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All organs

CHECKPOINT-INHIBITOR TOXICITY

Lung immune-related adverse events

Pneumonitis, whose symptoms and imaging are non-specific enough that the work-up is largely one of exclusion — infection, tumour progression, embolism, cardiac causes — and which can be radiographically visible while the patient is asymptomatic.

The cited incidences span 1% to 19% across class and setting, so this card carries the individual rates rather than a single band; see the entry's omitted rows for what is deliberately not summarised. Educational reference, not medical advice.

Anchored on the ASCO, ESMO and SITC chapters for this organ. Every source is named beside the position it supports, and labelled with what kind of source it is.

At a glance

ICI-associated pneumonitis

Also called: checkpoint inhibitor pneumonitis · CIP · IR-ILD · IR-pneumonitis · immune-related interstitial lung disease

Symptoms and imaging are non-specific and the work-up is largely exclusion — infection, tumour progression, embolism, cardiac causes — and the disease can be silent, visible only on CT. The pooled trial incidence is a fraction of what one institution recorded in routine practice, and both the pooled analysis and the cohort report deaths during treatment.

unclearcriticalonset: any time on therapy

Reported frequency

  • 2.7% (95% CI, 1.9%-3.6%) — any-grade pneumonitis, PD-1 monotherapy

    of 4496 unique patients in 20 single-tumour-type PD-1 inhibitor trials · Trial populations: 12 melanoma, 5 NSCLC and 3 RCC studies. A pooled trial rate; the routine-practice figure in the next row is on a different denominator and the two are not averaged

    pooled meta-analysis · 27540850

  • 19%, with 12% of patients grade 3 or higher — any-grade pneumonitis in routine clinical practice

    of patients in a single-institution retrospective study · One centre's routine practice, cited by SITC for the explicit point that trial numbers understate what is seen off-trial. SITC's sentence names no ICI class, so the any-ici value is the vocabulary's widest option rather than a stratum the source reports. The row renders at guideline weight because the guideline is what carries it — the underlying design is a single-institution retrospective study and the primary report is not cited here; see the omitted row on basis. Carried BESIDE the 2.7%, not instead of it

    guideline · 34172516

  • 4% (1% grade 3 or higher) — any-grade pneumonitis, PD-(L)1 inhibitors

    of patients receiving PD-(L)1 inhibitors · SITC's class-stratified figure. Its stratum is PD-1 and PD-L1 agents together; see the omitted row on agentClass, and the ESMO row below, which separates them

    guideline · 34172516

  • 2% — any-grade IR-pneumonitis, anti-PD-L1 inhibitors

    of patients in clinical studies of anti-PD-L1 therapy · ESMO is the one anchor that separates the PD-L1 stratum from PD-1, which it puts at approximately 4% in the same sentence. The stratum SITC's 4% figure lumps together

    guideline · 36270461

  • 1% (1% grade 3 or higher) — any-grade pneumonitis, anti-CTLA-4 therapy

    of patients receiving anti-CTLA-4 therapy · SITC's class-stratified figure

    guideline · 34172516

  • < 1% — any-grade pneumonitis, ipilimumab

    of trial participants receiving ipilimumab · ASCO's lung chapter, which states pneumonitis is less common with anti-CTLA-4 treatment

    guideline · 34724392

  • 7% (2% grade 3 or higher) — any-grade pneumonitis, combination ICIs

    of patients receiving combination ICIs · SITC's class-stratified figure, which it reports as significantly higher than the rate for patients treated with ICI monotherapies. The comparator is monotherapy as a whole; SITC does not test it against each single class separately

    guideline · 34172516

  • 19 of 199 (10%) with combination versus 24 of 716 (3%) with monotherapy — any-grade pneumonitis, combination versus monotherapy in one cohort

    of 199 patients on combination and 716 on monotherapy, within a 915-patient two-institution cohort · Anti-PD-1/PD-L1 monotherapy or combination with anti-CTLA-4, at Memorial Sloan Kettering and the Melanoma Institute of Australia. Pneumonitis developed in 43 of the 915 (5%; 95% CI, 3% to 6%); the 915 is the union of the two arms and is the denominator of neither percentage

    cohort · 27646942

  • 4.1% vs 1.6% (P = .002) — all-grade pneumonitis, NSCLC versus melanoma

    of patients in PD-1 monotherapy trials of NSCLC and of melanoma · Meta-analysis of 20 single-tumour-type trials. The P value above belongs to this raw comparison; the separate multivariable analysis gives higher odds of all-grade pneumonitis in NSCLC than melanoma (odds ratio 1.43; 95% CI, 1.08-1.89; P = .005). The two-institution cohort found incidence similar in melanoma and NSCLC (26 of 532 [5%] v nine of 209 [4%]), so the tumour-type effect is not consistent across sources and both are carried

    pooled meta-analysis · 27540850, 27646942

  • 4.1% vs 1.6% (P < .001) — all-grade pneumonitis, RCC versus melanoma

    of patients in PD-1 monotherapy trials of RCC and of melanoma · Same meta-analysis; the multivariable odds ratio for RCC against melanoma is 1.59 (95% CI, 1.32-1.92; P < .001). The excess is confined to all-grade disease: RCC was not higher than melanoma for grade 3 or higher pneumonitis

    pooled meta-analysis · 27540850

  • approximately 2% — chronic pneumonitis persisting after ICI discontinuation

    of patients with NSCLC or melanoma with immune-related toxicity (ASCO) · ASCO puts the 2% among patients with immune-related toxicity; SITC states the same figure over patients with NSCLC or melanoma treated with ICIs, a wider denominator. Both are carried because the share depends on which one is meant. It persists despite ICI discontinuation and may not resolve after more than 3 months of corticosteroids — a course, not an incidence of the acute event

    guideline · 34724392, 34172516

Severity and class

  • 0.8% (95% CI, 0.4%-1.2%) — grade 3 or higher pneumonitis, PD-1 monotherapy

    of 4496 unique patients in 20 single-tumour-type PD-1 inhibitor trials · Same meta-analysis as the pooled all-grade figure. Higher in NSCLC than melanoma at 1.8% vs 0.2% (P < .001), with a multivariable odds ratio of 2.85 (95% CI, 1.60-5.08). The routine-practice row above carries a far higher grade 3 or higher share on its own single-institution denominator; the two are not combined here

    pooled meta-analysis · 27540850

  • 5 patients died; the proximal cause was pneumonitis in 1, infection related to immunosuppression in 3, and progressive cancer in 1 — deaths during the course of pneumonitis treatment

    of 43 patients who developed pneumonitis among 915 treated with anti-PD-1/PD-L1 antibodies · Two-institution cohort. Most of these deaths were not the pneumonitis itself — three were infections related to the immunosuppression used to treat it, which is the risk the exclusion work-up above exists to keep from being incurred blindly

    cohort · 27646942

  • 6.6% vs 1.6% all-grade, and 1.5% vs 0.2% grade 3 or higher — pneumonitis with combination therapy versus PD-1 monotherapy

    of patients in melanoma trials of combination therapy and of PD-1 monotherapy · Meta-analysis of single-tumour-type PD-1 inhibitor trials. The comparison is made WITHIN melanoma, where both regimens were used, so it is a class effect measured in one tumour type rather than across the pooled cohort

    pooled meta-analysis · 27540850

Onset

ASCO puts the median time to onset at 34 weeks, with a range of 1.5 to 127 weeks. SITC reports that an analysis of ICI-treated patients who developed pneumonitis found the median onset to be 3 months. In the two-institution cohort, time to onset ranged from 9 days to 19.2 months.

Presentation

  • · Focal or diffuse inflammation of the lung parenchyma, typically identified on computed tomography imaging
  • · New or worsening cough, shortness of breath, increased oxygen requirement, chest pain and/or fever
  • · Dyspnoea, persistent cough, chest pain, fever and hypoxia, potentially leading to respiratory failure
  • · May be asymptomatic with detectable inflammation on CT: ESMO notes that many grade 1 cases are radiologically detectable and clinically silent, so a symptom-triggered pathway misses them
  • · No symptomatic, pathologic or radiographic feature is pathognomonic for pneumonitis
  • · Ground-glass opacities or patchy nodular infiltrates, predominantly in the lower lobes, are common findings on chest imaging
  • · SITC's radiologic range: discrete patchy or confluent consolidation with or without air bronchograms and a predominantly peripheral or subpleural distribution, ground-glass opacities, centrilobular nodules, a bronchiolitis-like appearance with tree-in-bud micronodularity, or patterns that do not clearly fit within other classifications
  • · Radiologic and pathologic features of pneumonitis were diverse in the two-institution cohort that characterised them

Differential

  • · Infectious pneumonia — bronchoalveolar lavage to rule out infection, with sputum, blood and urine culture if clinically indicated
  • · Tumour progression, and pleural carcinomatosis or effusion
  • · Pulmonary embolism
  • · Cardiac events, including heart failure, myocarditis, acute myocardial infarction and arrhythmias
  • · Pre-existing inflammatory lung disease and COPD, and drug-related pneumonitis from chemotherapy, targeted drugs or radiotherapy — ESMO names these as what makes the radiological diagnosis difficult, not as a reason to withhold treatment

Work-up

  • Full clinical work-up triggered by new dyspnoea · All patients

    ESMO makes breathlessness itself the trigger rather than a grade threshold, and names what it must exclude: infectious pneumonia, tumour progression, pulmonary embolism, cardiac events and pleural carcinomatosis or effusion.

    36270461

  • High-resolution chest CT · All patients

    SITC examines every patient with suspected pneumonitis by high-resolution CT of the chest. ESMO adds contrast — "a high-resolution chest CT with contrast should be considered to rule out other aetiologies" — where SITC's parallel recommendation does not specify it.

    34172516

  • Pulmonary function tests, including spirometry and DLCO · If atypical

    Considered if the CT scan is negative, to identify a potential functional deficit. Both ESMO and SITC state this condition; SITC adds that PFTs, where indicated, should include spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO).

    34172516

  • Bronchoalveolar lavage · If atypical

    Considered to rule out infection or tumour infiltration — the two alternatives that change the treatment entirely. ESMO frames it as a consideration, not a step for every patient.

    36270461

  • Sputum, blood and urine culture · If atypical

    Investigations for infection, if clinically indicated.

    36270461

  • Specialist referral before the ICI is started, for pre-existing ILD · All patients

    SITC refers patients with pre-existing autoimmune ILD to a specialist before initiation of ICI therapy, for consideration of pulmonary function tests and risk assessment; ESMO asks that patients with pre-existing ILD be discussed with a specialist before initiation. A pre-treatment step, not a mimic to exclude at presentation.

    34172516

  • Specialist consultation or referral after failure to improve · If refractory

    Arranged when there is no improvement within 72 hours of corticosteroids, alongside therapeutic escalation. SITC also refers any toxicity of grade 3 or higher, and any grade that does not respond to steroids.

    36270461

Sources differ here

Second-line therapy

  • ASCO 2021 (society guideline) — However, ICPi pneumonitis may not clinically improve after > 48 hours of corticosteroid therapy, at which time it is deemed steroid-refractory
  • SITC 2021 (society guideline) — 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 ... hdIVIG ... infliximab ... cyclophosphamide (LE: 3), or tocilizumab (LE: 4)
  • ESMO 2022 (society guideline) — If there is no improvement within 72 h of CS use, consultation with or referral to an expert should be arranged and therapeutic escalation should occur

Grade ladder

Grade 1

Continue the ICIOutpatient

Grade 1 — asymptomatic disease. ESMO notes that many grade 1 cases of IR-pneumonitis are radiologically detectable on CT while clinically silent, and SITC that patients may be asymptomatic yet show detectable inflammation on CT. Neither chapter prints the CTCAE boundary; see the omitted row.

Dose not carried

Both the ESMO and SITC lung chapters begin their corticosteroid recommendation at grade 2, and ASCO's grade-1 rule addresses only continuing the ICI with close monitoring. None of the three states whether a steroid is indicated at grade 1, so no dose is carried and none is inferred from the rung above.

  • · Radiographic-only disease is the case a symptom trigger misses: pneumonitis can be entirely asymptomatic with inflammation visible only on CT
  • · Complete the exclusion work-up — infection, tumour progression, pulmonary embolism, cardiac causes — before the event is attributed to the ICI
  • · Before an ICI is started, SITC refers patients with pre-existing autoimmune ILD to a specialist for consideration of PFTs and risk assessment, and ESMO asks that pre-existing ILD be discussed with a specialist
  • · Risk factors SITC names: pre-existing interstitial lung abnormalities, a history of asthma and/or smoking, prior curative-intent radiotherapy, and squamous tumour histology
  • · SITC continues the ICI with monitoring for grade 1 irAEs unless otherwise specified, and its lung chapter states no exception; ASCO's grade-1 exception list names neurologic, hematologic and cardiac toxicities, not the lung

Escalate when: New or worsening cough, breathlessness or oxygen requirement. ESMO makes dyspnoea itself the trigger for the full work-up.

Grade 2

Hold the ICIOutpatient

Grade 2 — the rung at which both lung chapters start corticosteroids and at which both societies withhold the ICI. Neither prints the CTCAE boundary; see the omitted row.

Corticosteroid 1–2 mg/kg/day (oral)

Taper over 4–6 weeks, starting once: ESMO starts the taper after improvement to grade less than 1. SITC gives the 4-6 week window without naming a start marker.

No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.

Second line

  • Mycophenolate mofetil — SITC 1-1.5 g two times per day, tapering in consultation with a pulmonary specialist; ESMO 1 g twice daily — High-dose corticosteroid therapy does not improve pneumonitis symptoms within 72 hours, or symptoms are life-threatening (SITC); no improvement within 72 h of corticosteroids (ESMO). SITC lists its options in no particular order.
  • Intravenous immunoglobulin 2 g/kg — SITC in divided doses over 2-5 days per institutional guidelines; ESMO over 2-5 days — Same 72-hour non-response trigger. One of the options both societies list.
  • Infliximab 5 mg/kg — SITC one dose with optional repeat 14 days later; ESMO one dose and every 2 weeks if needed — Same 72-hour non-response trigger.
  • Cyclophosphamide — listed by both societies for this indication; neither prints a dose for it — Same 72-hour non-response trigger.
  • Tocilizumab — ESMO 8 mg/kg, one dose and every 2 weeks if needed; SITC lists tocilizumab without a dose — Same 72-hour non-response trigger.
  • · The two societies do not agree on this dose: ESMO considers 1 mg/kg/day prednisolone, SITC 1-2 mg/kg/day prednisone. The lower bound is common ground and the upper bound is SITC's alone
  • · Taper over 4-6 weeks — the one window both chapters state at this grade. ESMO starts it after improvement to grade less than 1, a response marker rather than a calendar date
  • · Seventy-two percent (31 of 43) of pneumonitis cases in the two-institution cohort were grade 1 to 2, and 86% (37 of 43) improved or resolved with drug holding and immunosuppression
  • · Re-examine the exclusion work-up before escalating: five patients in that cohort died during pneumonitis treatment, three of infection related to the immunosuppression

Sources differ here

Corticosteroid dose

  • ESMO 2022 (society guideline) — In cases of grade 2 IR-ILD, 1 mg/kg/day prednisolone (or equivalent) should be considered
  • SITC 2021 (society guideline) — Patients experiencing grade 2 pneumonitis should receive 1–2 mg/kg/day prednisone (or equivalent), tapering over 4–6 weeks

Escalate when: No improvement within 72 hours of corticosteroids (ESMO and SITC), or progression to grade 3 or higher. ASCO sets the steroid-refractory mark earlier, at more than 48 hours without clinical improvement.

Grade 3

Hold the ICIAdmit

Grade 3 — inside both chapters' grade 3 or higher band, where each switches to intravenous methylprednisolone. Neither prints the CTCAE boundary; see the omitted row.

Corticosteroid 1–2 mg/kg/day (intravenous)

Taper over 6–8 weeks or longer, starting once: Improvement to grade less than 1.

No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.

Second line

  • Mycophenolate mofetil — SITC 1-1.5 g two times per day, tapering in consultation with a pulmonary specialist; ESMO 1 g twice daily — High-dose corticosteroid therapy does not improve pneumonitis symptoms within 72 hours, or symptoms are life-threatening (SITC); no improvement within 72 h of corticosteroids (ESMO). SITC lists its options in no particular order.
  • Intravenous immunoglobulin 2 g/kg — SITC in divided doses over 2-5 days per institutional guidelines; ESMO over 2-5 days — Same 72-hour non-response trigger. One of the options both societies list.
  • Infliximab 5 mg/kg — SITC one dose with optional repeat 14 days later; ESMO one dose and every 2 weeks if needed — Same 72-hour non-response trigger.
  • Cyclophosphamide — listed by both societies for this indication; neither prints a dose for it — Same 72-hour non-response trigger.
  • Tocilizumab — ESMO 8 mg/kg, one dose and every 2 weeks if needed; SITC lists tocilizumab without a dose — Same 72-hour non-response trigger.
  • · Both societies give 1-2 mg/kg/day methylprednisolone intravenously at grade 3 or higher. They part on the taper: ESMO runs 6-8 weeks or longer, SITC 4-6 weeks at every grade
  • · Keep infection in view while immunosuppressing: of the five deaths during pneumonitis treatment in the cohort, three were proximally caused by infection related to immunosuppression and one by the pneumonitis itself
  • · SITC refers any toxicity of grade 3 or higher to a specialist, and any grade that does not respond to steroid treatment
  • · ASCO suspends the ICI and starts high-dose corticosteroids for grade 3 toxicities in general — its cross-toxicity rule, not a lung-specific statement

Sources differ here

Taper

  • ESMO 2022 (society guideline) — CS tapering should be initiated after improvement to grade <1, over 4-6 weeks for grade 2 and over ≥6-8 weeks for grade ≥3
  • SITC 2021 (society guideline) — For pneumonitis of grade ≥3, patients should receive 1–2 mg/kg/day methylprednisolone IV or equivalent, tapering over 4–6 weeks

Escalate when: No improvement within 72 hours of corticosteroids moves to expert referral and therapeutic escalation. ASCO calls pneumonitis steroid-refractory after more than 48 hours without clinical improvement.

Grade 4

Discontinue permanentlyICU

Grade 4 — also inside the grade 3 or higher band, so it shares the grade 3 dose and taper. The two rungs part on the ICI decision, and that difference comes from ASCO's general grade-4 rule: SITC's lung chapter states no grade-4 exception, and its general framework makes rechallenge after grade 3 or 4 a risk-adjusted decision rather than an automatic discontinuation. See the divergence.

Corticosteroid 1–2 mg/kg/day (intravenous)

Taper over 6–8 weeks or longer, starting once: Improvement to grade less than 1.

No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.

Second line

  • Mycophenolate mofetil — SITC 1-1.5 g two times per day, tapering in consultation with a pulmonary specialist; ESMO 1 g twice daily — High-dose corticosteroid therapy does not improve pneumonitis symptoms within 72 hours, or symptoms are life-threatening (SITC); no improvement within 72 h of corticosteroids (ESMO). SITC lists its options in no particular order.
  • Intravenous immunoglobulin 2 g/kg — SITC in divided doses over 2-5 days per institutional guidelines; ESMO over 2-5 days — Same 72-hour non-response trigger. One of the options both societies list.
  • Infliximab 5 mg/kg — SITC one dose with optional repeat 14 days later; ESMO one dose and every 2 weeks if needed — Same 72-hour non-response trigger.
  • Cyclophosphamide — listed by both societies for this indication; neither prints a dose for it — Same 72-hour non-response trigger.
  • Tocilizumab — ESMO 8 mg/kg, one dose and every 2 weeks if needed; SITC lists tocilizumab without a dose — Same 72-hour non-response trigger.
  • · ASCO recommends permanent discontinuation for grade 4 toxicities in general — its cross-toxicity rule, not a lung-specific statement. SITC's lung chapter names no grade-4 exception and its general framework risk-adjusts the rechallenge decision instead
  • · Pneumonitis-related deaths were reported in the pooled analysis: four in patients with NSCLC on monotherapy, and one during combination therapy
  • · Approximately 2% of patients go on to a chronic course that persists despite ICI discontinuation and may not resolve after more than 3 months of corticosteroids

Sources differ here

Taper

  • ESMO 2022 (society guideline) — CS tapering should be initiated after improvement to grade <1, over 4-6 weeks for grade 2 and over ≥6-8 weeks for grade ≥3
  • SITC 2021 (society guideline) — For pneumonitis of grade ≥3, patients should receive 1–2 mg/kg/day methylprednisolone IV or equivalent, tapering over 4–6 weeks

ICI action

  • ASCO 2021 (society guideline) — In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement
  • SITC 2021 (society guideline) — The decision to re-challenge a patient who has experienced grade 3 or 4 irAEs should be risk-adjusted based on anticipated benefit with therapy versus the potential for toxicity (LE: 3)

Escalate when: Already the top rung. Failure to improve within 72 hours of corticosteroids is an expert-referral and therapeutic-escalation question.

Rechallenge

individualized

Both anchors allow rechallenge after grade 2 pneumonitis on complete resolution of symptoms: ESMO on an individual basis with close monitoring, SITC with more frequent physician consultations afterwards. In the multicentre lung-cancer cohort, 45 of 107 patients (42.1%) were rechallenged after checkpoint inhibitor-related pneumonitis; 9 (20.0%) had recurrent pneumonitis and 11 (24.4%) developed a new irAE. Who was rechallenged was not random — severe grade (grades 3 or higher) and ground-glass opacity of the pneumonitis lesions were negatively associated with rechallenge — so 20.0% is the recurrence rate among patients selected for it, not among everyone who had pneumonitis.

  • 9 of 45 (20.0%); a further 11 (24.4%) developed a new irAE — recurrent pneumonitis after ICI rechallenge

    of 45 patients rechallenged after checkpoint inhibitor-related pneumonitis · Multicentre retrospective cohort of advanced lung cancer patients with grade 1 or higher pneumonitis, of whom 45 of 107 (42.1%) were rechallenged. Severe grade and ground-glass opacity made rechallenge less likely, so this denominator is a selected, lower-risk group

    cohort · 36519018

  • · Complete resolution of symptoms — the condition both ESMO and SITC attach to rechallenge after grade 2 pneumonitis
  • · An individual, not protocolised, decision, with close monitoring and more frequent consultations afterwards
  • · Weigh the initial event: severe grade of pneumonitis and poor performance status at the initial episode were associated with a higher recurrence rate
  • · Note the markers the cohort found at the time of rechallenge — IL-6, CRP, and absolute white cell and neutrophil counts — were associated with a higher recurrence rate
  • · After grade 3 or 4, SITC risk-adjusts the decision against anticipated benefit rather than ruling rechallenge out

Deliberately not carried

  • ladder[].steroid.taper step cadence — Both chapters give a window and, in ESMO's case, a start trigger — 4-6 weeks at grade 2, 6-8 weeks or longer at grade 3 or higher for ESMO, 4-6 weeks at every grade for SITC — and neither states a step size or interval. No anchor guideline states a cadence for any organ, so it is null here as on the renal, hepatic and GI entries rather than borrowed from the beta taper planner's illustrative figure.
  • onset.medianWeeks — Null on purpose. ASCO states a median time to onset of 34 weeks; SITC states a median onset of 3 months. Both are cited on this card and the two do not describe the same interval. The field renders as THE median, so promoting either would present a contested number as settled, and IraeDivergence.field has no onset member to hold the disagreement. Both figures are in onset.note with their sources.
  • onset.rangeWeeksLow / onset.rangeWeeksHigh provenance — The numeric bounds are ASCO's 1.5 to 127 weeks. The cohort's 9 days to 19.2 months is left in the units its source printed rather than converted into weeks, which would render a number no source states. Both are in the note.
  • frequencyBand — Set to unclear rather than a band. The rates this entry cites span 1% for anti-CTLA-4, 2.7% pooled across PD-1 monotherapy trials, 7% for combination ICIs and 19% in one institution's routine practice — an order of magnitude between trial and practice settings, on different denominators. A single scoping word beside those rows would be a claim no source makes.
  • incidence[].basis for the routine-practice figure — The 19% row is filed as guideline because SITC is the citation that carries it, and BASIS_FOR_TIER permits that at tier 1. The underlying design is a single-institution retrospective study, which is a weaker design than the pooled meta-analysis rendering beside it, and the vocabulary has no value for guideline-quoted primary data. The design is stated in the row's denominator and population so the tier does not silently upgrade it.
  • incidence[].agentClass for the SITC PD-(L)1 figure — SITC reports 4% for PD-(L)1 inhibitors — PD-1 and PD-L1 agents in one stratum. The atlas vocabulary has no combined PD-(L)1 class, so the row is filed under pd1 with the stratum stated in its population, and ESMO's separate 2% anti-PD-L1 figure is carried as its own row. Filing SITC's figure as any-ici would assert it covers anti-CTLA-4, which the same sentence reports separately at 1%.
  • ladder[].gradeDefinition (CTCAE boundaries) — The ESMO and SITC lung chapters state their recommendations by grade without printing the boundaries, and ASCO's per-organ grade table is an image that did not survive extraction. The rungs are therefore described by what each anchor does at that grade, plus ESMO's and SITC's statements about asymptomatic grade-1 disease, not by an invented CTCAE definition.
  • ladder[].hospitalization — The ESMO and SITC lung chapters state no care setting for pneumonitis, and ASCO's grade table did not survive extraction. The values at grade 3 and 4 follow both chapters' switch to intravenous methylprednisolone and the severity of the rung; they are an editorial mapping, not a quoted recommendation.
  • ladder.g2.steroid.route — Neither chapter prints a route at grade 2. Oral is read from the contrast each society draws with its own grade 3 or higher rung, where both name intravenous methylprednisolone: SITC's grade-2 agent is prednisone (or equivalent) and ESMO's is prednisolone. It is an inference from two sources, not a quoted instruction.
  • ladder.g1.steroid dose — Recorded as kind: unsourced rather than kind: none. Neither lung chapter says whether a corticosteroid is indicated at grade 1 — both begin dosing at grade 2 — and kind: none would assert an absence of indication that no anchor states.
  • pulse steroid — Neither lung chapter describes pulse methylprednisolone for pneumonitis. The switch from oral prednisolone or prednisone to intravenous methylprednisolone at grade 3 or higher is a change of route and agent at 1-2 mg/kg/day, not a pulse, and is not recorded as one.
  • workup[].whenIndicated for pulmonary function tests — ESMO's and SITC's trigger is "if the CT scan is negative", and the whenIndicated vocabulary has no member for it. The row uses if-atypical, which is true of a negative CT in a patient with suspected pneumonitis, and states the exact condition in its purpose. Adding an if-ct-negative member to the union in irae.ts would render the trigger directly.
  • mortality rate — No cited source reports a case-fatality rate for ICI pneumonitis. The cohort's five deaths are carried as a count against their denominator and are not converted into a percentage, and the pooled analysis's pneumonitis-related deaths are counts as well.
  • risk factors — The entry has no structured risk-factor field, so the risk factors it carries are the ones the anchor chapters state, on the grade-1 rung and in the pre-treatment referral. The largest pneumonitis risk-factor meta-analysis available was reviewed and is NOT cited: three distinct clinical exposures in it share one identical pooled odds ratio and confidence interval, and two laboratory markers share another, which cannot be independent measurements of different exposures. Carrying selected rows from it would mean vouching for a table whose internal consistency this repository could not establish.
  • guidelinePmids — Left empty although all three anchors are rows in guidelines.ts. Their stored keyRecommendation strings are renal-scoped, so linking them here would surface kidney advice on a lung card — the substitution assertion 19.5 exists to block. The lung chapters are carried in citations with their own quotes instead.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: The class-stratified any-grade incidence, including the anti-PD-L1 stratum SITC does not separate; the conditions that make the diagnosis difficult; the symptom set and radiologically detectable grade-1 disease; the dyspnoea-triggered work-up and the alternative causes it must exclude; the imaging and bronchoalveolar-lavage recommendations; the grade-indexed corticosteroid dose and route; the GRADE-DEPENDENT taper windows and their shared start trigger; the 72-hour escalation trigger with its full agent list and doses; and the grade-2 rechallenge position. PULMONARY SCOPE.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: The definition and presenting symptoms, the absence of any pathognomonic feature, the median and range of time to onset, the radiologic pattern, the reported incidence range with its pooled PD-1 and ipilimumab figures, chronic pneumonitis in approximately 2%, the improvement rate on initial corticosteroids, and the 48-hour threshold at which ASCO calls pneumonitis steroid-refractory. The cross-toxicity paragraph is ASCO's GENERAL grade ladder rather than its lung chapter, and is cited only for the grade-indexed ICI action and the at-least-4-6-week taper floor.Supporting text: the full text + the PubMed abstract (checkable at the link above)
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: The general grade-indexed ICI action, the specialist-referral rule and the risk-adjusted stance on rechallenge after grade 3 or 4; the symptom set including hypoxia and asymptomatic CT-detected disease; the radiologic patterns; the named risk factors; class-stratified incidence with the grade 3 or higher share for each class; SITC's explicit statement that trial-recorded incidence may be lower than routine practice, with the single-institution figures it cites for that point; the 3-month median onset; chronic pneumonitis in approximately 2%; and the whole pulmonary panel — the pre-existing-autoimmune-ILD referral, the CT-then-PFT rule with spirometry and DLCO, the grade-indexed dose and 4-6 week taper, the steroid-refractory agent list with doses, and the grade-2 rechallenge position.Supporting text: the full text
  • Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS (2016) Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis.Cited for: Pooled all-grade and grade 3 or higher incidence during PD-1 monotherapy; the NSCLC-versus-melanoma and RCC-versus-melanoma differences, with the raw comparison and its P value kept separate from the multivariable odds ratio and its own P value; the combination-versus-monotherapy comparison within melanoma; and the pneumonitis-related deaths.Supporting text: the PubMed abstract (checkable at the link above)
  • Naidoo J, et al. (2017) Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.Cited for: The two-institution design, its regimens and its case definition; the observed onset range; the cohort incidence and its combination-versus-monotherapy split with the arm sizes; the melanoma-versus-NSCLC comparison; the grade distribution and the improvement fraction; the deaths during pneumonitis treatment with their proximal causes; and the diversity of radiologic and pathologic appearances.Supporting text: the PubMed abstract (checkable at the link above)
  • Lin X, et al. (2022) Safety and efficacy of immunotherapy rechallenge following checkpoint inhibitor-related pneumonitis in advanced lung cancer patients: a retrospective multi-center cohort study.Cited for: The cohort and its entry criterion, the proportion rechallenged after checkpoint inhibitor-related pneumonitis, what predicted being rechallenged at all, the recurrence and new-irAE rates after rechallenge, and the factors associated with a higher recurrence rate.Supporting text: the PubMed abstract (checkable at the link above)

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