the librarians Myung-Ah Shim and Jaero
Park for their dedicated support of manuscript formatting. Both librarians are working at the Samsung Medical Information & Media Services of Samsung Medical
Center located in Seoul, South Korea.
Author contributions: Guarantors of integrity of entire study, T.J., K.S.L., T.F.,
Y.I., H.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important
intellectual content, all authors; approval of final version of submitted manuscript,
all authors; agrees to ensure any questions related to the work are appropriately
resolved, all authors; literature research, T.J., K.S.L., M.N., J.H.R., H.Y.L., T.F.,
K.K.B., J.M.G., H.U.K., L.R., C.M.S.P., C.P., H.H.; clinical studies, T.J., K.S.L.,
M.N., J.H.R., H.Y.L., J.V., Y.I., H.H.; and manuscript editing, T.J., K.S.L., M.N.,
W.D.T., J.H.R., H.Y.L., C.J.R., A.A.B., K.K.B., J.M.G., H.U.K., D.A.L., A.G.N.,
L.R., C.M.S.P., J.V., S.R., G.D.R., C.P., Y.I., H.H.
Disclosures of Conflicts of Interest: T.J. disclosed no relevant relationships.

K.S.L. Activities related to the present article: disclosed no relevant relationships.
Activities not related to the present article: receives royalties from Elsevier, Lippincott, and Springer. Other relationships: disclosed no relevant relationships. M.N.
Activities related to the present article: disclosed no relevant relationships. Activities
not related to the present article: is a consultant for Daiichi Sankyo and AstraZeneca; has grants/grants pending with Merck, Canon Medical Systems, Daiichi
Sankyo, and AstraZeneca; received payment for lectures including service on speakers bureaus from Roche. Other relationships: disclosed no relevant relationships.
W.D.T. disclosed no relevant relationships. J.H.R. disclosed no relevant relationships. H.Y.L. disclosed no relevant relationships. C.J.R. disclosed no relevant relationships. T.F. disclosed no relevant relationships. A.A.B. Activities related to thepresent article: disclosed no relevant relationships. Activities not related to thepresent article: is a consultant for Daiichi Pharmaceutical and Olympus Medical;
received payment for lectures including service on speakers bureaus from Olympus
Medical; receives royalties from Elsevier. Other relationships: disclosed no relevant
relationships. K.K.B. Activities related to the present article: disclosed no relevant
relationships. Activities not related to the present article: is DMC chair of Bioge andHumanetics; is member of scientific advisory board for Galecto, Third Pole, Galapagos, Boehringer Ingelheim, Theravance, Lifemax, Pliant, Blade Therapeutics, Open
Source Imaging Consortium, Huitai Biomedicine, Lilly, Dispersol, and DevPro Biopharma; has grants/grants pending with NHLBI. Other relationships: disclosed no
relevant relationships. J.M.G. Activities related to the present article: disclosed no
relevant relationships. Activities not related to the present article: has grants/grants
pending with Infinitt Healthcare and Dongkook Lifescience. Other relationships:
disclosed no relevant relationships. H.U.K. Activities related to the present article:
disclosed no relevant relationships. Activities not related to the present article: hasradiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al
grants/grants pending with Siemens, Philips, and Bayer; received payment for lectures including service on speakers bureaus from Philips, Astra Zeneca, Boehringer
Ingelheim, and Merck, Sharp & Dohme. Other relationships: disclosed no relevant
relationships. D.A.L. Activities related to the present article: disclosed no relevant
relationships. Activities not related to the present article: is a consultant for Astra
Zeneca, Boehringer Ingelheim, Daiichi Sankyo, and Parexel. Other relationships:
disclosed no relevant relationships. A.G.N. Activities related to the present article:
disclosed no relevant relationships. Activities not related to the present article: isa consultant for Boehringer Ingelheim, Medical Quantitative Image Analysis, andGalapagos; received payment for lectures including service on speakers bureaus from
Boehringer Ingelheim; received payment for development of educational presentations from Up To Date. Other relationships: disclosed no relevant relationships.
L.R. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a consultant for Boehringer Ingelheim,
Roche, Fibrogen, Promedior, Zambon, Veracyte, RespiVant, Mitoimmune, Pliant
Therapeutics, Daewoo Pharmaceuticals, and DevPro Biopharma; has grants/grants
pending with Boehringer Ingelheim; received payment for lectures including service
on speakers bureaus from Boehringer Ingelheim, Cipla, and Roche. Other relationships: disclosed no relevant relationships. C.M.S.P. disclosed no relevant relationships. J.V. Activities related to the present article: disclosed no relevant relationships.
Activities not related to the present article: received payment for lectures including
service on speakers bureaus from Boehringer Ingelheim and Roche. Other relationships: disclosed no relevant relationships. S.R. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article:
is employee of Lenox Hill Hospital; receives royalties and payment for developmentof educational presentations from American College of Chest Physicians. Other
relationships: disclosed no relevant relationships. G.D.R. disclosed no relevant relationships. C.P. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a consultant for Daiichi Sankyo,
Astra Zeneca, and Siemens. Other relationships: disclosed no relevant relationships.
Y.I. disclosed no relevant relationships. H.H. Activities related to the present article:
disclosed no relevant relationships. Activities not related to the present article: is aconsultant for Mitsubishi Chemical and Canon Medical Systems; has grants/grants
pending with Konica-Minolta and Canon Medical Systems. Other relationships:
disclosed no relevant relationships.

References

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously
treated non-small-cell lung cancer. N Engl J Med 2005;353(2):123–132.
2. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation
with clinical response to gefitinib therapy. Science 2004;304(5676):1497–
1500.
3. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the
response of T cells to stimulation. J Exp Med 1995;182(2):459–465.
4. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, anovel member of the immunoglobulin gene superfamily, upon programmed
cell death. EMBO J 1992;11(11):3887–3895.
5. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumabin patients with metastatic melanoma. N Engl J Med 2010;363(8):711–723[Published correction appears in N Engl J Med 2010;363(13):1290.].
6. Nishino M, Hatabu H, Hodi FS. Imaging of Cancer Immunotherapy: Current Approaches and Future Directions. Radiology 2019;290(1):9–22.
7. Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. NonSmall-Cell Lung Cancer: Role of the Immune System and Potential for
Immunotherapy. J Thorac Oncol 2015;10(7):974–984.
8. Haslam A, Prasad V. Estimation of the Percentage of US Patients With Cancer
Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy
Drugs. JAMA Netw Open 2019;2(5):e192535.
9. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia
and gefitinib. Lancet 2003;361(9352):137–139.
10. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the ImmuneRelated Adverse Effects of Immune Checkpoint Inhibitors: A Review. JAMA
Oncol 2016;2(10):1346–1353.
11. Tirumani SH, Ramaiya NH, Keraliya A, et al. Radiographic Profiling of
Immune-Related Adverse Events in Advanced Melanoma Patients Treatedwith Ipilimumab. Cancer Immunol Res 2015;3(10):1185–1192.
12. Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD1-Related Pneumonitis during Cancer Immunotherapy. N Engl J Med
2015;373(3):288–290.
13. Hotta K, Harita S, Bessho A, et al. Interstitial lung disease (ILD) during
gefitinib treatment in Japanese patients with non-small cell lung cancer(NSCLC): Okayama Lung Cancer Study Group. J Clin Oncol 2004;22(14_suppl):7063https://doi.org/10.1200/jco.2004.22.90140.7063.
14. Makris D, Scherpereel A, Copin MC, et al. Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer 2007;7(1):150.

Radiology: Volume 00: Number 0— 2021 n radiology.rsna.org

15. Liu V, White DA, Zakowski MF, et al. Pulmonary toxicity associated witherlotinib. Chest 2007;132(3):1042–1044.
16. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitiallung disease, antitumor response, and survival in non-small-cell lung cancer
patients treated with gefitinib. J Clin Oncol 2006;24(16):2549–2556.
17. Hotta K, Kiura K, Tabata M, et al. Interstitial lung disease in Japanese patientswith non-small cell lung cancer receiving gefitinib: an analysis of risk factors
and treatment outcomes in Okayama Lung Cancer Study Group. Cancer J
2005;11(5):417–424.
18. Hotta K, Kiura K, Takigawa N, et al. Comparison of the incidence andpattern of interstitial lung disease during erlotinib and gefitinib treatment
in Japanese Patients with non-small cell lung cancer: the Okayama Lung
Cancer Study Group experience. J Thorac Oncol 2010;5(2):179–184.
19. Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lungdisease and predictive factors for tumor response in patients with advanced
non-small cell lung cancer treated with gefitinib. Lung Cancer 2004;45(1):93–
104.
20. Seto T, Yamamoto N. Interstitial lung diseases (ILD) induced by gefitinibin patients with advanced non-small cell lung cancer (NSCLC): Results ofa West Japan Thoracic Oncology Group (WJTOG) epidemiological survey.
J Clin Oncol 2004;22(14_suppl):7064.
21. Chou CL, Ko HW, Wang CW, Yu CT, Kuo HP, Huang CD. Erlotinibassociated near-fatal interstitial pneumonitis in a patient with relapsed lungadenocarcinoma. Chang Gung Med J 2010;33(1):100–105.
22. Vahid B, Esmaili A. Erlotinib-associated acute pneumonitis: report of twocases. Can Respir J 2007;14(3):167–170.
23. Del Castillo Y, Espinosa P, Bodí F, et al. Interstitial lung disease associatedto erlotinib treatment: a case report. Cases J 2010;3(1):59.
24. Park H, Sholl LM, Hatabu H, Awad MM, Nishino M. Imaging ofPrecision Therapy for Lung Cancer: Current State of the Art. Radiology
2019;293(1):15–29.
25. Duchemann B, Annesi-Maesano I, Jacobe de Naurois C, et al. Prevalence
and incidence of interstitial lung diseases in a multi-ethnic county of Greater
Paris. Eur Respir J 2017;50(2):1602419.
26. Thomeer MJ, Costabe U, Rizzato G, Poletti V, Demedts M. Comparison ofregistries of interstitial lung diseases in three European countries. Eur Respir
J Suppl 2001;32:114s–118s.
27. Skeoch S, Weatherley N, Swift AJ, et al. Drug-Induced Interstitial Lung
Disease: A Systematic Review. J Clin Med 2018;7(10):E356.
28. Ryu JH. Chemotherapy-induced pulmonary toxicity in lung cancer patients.
J Thorac Oncol 2010;5(9):1313–1314.
29. Camus P, Bonniaud P, Fanton A, Camus C, Baudaun N, Foucher P.
Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med
2004;25(3):479–519, vi.
30. Myers JL, Limper AH, Swensen SJ. Drug-induced lung disease: a pragmaticclassification incorporating HRCT appearances. Semin Respir Crit Care Med
2003;24(4):445–454.
31. Erasmus JJ, McAdams HP, Rossi SE. High-resolution CT of drug-induced
lung disease. Radiol Clin North Am 2002;40(1):61–72.
32. Nishino M, Hatabu H, Hodi FS, Ramaiya NH. Drug-Related Pneumonitis in the Era of Precision Cancer Therapy. JCO Precis Oncol 2017;1(1):
1–12.
33. Kroschinsky F, Stölzel F, von Bonin S, et al. New drugs, new toxicities:
severe side effects of modern targeted and immunotherapy of cancer andtheir management. Crit Care 2017;21(1):89.
34. Cancer Therapy Evaluation Program. Common Terminology Criteria for
Adverse Events. Version 5.0. https://ctep.cancer.gov/protocoldevelopment/
electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Published November 27, 2017. Accessed October 1, 2019.
35. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With
Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin
Oncol 2017;35(7):709–717 [Published correction appears in J Clin Oncol
2017;35(22):2590.].
36. Nishino M, Chambers ES, Chong CR, et al. Anti-PD-1 Inhibitor-Related
Pneumonitis in Non-Small Cell Lung Cancer. Cancer Immunol Res
2016;4(4):289–293.
37. Kuhlman JE. The role of chest computed tomography in the diagnosis ofdrug-related reactions. J Thorac Imaging 1991;6(1):52–61.
38. Taylor CR. Diagnostic imaging techniques in the evaluation of drug-induced
pulmonary disease. Clin Chest Med 1990;11(1):87–94.
39. Maldonado F, Danoff SK, Wells AU, et al. Transbronchial Cryobiopsy for
the Diagnosis of Interstitial Lung Diseases: CHEST Guideline and Expert
Panel Report. Chest 2020;157(4):1030–1042.
40. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-Hospital
Mortality after Surgical Lung Biopsy for Interstitial Lung Disease in the UnitedStates. 2000 to 2011. Am J Respir Crit Care Med 2016;193(10):1161–1167.
15

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis
41. Han Q, Luo Q, Xie JX, et al. Diagnostic yield and postoperative mortality associated with surgical lung biopsy for evaluation of interstitial lungdiseases: A systematic review and meta-analysis. J Thorac Cardiovasc Surg
2015;149(5):1394–401.e1.
42. Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic
Society clinical practice guideline: the clinical utility of bronchoalveolar
lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care
Med 2012;185(9):1004–1014.
43. Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities oftargeted anticancer therapies. CA Cancer J Clin 2013;63(4):249–279.
44. National Comprehensive Cancer Network. Management of Immunotherapy-related toxicities. Version 1. https://www.nccn.org/store/login/login.
aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/
immunotherapy.pdf. Published 2019. Accessed October 1, 2019.
45. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of ImmuneRelated Adverse Events in Patients Treated With Immune Checkpoint
Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice
Guideline. J Clin Oncol 2018;36(17):1714–1768.
46. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated withimmune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working
Group. J Immunother Cancer 2017;5(1):95.
47. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from
immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. Ann Oncol 2017;28(suppl_4):iv119–iv142 [Published correction appears in Ann Oncol 2018;29(Suppl 4):iv264–iv266.].
48. Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the
diagnosis and treatment of drug-induced lung injuries. Respir Investig
2013;51(4):260–277.
49. Eaden JA, Skeoch S, Waterton JC, Chaudhuri N, Bianchi SM. How consistently do physicians diagnose and manage drug-induced interstitial lungdisease? Two surveys of European ILD specialist physicians. ERJ Open Res
2020;6(1):00286-2019.
50. Chuzi S, Tavora F, Cruz M, et al. Clinical features, diagnostic challenges,
and management strategies in checkpoint inhibitor-related pneumonitis.
Cancer Manag Res 2017;9:207–213.
51. Toi Y, Sugawara S, Kawashima Y, et al. Association of Immune-Related Adverse
Events with Clinical Benefit in Patients with Advanced Non-Small-Cell Lung
Cancer Treated with Nivolumab. Oncologist 2018;23(11):1358–1365.
52. Haratani K, Hayashi H, Chiba Y, et al. Association of Immune-Related
Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer.
JAMA Oncol 2018;4(3):374–378.
53. Dabydeen DA, Jagannathan JP, Ramaiya N, et al. Pneumonitis associated with
mTOR inhibitors therapy in patients with metastatic renal cell carcinoma:
incidence, radiographic findings and correlation with clinical outcome. Eur
J Cancer 2012;48(10):1519–1524.
54. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and ClinicalCourse. Clin Cancer Res 2016;22(24):6051–6060.
55. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agentsfor solid tumors. Chest 2008;133(2):528–538.
56. Nishino M, Hatabu H, Sholl LM, Ramaiya NH. Thoracic Complications ofPrecision Cancer Therapies: A Practical Guide for Radiologists in the New
Era of Cancer Care. RadioGraphics 2017;37(5):1371–1387.
57. Cleverley JR, Screaton NJ, Hiorns MP, Flint JD, Müller NL. Drug-induced
lung disease: high-resolution CT and histological findings. Clin Radiol
2002;57(4):292–299.
58. Min JH, Lee HY, Lim H, et al. Drug-induced interstitial lung disease intyrosine kinase inhibitor therapy for non-small cell lung cancer: a review oncurrent insight. Cancer Chemother Pharmacol 2011;68(5):1099–1109.
59. Rossi SE, Erasmus JJ, McAdams HP, Sporn TA, Goodman PC. Pulmonary
drug toxicity: radiologic and pathologic manifestations. RadioGraphics
2000;20(5):1245–1259.
60. Kim Y, Lee KS, Choi DC, Primack SL, Im JG. The spectrum of eosinophiliclung disease: radiologic findings. J Comput Assist Tomogr 1997;21(6):920–
930.
61. Bernheim A, McLoud T. A Review of Clinical and Imaging Findings in
Eosinophilic Lung Diseases. AJR Am J Roentgenol 2017;208(5):1002–1010.
62. Pietra GG. Pathologic mechanisms of drug-induced lung disorders. J Thorac
Imaging 1991;6(1):1–7.
63. Padley SP, Adler B, Hansell DM, Müller NL. High-resolution computed
tomography of drug-induced lung disease. Clin Radiol 1992;46(4):232–236.
64. Rosenow EC 3rd, Myers JL, Swensen SJ, Pisani RJ. Drug-induced pulmonary
disease. An update. Chest 1992;102(1):239–250.
65. Nishino M, Brais LK, Brooks NV, Hatabu H, Kulke MH, Ramaiya NH.
Drug-related pneumonitis during mammalian target of rapamycin inhibitor

16

therapy in patients with neuroendocrine tumors: a radiographic pattern-based
approach. Eur J Cancer 2016;53:163–170.
66. Silva CI, Müller NL. Drug-induced lung diseases: most common reaction
patterns and corresponding high-resolution CT manifestations. Semin
Ultrasound CT MR 2006;27(2):111–116.
67. Ellis SJ, Cleverley JR, Müller NL. Drug-induced lung disease: high-resolution
CT findings. AJR Am J Roentgenol 2000;175(4):1019–1024.
68. Johkoh T, Müller NL, Taniguchi H, et al. Acute interstitial pneumonia:
thin-section CT findings in 36 patients. Radiology 1999;211(3):859–863.
69. Tamiya A, Okamoto I, Miyazaki M, Shimizu S, Kitaichi M, Nakagawa
K. Severe acute interstitial lung disease after crizotinib therapy in a patient with EML4-ALK-positive non-small-cell lung cancer. J Clin Oncol
2013;31(1):e15–e17.
70. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease.
Part 2: Noncytotoxic drugs. Am Rev Respir Dis 1986;133(3):488–505.
71. Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J
Rheumatol 1987;14(6):1164–1171.
72. Lee H, Lee HY, Sun JM, et al. Transient Asymptomatic Pulmonary Opacities
During Osimertinib Treatment and its Clinical Implication. J Thorac Oncol
2018;13(8):1106–1112.
73. Suh CH, Park HS, Kim KW, Pyo J, Hatabu H, Nishino M. Pneumonitis
in advanced non-small-cell lung cancer patients treated with EGFR tyrosine
kinase inhibitor: Meta-analysis of 153 cohorts with 15,713 patients: Metaanalysis of incidence and risk factors of EGFR-TKI pneumonitis in NSCLC.
Lung Cancer 2018;123:60–69.
74. Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease in Japanesepatients with lung cancer: a cohort and nested case-control study. Am J Respir
Crit Care Med 2008;177(12):1348–1357.
75. Atagi S, Katakami N, Yoshioka H, et al. Nested case control study of proteomic
biomarkers for interstitial lung disease in Japanese patients with non-small-celllung cancer treated with erlotinib: a multicenter phase IV study (JO21661).
Clin Lung Cancer 2013;14(4):407–417.
76. Nyberg F, Barratt BJ, Mushiroda T, et al. Interstitial lung disease in gefitinibtreated Japanese patients with non-small-cell lung cancer: genome-wide
analysis of genetic data. Pharmacogenomics 2011;12(7):965–975.
77. Nyberg F, Ogiwara A, Harbron CG, et al. Proteomic biomarkers for acuteinterstitial lung disease in gefitinib-treated Japanese lung cancer patients.
PLoS One 2011;6(7):e22062.
78. Kotake M, Murakami H, Kenmotsu H, Naito T, Takahashi T. Highincidence of interstitial lung disease following practical use of osimertinibin patients who had undergone immediate prior nivolumab therapy. Ann
Oncol 2017;28(3):669–670.
79. Noonan SA, Sachs PB, Camidge DR. Transient Asymptomatic Pulmonary
Opacities Occurring during Osimertinib Treatment. J Thorac Oncol
2016;11(12):2253–2258.
80. Duran I, Siu LL, Oza AM, et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 2006;42(12):1875–1880.
81. Maroto JP, Hudes G, Dutcher JP, et al. Drug-related pneumonitis in patientswith advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol
2011;29(13):1750–1756.
82. Nishino M, Boswell EN, Hatabu H, Ghobrial IM, Ramaiya NH. Drug-Related
Pneumonitis During Mammalian Target of Rapamycin Inhibitor Therapy:
Radiographic Pattern-Based Approach in Waldenström Macroglobulinemia
as a Paradigm. Oncologist 2015;20(9):1077–1083.
83. Albiges L, Chamming’s F, Duclos B, et al. Incidence and management ofmTOR inhibitor-associated pneumonitis in patients with metastatic renal
cell carcinoma. Ann Oncol 2012;23(8):1943–1953.
84. Suh CH, Kim KW, Pyo J, Hatabu H, Nishino M. The incidence of ALK
inhibitor-related pneumonitis in advanced non-small-cell lung cancer patients:
A systematic review and meta-analysis. Lung Cancer 2019;132:79–86.
85. Gemma A, Kusumoto M, Kurihara Y, et al. Interstitial Lung Disease Onset
and Its Risk Factors in Japanese Patients With ALK-Positive NSCLC After
Treatment With Crizotinib. J Thorac Oncol 2019;14(4):672–682.
86. Hadjinicolaou AV, Nisar MK, Parfrey H, Chilvers ER, Ostör AJ. Noninfectious pulmonary toxicity of rituximab: a systematic review. Rheumatology(Oxford) 2012;51(4):653–662.
87. Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immunecheckpoint blockade: response evaluation and biomarker development. Nat
Rev Clin Oncol 2017;14(11):655–668.
88. Barjaktarevic IZ, Qadir N, Suri A, Santamauro JT, Stover D. Organizing
pneumonia as a side effect of ipilimumab treatment of melanoma. Chest
2013;143(3):858–861.
89. Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidenceof Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With

radiology.rsna.org n Radiology: Volume 00: Number 0— 2021

Johkoh and Lee et al
Advanced Cancer: A Systematic Review and Meta-analysis. JAMA Oncol
2016;2(12):1607–1616.
90. Khunger M, Rakshit S, Pasupuleti V, et al. Incidence of Pneumonitis WithUse of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors
in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
of Trials. Chest 2017;152(2):271–281.
91. Ahn MJ, Gandhi L, Hamid O, et al. Risk of pneumonitis in patients withadvanced NSCLC treated with pembrolizumab in KEYNOTE-001. Ann
Oncol 2015;26(Supplement 9):ix125.
92. Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir
J 2017;50(2):1700050 [Published correction appears in Eur Respir J
2017;50(5):1750050.].
93. Wang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With
Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.
JAMA Oncol 2018;4(12):1721–1728 [Published correction appears in
JAMA Oncol 2018;4(12):1792.].
94. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary
Consensus Classification of the Idiopathic Interstitial Pneumonias. This
joint statement of the American Thoracic Society (ATS), and the European
Respiratory Society (ERS) was adopted by the ATS board of directors, June
2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit
Care Med 2002;165(2):277–304 [Published correction appears in Am J
Respir Crit Care Med 2002;166(3):426.].
95. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic
Society/European Respiratory Society statement: Update of the international
multidisciplinary classification of the idiopathic interstitial pneumonias. Am
J Respir Crit Care Med 2013;188(6):733–748.
96. Larsen BT, Chae JM, Dixit AS, Hartman TE, Peikert T, Roden AC. Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related
Pneumonitis. Am J Surg Pathol 2019;43(10):1331–1340.
97. Solazzo A, Botta C, Nava F, Baisi A, Bonucchi D, Cappelli G. Interstitial
Lung Disease After Kidney Transplantation and the Role of Everolimus.
Transplant Proc 2016;48(2):349–351.
98. Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lungdisease induced by drugs and radiation. Respiration 2004;71(4):301–326.
99. Foy R, Hempel S, Rubenstein L, et al. Meta-analysis: effect of interactive communication between collaborating primary care physicians andspecialists. Ann Intern Med 2010;152(4):247–258.
100. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia:
what is the effect of a multidisciplinary approach to diagnosis? Am J Respir
Crit Care Med 2004;170(8):904–910.
101. Flaherty KR, Andrei AC, King TE Jr, et al. Idiopathic interstitial pneumonia:
do community and academic physicians agree on diagnosis? Am J Respir Crit
Care Med 2007;175(10):1054–1060.
102. Watson S, Chandler RE, Taavola H, et al. Safety Concerns Reported by
Patients Identified in a Collaborative Signal Detection Workshop using
VigiBase: Results and Reflections from Lareb and Uppsala Monitoring
Centre. Drug Saf 2018;41(2):203–212.
103. Strandell J, Caster O, Hopstadius J, Edwards IR, Norén GN. The development and evaluation of triage algorithms for early discovery of adverse druginteractions. Drug Saf 2013;36(5):371–388.
104. Trinh S, Le A, Gowani S, La-Beck NM. Management of Immune-Related
Adverse Events Associated with Immune Checkpoint Inhibitor Therapy:
a Minireview of Current Clinical Guidelines. Asia Pac J Oncol Nurs
2019;6(2):154–160.

Radiology: Volume 00: Number 0— 2021 n radiology.rsna.org

105. Chen X, Zhang Z, Hou X et al. Immune-related pneumonitis associatedwith immune checkpoint inhibitors in lung cancer: a network meta-analysis.
J Immunother Cancer 2020;8(2):e001170.
106. Niho S, Kubota K, Goto K, et al. First-line single agent treatment withgefitinib in patients with advanced non-small-cell lung cancer: a phase II
study. J Clin Oncol 2006;24(1):64–69.
107. Yoh K, Kenmotsu H, Yamaguchi Y, et al. Severe interstitial lung diseaseassociated with amrubicin treatment. J Thorac Oncol 2010;5(9):1435–1438.
108. White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after
everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care
Med 2010;182(3):396–403.
109. Togashi Y, Masago K, Handa T, et al. Prognostic significance of preexisting
interstitial lung disease in Japanese patients with small-cell lung cancer. Clin
Lung Cancer 2012;13(4):304–311.
110. Johkoh T, Sakai F, Kusumoto M, et al. Association between baseline pulmonary
status and interstitial lung disease in patients with non-small-cell lung cancer
treated with erlotinib--a cohort study. Clin Lung Cancer 2014;15(6):448–454.
111. Nakagawa K, Kudoh S, Ohe Y, et al. Postmarketing surveillance study oferlotinib in Japanese patients with non-small-cell lung cancer (NSCLC):
an interim analysis of 3488 patients (POLARSTAR). J Thorac Oncol
2012;7(8):1296–1303.
112. Koyama N, Katayanagi S, Kawachi S. Pre-existing interstitial lung disease
as a risk factor for pneumonitis associated with ramucirumab and paclitaxel
in patients with gastric cancer: The impact of usual interstitial pneumonia.
PLoS One 2018;13(6):e0198886.
113. Sears CR, Peikert T, Possick JD, et al. Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official
American Thoracic Society Research Statement. Am J Respir Crit Care Med
2019;200(6):e31–e43.
114. Yamaguchi T, Shimizu J, Hasegawa T, et al. Pre-existing pulmonary fibrosis
is a risk factor for anti-PD-1-related pneumonitis in patients with non-small
cell lung cancer: A retrospective analysis. Lung Cancer 2018;125:212–217.
115. Cho JY, Kim J, Lee JS, et al. Characteristics, incidence, and risk factors of
immune checkpoint inhibitor-related pneumonitis in patients with nonsmall cell lung cancer. Lung Cancer 2018;125:150–156.
116. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lungdisease induced or exacerbated by TNF-targeted therapies: analysis of 122
cases. Semin Arthritis Rheum 2011;41(2):256–264.
117. Yoshii N, Suzuki T, Nagashima M, Kon A, Kakihata K, Gemma A.
Clarification of clinical features of interstitial lung disease induced by irinotecan based on postmarketing surveillance data and spontaneous reports.
Anticancer Drugs 2011;22(6):563–568.
118. Fujimoto D, Kato R, Morimoto T, et al. Characteristics and Prognostic
Impact of Pneumonitis during Systemic Anti-Cancer Therapy in Patientswith Advanced Non-Small-Cell Lung Cancer. PLoS One 2016;11(12):e0168465.
119. Kanaji N, Tadokoro A, Kita N, et al. Impact of idiopathic pulmonary fibrosis
on advanced non-small cell lung cancer survival. J Cancer Res Clin Oncol
2016;142(8):1855–1865.
120. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated
EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med
2018;378(2):113–125.
121. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy
J. Fleischner Society: glossary of terms for thoracic imaging. Radiology
2008;246(3):697–722.

17