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Immunotherapy can inflame the lungs. A new cough, breathlessness or chest pain during or after immunotherapy should be reported to your cancer team the same day. A CT scan of the chest confirms it, and steroids are the main treatment; severe cases need hospital and steroids through a drip.
Pneumonitis occurs in about 4% of people on PD-(L)1 inhibitors (1% grade 3 or more), 1% on anti-CTLA-4 and 7% on combinations in trials, with higher rates in single-centre practice (19% in one series) and in lung and kidney cancer, smokers, people with asthma or prior chest radiotherapy (SITC 2021). Median onset is about 3 months.
SITC 2021: high-resolution CT of the chest for suspected pneumonitis, with pulmonary function tests (spirometry and DLCO) if the CT is negative. Grade 2: prednisone 1 to 2 mg/kg/day, tapered over 4 to 6 weeks. Grade 3 or more: intravenous methylprednisolone 1 to 2 mg/kg/day, tapered over 4 to 6 weeks. If high-dose steroids do not help within 72 hours, or the illness is life-threatening, the options, in no order, are mycophenolate mofetil, high-dose IVIG, infliximab, cyclophosphamide or tocilizumab, each on low-level evidence. After grade 2, re-challenge may follow complete resolution, with closer follow-up; recurrence was 25% in a small series.
ASCO 2021 gives the general frame: hold for grade 2, high-dose steroids for grade 3, taper over at least 4 to 6 weeks, permanently stop for grade 4. The Chinese 2022 consensus grades by symptoms and the share of lung involved on CT, monitors grade 1, treats grades 2 to 3 with prednisolone-equivalent 1 to 2 mg/kg/day, assesses response at 48 to 72 hours and keeps steroid courses to 6 to 8 weeks, not over 12. ESMO 2022 could not be read.
Why: Existing lung scarring raises the risk of pneumonitis, so a baseline helps both the decision to treat and later comparison.
“Patients with pre-existing autoimmune ILD should be referred to a specialist where possible before initiation of ICI therapy for the consideration of pulmonary function tests (PFTs) and risk assessment”
Why: Pneumonitis can worsen quickly, so it needs prompt assessment.
“Patients should receive dedicated education on irAEs by a medical professional and may receive additional materials such as informational booklets or reference cards.”
Why: CT shows the inflammation; lung function tests can find a deficit that the scan misses.
“Patients with suspected pneumonitis should be examined via high-resolution CT of the chest. If the CT scan is negative, PFTs should be considered to identify a potential functional deficit”
Why: Infection, clots, heart failure, radiation pneumonitis and the cancer itself can all look like pneumonitis.
“Diagnostic evaluation for all irAEs should attempt to rule out other possible etiologies (eg, diarrhea/colitis associated with Clostridium difficile infection), but treatment for irAEs should be initiated as is deemed clinically appropriate.”
Why: Under the general rules, grade 1 can continue with close follow-up and grade 2 needs a pause and treatment.
“Unless otherwise specified, patients experiencing grade 2 irAEs should have ICI therapy temporarily withheld and be treated with corticosteroids depending on the toxicity in question.”
Why: Steroids settle the inflammation in most people; the slower taper reduces relapse.
“Patients experiencing grade 2 pneumonitis should receive 1–2 mg/kg/day prednisone (or equivalent), tapering over 4–6 weeks. For pneumonitis of grade ≥3, patients should receive 1–2 mg/kg/day methylprednisolone IV or equivalent, tapering over 4–6 weeks”
Why: Long courses of high-dose steroids raise the risk of infection, high blood sugar and mood change.
“When beginning corticosteroid therapy, patients should be specifically counseled about potential toxicities, including hyperglycemia, mood disturbances, insomnia, gastritis, weight gain, and opportunistic infections (eg, Pneumocystis pneumonia)”
Why: Life-threatening pneumonitis generally rules out further checkpoint inhibitor treatment under ASCO's general rules.
“In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement.”
ASCO, Journal of Clinical Oncology 2021 · expert consensus
Why: Steroid-refractory pneumonitis has a high death rate; SITC lists mycophenolate mofetil, high-dose IVIG, infliximab, cyclophosphamide or tocilizumab in no particular order.
“If high-dose corticosteroid therapy does not improve pneumonitis symptoms within 72 hours (or if symptoms are life-threatening), options include (in no particular order) mycophenolate mofetil (1–1.5 g two times per day, tapering in consultation with a pulmonary specialist”
SITC, Journal for ImmunoTherapy of Cancer 2021 · LE: 3 (mycophenolate), LE: 4 (IVIG, infliximab, tocilizumab)
Why: Pneumonitis can come back, with or without re-challenge.
“If patients have experienced grade 2 pneumonitis, they may be re-challenged with ICIs upon complete resolution of symptoms. These patients should be monitored through more frequent consultations with their physician”
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
SITC 2021 is the most detailed guideline that could be read: high-resolution chest CT, prednisone 1 to 2 mg/kg/day for grade 2 and intravenous methylprednisolone 1 to 2 mg/kg/day for grade 3 or more, each tapered over 4 to 6 weeks (LE: 3), a second immunosuppressant after 72 hours without response, and re-challenge after grade 2 only when symptoms have fully resolved. ASCO 2021 agrees on the frame and on a taper of at least 4 to 6 weeks, and permanently stops checkpoint inhibitors after grade 4. The Chinese 2022 consensus adds CT extent to the grade, a 48 to 72 hour response check and a 6 to 8 week, at most 12 week, steroid course. ESMO 2022 was not read. All the second-line drugs rest on case series or small cohorts; none has been compared in a randomised trial that could be read.
SITC, Journal for ImmunoTherapy of Cancer 2021 · ASCO, Journal of Clinical Oncology 2021 · Thoracic Cancer (Chinese expert panel) 2022 · ESMO, Annals of Oncology 2022
Where it differs: Grades pneumonitis by symptoms together with the share of lung involved on CT (under 25%, 25 to 50%, over 50%), recommends prednisolone-equivalent 1 to 2 mg/kg/day for grades 2 to 3 and intravenous steroids for more severe or acute cases, checks response at 48 to 72 hours and limits the course to 6 to 8 weeks, not more than 12. It judges Pneumocystis prophylaxis generally unnecessary except for 20 mg a day for more than 6 weeks.
Evidence: Expert consensus, not graded.
Where it differs: States permanent discontinuation for grade 4 toxicities in general; SITC allows re-challenge only after grade 2 pneumonitis.
Evidence: Expert consensus.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Grade 2: prednisone 1 to 2 mg/kg/day; grade 3 or more: intravenous methylprednisolone 1 to 2 mg/kg/day; taper over 4 to 6 weeks | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| High-resolution chest CT for suspected pneumonitis; lung function tests if CT is negative | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Mycophenolate mofetil for steroid-refractory pneumonitis | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| High-dose IVIG, infliximab or tocilizumab for steroid-refractory pneumonitis | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Re-challenge after grade 2 once symptoms have completely resolved | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Steroid taper over at least 4 to 6 weeks; permanent discontinuation after grade 4 “Corticosteroids should be tapered over the course of at least 4-6 weeks.” | expert consensus | ASCO, Journal of Clinical Oncology 2021 |
| Response to steroids assessed within 48 to 72 hours “For CIP, clinical improvements should be assessed within 48 to 72 hours of GCS treatment.” | expert consensus (not graded) | Thoracic Cancer (Chinese expert panel) 2022 |
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