TABLE 1.
Common immune-related adverse events.
| irAEs | Incidence in NSCLC | Symptoms, signs, and laboratory test | Susceptibility factors | Imaging features | Intervention |
|---|---|---|---|---|---|
| Gastrointestinal toxicity | Anti-PD-1: 8% (Davies and Duffield, 2017) | Diarrhea, abdominal pain, vomiting, fever, and hematochezia (Sosa et al., 2018) | Diffuse or segmental bowel wall thickening, with increased enhancement and FDG uptake (Costa et al., 2021) | Symptomatic treatment, including oral hydration, oral or intravenous corticosteroids, and immunosuppressive agents; discontinuation of ICIs in severe cases (Sosa et al., 2018) | |
| Dermatologic toxicity | Anti-PD-1: 9% (Davies and Duffield, 2017; Sosa et al., 2018) | Rash, pruritus, vitiligo, photosensitivity reactions, and xerosis cutis (Sosa et al., 2018) | Rarely shown at CT, MR, and PET/CT (Costa et al., 2021) | Symptomatic treatment, including topical corticosteroids and oral antihistamines (Sosa et al., 2018) | |
| Endocrine toxicity | |||||
| Thyroiditis | Anti-PD-1: hyperthyroidism 1–8%, hypothyroidism 4–9% (Davies and Duffield, 2017) | Asymptomatic or with symptoms and signs of short-term hyperthyroidism and subsequent temporary or permeant hypothyroidism (Sosa et al., 2018) | Female, more cycles of ICIs (Davies and Duffield, 2017) | Normal or diffuse FDG uptake (Costa et al., 2021) | Monitor thyroid function monthly or every two cycles during ICI; temporary or persistent hormone replacement therapy, but the ICI may be continued (Sosa et al., 2018) |
| Anti-PD-L1: hyperthyroidism 1%, hypothyroidism 4% (Davies and Duffield, 2017) | |||||
| Hypophysitis | Anti-PD-1: ≤ 1% (Sosa et al., 2018) | Fatigue, headache, and visual field changes; the abnormality of relevant hormone (Sznol et al., 2017) | Normal or diffuse FDG and uptake with or without the swollen size (Sznol et al., 2017) | Hormone replacement therapy, but the ICI may be continued (Sosa et al., 2018) | |
| Adrenalitis | Rare (only case report) (Sznol et al., 2017) | Fatigue, postural dizziness, orthostatic hypotension, anorexia, weight loss, and abdominal discomfort; the abnormality of relevant hormone (Sznol et al., 2017) | Bilateral mild and diffuse gland enlargement with FDG uptake (Sznol et al., 2017) | Stress-dose and emergency corticosteroid administration when PAI is confirmed; long-term glucocorticoid and mineralocorticoid replacement (Sznol et al., 2017) | |
| Hepatotoxicity | Anti-PD-1: 2% (Davies and Duffield, 2017) | Asymptomatic increase of ALT, AST, or total bilirubin (Sosa et al., 2018) | patients with prior autoimmune disease (Sosa et al., 2018) | Hepatomegaly, periportal edema, or heterogeneous liver enhancement, with or without diffuse FDG uptake (Costa et al., 2021) | Monitor transaminases and bilirubin twice a week during ICI. Oral corticosteroids when LFTs remain elevated after 1-2 weeks and re-starting the ICI once LFTs have improved and steroid has been tapered (Sosa et al., 2018) |
| Pancreatitis | 4% (Sosa et al., 2018) | Elevated levels of pancreatic enzymes with or without abdominal pain, nausea, and vomiting (Sosa et al., 2018) | Diffuse pancreatic enlargement with FDG uptake at PET with or without peripancreatic fat stranding (Costa et al., 2021). | Routine monitoring of amylase and lipase is not recommended; symptomatic mild elevations of these enzymes should not be treated (Sosa et al., 2018) | |
| Pulmonary toxicity | Anti-PD-1: 3–6%; anti-PD-L1: 4% (Davies and Duffield, 2017) | Highly variable in extent of severity (Sosa et al., 2018) | Male former smokers, previous lung radiation therapy, lung fibrosis (Davies and Duffield, 2017) | 1. COP: multifocal GGOs and consolidations with a predominantly peripheral distribution; 2. NSIP: mild GGOs with a tendency for peripheral distribution; 3. HP: diffuse mild GGOs and centrilobular nodules; 4. AIP/ARDS: diffuse GGOs, consolidations, and lung volume loss | Systemic treatment with corticosteroids and antibiotics and withholding ICI treatment with 2–4 grades (Sosa et al., 2018) |
| Asymptomatic or dry cough, fever, chest pain, progressive dyspnea, and fine inspiratory crackles (Sosa et al., 2018) | Such pulmonary opacities can show different intensities of FDG uptake with or without mediastinal lymphadenopathy and pleural effusions (Costa et al., 2021) | ||||
| Nephrotoxicity | Anti-PD-1: 1–3% (Davies and Duffield, 2017) | Asymptomatic elevation of creatinine (Sosa et al., 2018) | Rarely shown at CT, MR, and PET/CT. | Stopping any concomitant nephrotoxic drugs; evaluating etiologies; corticosteroid treatment and withholding ICI (Sosa et al., 2018) | |
| Neurological toxicity | Anti-PD-1: < 1% (Davies and Duffield, 2017) | Polyneuropathy, facial paralysis, optic neuritis, GBS, myasthenia gravis, transverse myelitis, encephalitis, and aseptic meningitis (Sosa et al., 2018) | Imaging examinations, especially MR to rule out metastasis (Sosa et al., 2018) | Steroid treatment; higher doses or other procedures (e.g., intravenous immunoglobulin for GBS) might be required for more severe toxicity (Sosa et al., 2018) | |
| Cardiotoxicity | Myocarditis 0.27% of anti-CTLA-4, 0.06% of anti-PD-1 (Sosa et al., 2018) | Heart failure, cardiomyopathy, heart block, myocardial fibrosis, myocarditis, pericarditis, cardiomyopathy, and arrhythmias (Sosa et al., 2018) | Abnormal signal could be detected by MR. | Consultation with cardiologists and treatment with steroids (Sosa et al., 2018) | |
| Musculoskeletal and rheumatologic toxicity | Arthralgia: 43%, myalgia: 21%, arthritis/tenosynovitis: 1–7%, myositis/fasciitis: <1% (Sosa et al., 2018) | Arthralgia, myalgia, arthritis/tenosynovitis, myositis/fasciitis, rheumatoid arthritis, polymyalgia rheumatica, lupus erythematosus, and Sjögren syndrome (Sosa et al., 2018) | Joint effusion, synovial thickening, or tendon/muscle edema with increased enhancement and FDG uptake (Costa et al., 2021) | Symptomatic or low-dose steroids (Sosa et al., 2018) | |
| Sarcoidosis or sarcoid-like reaction | 5–7% (Nishino et al., 2018) | Asymptomatic (Nishino et al., 2018) | FDG avid enlarged lymph nodes of mediastinum, bilateral hilar, neck and abdomen; seldom manifestation: perilymphatic pulmonary nodules, focal lung consolidation, splenic or hepatic nodule (Nishino et al., 2018) | Holding ICIs without any specific treatment (Kelly et al., 2021) | |
irAEs: immune-related adverse events; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; PD-1: programmed cell death 1; PD-L1: PD-ligand 1; CT: computed tomography; MR: magnetic resonance; PET/CT: positron emission tomography/computed tomography; ICIs: immune checkpoint inhibitors; FDG: fluorodeoxyglucose; PAI: primary adrenal insufficiency; ALT: alanine aminotransferase; AST: aspartate aminotransferase; LFTs: liver function tests; COP: cryptogenic organizing pneumonia; GGOs, ground-glass opacities; NSIP: nonspecific interstitial pneumonia; HP: hypersensitivity pneumonitis; AIP/ARDS: acute interstitial pneumonia/acute respiratory distress syndrome; GBS: Guillain–Barre syndrome.