The Drug-Induced Respiratory Disease Website and App

Immune checkpoint inhibitors (ICI) - ICI combinatorial Rx

The manifold possible adverse effects from ICI in varied organs must be checked in every patient receiving these medications. AEs tend to occur with higher frequency with combo theray than when these agent are taken in isolation. Anti CTLA-4, anti-CD52, anti-PD1, anti-PDL-1 antibodies (PMID 23714523, 24904570, 25776466). For review of pulmonary and nonpulmonary AEs, and management guidelines see under PMID 26371282, 29442540. Can be fatal (PMID: 29735504). For review see PMID 32158597.

Frequency - Incidence

Incidence of respiratory adverse event(s) due to the specific drug as assessed by number of reported/published cases in the literature. Red digits in stars indicate: 0 = Very rare, questionable signal · 1 = < 10 cases · 2 = 10-50 cases · 3 = 50–100 cases · 4 = 100-200 cases · 5 = >200 cases

Evidence level/grade

Evidence level for respiratory adverse event(s) due to the specific drug as estimated using Hill’s (1965), Naranjo’s (1981), and Bégaud’s (1985) criteria applied to published cases. Blue digits in stars indicate: 0 = Questionable · 1 = Low · 2 = Moderate · 3 = Robust · 4 = Definite · 5 = Unquestionable, pathognomonic

I - Interstitial/parenchymal lung disease

I.a

Pneumonitis (ILD), acute and/or severe (may produce the ARDS pattern)

I.b

Pneumonitis (interstitial lung disease/ILD)

I.c

Eosinophilic pneumonia (pulmonary infiltrates and eosinophilia)

I.d

Organizing pneumonia pattern (an area or areas of consolidation on imaging)

I.e

Acute eosinophilic pneumonia (AEP)

I.f

Acute fibrinous organizing pneumonia (AFOP)

I.g

Pulmonary fibrosis

I.u

Relapsing or migrating pneumonitis/pneumonia (see also Id)

I.v

Abnormal lung function/pulmonary physiology (PFTs) without necessarily imaging or clinical evidence

I.w

Rapidly progressive ILD/pulmonary fibrosis (Hamman-Rich syndrome)

I.y

Progression, acceleration or exacerbation of preexisting ILD/fibrosis

I.aa

Delayed ILD, -pneumonitis, -fibrosis

I.ad

Radiation recall pneumonitis

I.aj

Shrinking lung syndrome

I.ax

Chronic pneumonitis

II - Pulmonary edema - Acute lung injury - ARDS

II.b

ARDS - Acute lung injury

II.d

Pulmonary edema, cardiogenic

III - Pulmonary/alveolar/airway hemorrhage/bleeding

III.m

Coagulopathy

IV - Airway involvement

IV.a

Bronchospasm - Wheezing - Asthma

IV.c

Obliterative bronchiolitis (a pattern consistent with) (see also IVn, XVx)

IV.n

Obstructive airway dysfunction (see also IVc, XVx)

IV.y

Eosinophilic airway disease (asthma, bronchitis, bronchiolitis)

IV.ab

Exacerbation or deterioration of preexisting COPD

IV.al

Sputum production - Bonchorrhea - ‘Bronchitis’

V - Pleural and/or pericardial involvement

V.a

Pleural effusion (uni- or bilateral) (can accompany DI-LDs)

V.i

Pleuritis (can cause chest pain)

V.s

Serositis - Polyserositis

VI - Pulmonary vasculopathy

VI.a

Pulmonary embolism - Venous thrombosis/thromboembolism

VI.b

Pulmonary arterial hypertension

VII - Mediastinal involvement

VII.a

Lymphadenopathy (intrathoracic)

VIII - Central-large-upper airway (incl. pharyngeal-nasal) involvement

VIII.t

Vocal cord paresis/paralysis

IX - Neuromuscular / CNS involvement - Disordered breathing (during sleep)

IX.a

Diaphragm/inspiratory muscle weakness/paralysis (w/wo ARF)

IX.d

Respiratory failure from ventilatory depression (due to neuromuscular blockade/paralysis)

IX.r

Myasthenia gravis - Myasthenic-like syndrome

IX.ab

Guillain-Barré (or GB-like) syndrome (w/wo ARF)

IX.ac

Myositis of the respiratory muscles (May lead to respiratory muscle paralysis)

X - Systemic/Distant conditions, syndromes and reactions

X.a

DRES syndrome - DRESS-like reaction

X.c

Capillary leak syndrome (CLS)

X.d

Lupus - Lupus syndrome (see also Vd)

X.e

Autoimmunity-Autoimmune conditions (+ANA, +anti-ds-DNA, +ANCAs, other auto-Abs)

X.f

Anaphylaxis-Anaphylactoid reaction (can be fatal)

X.g

Hypersensitivity reaction (may manifest with fever and/or skin, throat or airway involvement)

X.h

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

X.j

Myopathy-Myositis-Polymyositis (see also under Xba)

X.k

Sarcoid-like granulomatosis (endo-/extrathoracic)

X.m

Vascultis (pulmonary, extrathoracic or systemic)-ANCA status unknown or negative)

X.n

Tumor lysis syndrome (TLS)

X.s

Vasculitis, pulmonary (w/wo AH), extrapulmonary, systemic: ANCA-positive

X.u

Multiple organ dysfunction/failure (MODS/MOF)

X.am

Immune-related adverse effect/toxicity

X.an

Cytokine release syndrome - Cytokine storm

X.aw

Connective tissue disease

X.ay

Polymyalgia rheumatica

X.bi

Temporal arteritis (Horton’s)

XI - Miscellaneous

XI.n

Neutropenia, agranulocytosis (w/wo infection/sepsis)

XI.y

Adrenal suppression

XI.ag

Vertebral compression fracture

XI.au

Graft vs. host disease in transplant recipients

XI.av

Deterioration of graft function in SOT recipients

XI.ba

Nonrespiratory AE of interest

XII - Cardiovascular involvement / toxicity

XII.a

Left or biventricular dysfunction/failure

XII.c

Pericardial effusion (w/wo tamponade)

XII.d

Myocarditis (can be fulminant)

XII.e

Takotsubo (stress) cardiomyopathy

XII.g

Coronary artery disease (acute) - Myocardial ischemia/infarction

XII.l

Cardiac arrhythmias or dysrhythmias (AF, VT, VF, TdP)

XII.n

Cardiovascular collapse - Cardiogenic shock - Hypotension

XII.r

Heart failure (biventricular, congestive)

XII.s

Heart block (bundle branch- or AV-)

XII.ai

Cardiotoxicity

XII.ax

Necrotizing myocarditis (w/o evidence for CAD)

XII.ba

Sudden cardiac death

XV - Pathology

XV.a

Path: NSIP-cellular pattern (see also Ia, Ib)

XV.b

Path: Eosinophilic pneumonia (subacute or acute) (see also Ic)

XV.c

Path: Organizing pneumonia (OP/BOOP) pattern (see also Id)

XV.d

Path: Acute fibrinous organizing pneumonia (AFOP-pattern) (see also pattern If)

XV.e

Path: ILD with a granulomatous component (see also Im)

XV.f

Path: Diffuse alveolar damage (DAD-pattern) (see also IL)

XV.l

Path: Pulmonary fibrosis (not otherwise specified or unclassifiable)

XV.v

Path: Micronodular organizing pneumonia/BOOP

XV.x

Path: Acute/subacute bronchiolitis (see also IVc, IVi)

XV.ba

Path: Granulomatous lymphadenopathy

XV.ca

Path: Myocarditis

XV.co

Path: Foamy inclusions in alveolar macrophages and/or in other lung cells

XV.cp

Path: Pneumocyte vacuolization

XV.cw

Path: Myocardial vasculitis

XVI - Imaging

XVI.k

Imaging: An area or areas of consolidation

XVI.v

Imaging: Centrilobular micronodules (can be diffuse)

XVI.w

Imaging: Lung nodule or nodules

XVI.bh

Imaging: F18-PET scan positive lympadenopathy

XVI.bm

Imaging: Avid pleural uptake on PET-scan

XVI.bt

Imaging: A subsolid lung nodule or nodules

XVII - Infections & related conditions

XVII.b

Opportunistic pulmonary/systemic infections

XVII.c

Aspergillosis, pulmonary (invasive, allergic [ABPA], or mycetoma)

XVII.e

Pneumocystis jiroveci pneumonia

XVII.g

Tuberculosis (pulmonary, pulmonary, extrapulmonary or disseminated). Reactivation or de novo

XVII.q

Viral pneumonia

XVII.r

Fungal infection (pulmonary/extrapulmonary)

XIX - Cytological, biochemical features of/in BAL, pleural fluid or FNA

XIX.a

BAL: An excess proportion of lymphocytes

XIX.b

BAL: An excess proportion of neutrophils

XIX.c

BAL: An excess proportion of eosinophils