Immune Checkpoint Inhibitor Toxicities – What the Internist Must Know: A Clinical Review for Critical Care Practice

Dr Neeraj Manikath, Claude.ai

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, with over 40% of cancer patients now eligible for these therapies. However, immune-related adverse events (irAEs) occur in 60-90% of patients, with 10-15% experiencing severe Grade 3-4 toxicities requiring immediate intervention.

Objective: To provide internists and critical care physicians with evidence-based strategies for recognizing, grading, and managing life-threatening ICI toxicities.

Key Points: Early recognition and prompt immunosuppression are crucial for preventing irreversible organ damage. The diagnostic challenge lies in distinguishing irAEs from infection, disease progression, or drug-related toxicities. Multidisciplinary coordination with oncology is essential for optimal outcomes.

Keywords: Immune checkpoint inhibitors, immune-related adverse events, pneumonitis, myocarditis, colitis, immunosuppression

Introduction

The advent of immune checkpoint inhibitors has transformed oncological practice, with PD-1/PD-L1 and CTLA-4 inhibitors now standard therapy across multiple malignancies. By unleashing the immune system against cancer cells, these agents inevitably trigger autoimmune-like toxicities termed immune-related adverse events (irAEs). While most irAEs are manageable, severe toxicities can be life-threatening and require immediate recognition and intervention by internists and intensivists.

Unlike traditional chemotherapy toxicities, irAEs follow unique temporal patterns, can affect any organ system, and may occur months to years after treatment completion. The incidence of severe irAEs varies by agent: combination ipilimumab/nivolumab (55%), anti-CTLA-4 monotherapy (25%), and anti-PD-1/PD-L1 monotherapy (10-15%).

Pathophysiology and Risk Factors

Mechanisms of irAE Development

ICIs work by blocking inhibitory signals that normally prevent T-cell activation. PD-1/PD-L1 inhibitors primarily affect peripheral tolerance, while CTLA-4 inhibitors impact central tolerance in lymphoid organs. This leads to:

Loss of peripheral tolerance: Activation of autoreactive T-cells normally held in check
Molecular mimicry: Cross-reactivity between tumor antigens and normal tissue
Epitope spreading: Immune response expands beyond initial targets
Pre-existing autoimmunity unmasking: Subclinical autoimmune conditions become clinically apparent

High-Risk Populations

Clinical Pearl: Patients with pre-existing autoimmune conditions have 2-3 fold higher risk of irAEs, but this is not an absolute contraindication to ICI therapy.

Risk factors include:

History of autoimmune disease (relative risk 2.8)
Prior radiation therapy to the affected organ
Combination ICI therapy
Female gender (for certain irAEs)
Specific HLA genotypes (HLA-DRB1*11:01 for pneumonitis)

Clinical Recognition and Differential Diagnosis

The irAE Mimics: Avoiding Diagnostic Pitfalls

Oyster Alert: irAEs are master mimics that can present identically to infections, malignancy, or other drug toxicities.

Key Distinguishing Features:

Feature	irAE	Infection	Malignancy
Timing	Days to months post-ICI	Variable	Progressive
Fever Pattern	Low-grade, intermittent	High-grade, sustained	Variable
Response to Antibiotics	None	Improvement	None
Inflammatory Markers	Elevated ESR/CRP	Very high PCT/CRP	Variable
Imaging Pattern	Bilateral, symmetric	Focal, cavitation	Mass lesions

Temporal Patterns: When to Suspect irAEs

Hack: Use the "6-6-6 Rule" for timing:

Skin/GI: 6 weeks (earliest)
Liver/Lung: 6 months (peak incidence)
Endocrine/Neuro: 6+ months (can be delayed)

Organ-Specific irAEs: Recognition and Management

1. Immune-Related Pneumonitis

Incidence: 3-5% (anti-PD-1), 10% (combination therapy) Mortality: 10-15% if untreated

Clinical Presentation

Symptoms: Progressive dyspnea, dry cough, fatigue
Physical Exam: Fine crackles, oxygen desaturation
Chest X-ray: Often normal in early stages

Diagnostic Approach

Pearl: CT chest should be obtained in all patients with unexplained dyspnea on ICIs, even with normal chest X-ray.

HRCT Patterns (in order of frequency):

Cryptogenic organizing pneumonia (COP) - peripheral consolidation
Nonspecific interstitial pneumonia (NSIP) - ground-glass opacities
Hypersensitivity pneumonitis - centrilobular nodules
Acute interstitial pneumonia - diffuse alveolar damage

Pneumonitis vs. Pneumonia: The Critical Decision

Hack - The "P-COIN" Approach:

Procalcitonin <0.5 ng/mL (suggests irAE)
Cultures negative
Oxygen requirement out of proportion to findings
Imaging: bilateral, peripheral, ground-glass
No response to antibiotics in 48-72 hours

Management Protocol

Grade 1 (Asymptomatic):

Hold ICI
Monitor closely
Consider rechallenge if resolved

Grade 2 (Symptomatic):

Hold ICI permanently
Prednisone 1-2 mg/kg/day
Consider hospitalization

Grade 3-4 (Severe/Life-threatening):

ICU admission if respiratory failure
Methylprednisolone 2-4 mg/kg/day IV
If no improvement in 48-72h: add infliximab 5 mg/kg
Prophylaxis: PCP prophylaxis, bone protection

Oyster: Never give antibiotics empirically for suspected pneumonitis without strong evidence of infection - this delays steroid therapy and worsens outcomes.

2. Immune-Related Myocarditis

Incidence: <1% but mortality up to 50% Onset: Median 27 days (can be within days)

Clinical Presentation

Symptoms: Chest pain, dyspnea, fatigue, palpitations
Often subclinical: Routine troponin screening recommended

Pearl: Myocarditis can present with isolated troponin elevation without symptoms or ECG changes.

Diagnostic Workup

Troponin T/I: Most sensitive early marker
ECG: ST changes, arrhythmias, heart block
Echocardiogram: Wall motion abnormalities, reduced EF
Cardiac MRI: Gold standard for diagnosis
Endomyocardial biopsy: Reserved for severe cases

The Myositis Connection

Critical Pearl: 25-50% of ICI myocarditis patients have concurrent myositis and/or myasthenia gravis. Check CK, acetylcholine receptor antibodies.

Management

Any Grade Myocarditis:

Immediate ICI discontinuation (permanent)
High-dose steroids: methylprednisolone 1000 mg IV daily × 3-5 days
Cardiology consultation emergently
Monitor for arrhythmias and heart failure

Refractory Cases:

Infliximab 5 mg/kg (avoid if heart failure)
Mycophenolate mofetil 1g BID
Plasmapheresis or IVIG
Temporary mechanical support if needed

3. Immune-Related Colitis

Incidence: 8-12% (anti-CTLA-4), 1-3% (anti-PD-1) Peak onset: 6-7 weeks

Clinical Presentation

Symptoms: Diarrhea (>6 stools/day), abdominal pain, blood/mucus in stool
Systemic: Fever, dehydration, electrolyte abnormalities

Diagnostic Approach

Stool Studies (Essential):

C. difficile toxin (PCR)
Bacterial culture
Parasites (especially Cryptosporidium in immunocompromised)
Calprotectin (>250 μg/g suggests colitis)

Endoscopy Indications:

Grade 2-3 colitis
Uncertain diagnosis
No improvement with steroids in 3-5 days

Colonoscopy Findings:

Sigmoid-predominant: Similar to ulcerative colitis
Pan-colonic: More severe disease
Microscopic: Increased intraepithelial lymphocytes

Management Strategy

Grade 1 (2-3 stools/day):

Continue ICI with close monitoring
Loperamide, dietary modification

Grade 2 (4-6 stools/day):

Hold ICI
Prednisone 1 mg/kg/day
If no improvement in 3-5 days: increase to 1-2 mg/kg

Grade 3-4 (≥7 stools/day or severe symptoms):

Hospitalization
IV methylprednisolone 1-2 mg/kg/day
If no response in 3-5 days: infliximab 5 mg/kg

Hack - The "3-Day Rule": If no improvement in diarrhea frequency by day 3 of steroids, escalate therapy immediately.

4. Immune-Related Hepatitis

Incidence: 5-10% (combination), 1-3% (monotherapy) Onset: 6-14 weeks (median 8 weeks)

Clinical Presentation

Usually asymptomatic (found on routine labs)
When symptomatic: fatigue, nausea, RUQ pain, jaundice

Laboratory Patterns

Hepatocellular Pattern (Most Common):

ALT/AST >5× ULN
ALT:ALP ratio >5

Cholestatic Pattern:

ALP >2× ULN with minimal ALT elevation
Associated with higher mortality

Mixed Pattern:

ALT >3× ULN and ALP >2× ULN

Essential Workup

Viral serologies: HBV, HCV, CMV, EBV
Autoimmune markers: ANA, anti-smooth muscle, anti-LKM
Imaging: US/CT to exclude obstruction, metastases
Drug history: Recent antibiotics, supplements

Management Approach

Grade 1 (1.5-3× ULN):

Continue ICI with weekly monitoring
Rule out other causes

Grade 2 (3-5× ULN):

Hold ICI
Prednisone 1 mg/kg/day
Monitor liver function twice weekly

Grade 3-4 (>5× ULN or symptoms):

Permanent ICI discontinuation
Methylprednisolone 1-2 mg/kg/day IV
Consider mycophenolate if steroid-refractory

Pearl: Unlike viral hepatitis, irAE hepatitis typically has normal or mildly elevated bilirubin despite high transaminases.

Advanced Management Strategies

Steroid-Refractory irAEs

Definition: No improvement or worsening after 3-5 days of high-dose steroids

Second-Line Options:

Infliximab 5 mg/kg - avoid in heart failure, active infection
Mycophenolate mofetil 1g BID - preferred for hepatitis
Tocilizumab 8 mg/kg - for pneumonitis, arthritis
Rituximab - for severe hematologic irAEs

The Steroid Taper: Avoiding Flares

Hack - The "50-25-10 Rule":

Reduce by 50% weekly until 25 mg prednisone
Then reduce by 25% weekly until 10 mg
Then reduce by 2.5 mg every 1-2 weeks

Total duration: Minimum 6-8 weeks for Grade 2-3 irAEs

Prophylaxis During Immunosuppression

Standard Prophylaxis for High-Dose Steroids (>20 mg/day):

PCP prophylaxis: Trimethoprim-sulfamethoxazole DS 3×/week
Bone protection: Calcium 1200 mg + Vitamin D 800 IU daily
GI protection: PPI if risk factors for ulcers
Ophthalmologic: Annual screening for cataracts/glaucoma

Rechallenge Decisions: Art Meets Science

Safe Rechallenge Criteria

Grade 1-2 irAE that resolved completely
No life-threatening toxicity (myocarditis, pneumonitis Grade 3-4)
Adequate steroid taper completed
Oncologic benefit outweighs risk

Permanent Contraindications

Myocarditis (any grade)
Pneumonitis Grade 3-4
Neurologic irAEs (encephalitis, transverse myelitis)
Grade 4 any irAE

Pearl: Rechallenge success rate is 60-70% for Grade 1-2 irAEs, but recurrence tends to be more severe.

Special Situations and Complications

Concurrent Infections in irAE Patients

The Diagnostic Dilemma: Distinguishing infection from irAE flare in immunosuppressed patients

Approach:

Obtain cultures before escalating immunosuppression
Procalcitonin >2 ng/mL suggests bacterial infection
Imaging patterns: New focal findings suggest infection
Consider empiric antimicrobials if high suspicion

Managing irAEs in ICU Settings

Critical Care Considerations:

Avoid empiric antibiotics unless strong infection suspicion
Early aggressive immunosuppression improves outcomes
Monitor for secondary infections during treatment
Coordinate with oncology for all decisions

Drug Interactions and Complications

Infliximab Considerations:

Screen for tuberculosis before use (QuantiFERON, chest CT)
Contraindicated in moderate-severe heart failure
Monitor for infusion reactions (premedicate with steroids, antihistamines)

Quality Measures and Outcomes

Key Performance Indicators

Time to irAE recognition: <48 hours from symptom onset
Time to steroid initiation: <24 hours from diagnosis
30-day mortality from severe irAEs: <5%
Rate of steroid-refractory cases: <20%

Long-term Monitoring

Endocrine irAEs often permanent (hypothyroidism, adrenal insufficiency)
Pneumonitis survivors need long-term pulmonary follow-up
Cardiac irAEs require ongoing cardio-oncology surveillance

Practical Pearls for Clinical Practice

Assessment Pearls

"The Rule of Timing": New symptoms in ICI patients are irAEs until proven otherwise
"Steroid Test": Rapid improvement with steroids confirms irAE diagnosis
"The Organ Connection": Always screen for multi-organ irAEs (myocarditis + myositis)

Management Pearls

"Go Big, Go Early": High-dose steroids early prevent irreversible damage
"The 72-Hour Rule": If no improvement in 72 hours, escalate therapy
"Taper Slowly": Rapid steroid withdrawal causes irAE flares

Communication Pearls

Document rechallenge eligibility clearly in all notes
Educate patients about irAE symptoms and when to seek care
Coordinate closely with oncology for all ICI decisions

Future Directions and Research

Emerging strategies include biomarker-guided therapy, targeted immunosuppression based on irAE mechanisms, and prophylactic approaches for high-risk patients. Clinical trials are investigating checkpoint inhibitor rechallenge protocols and optimal immunosuppressive regimens.

Conclusion

ICI toxicities represent a paradigm shift in supportive cancer care, requiring internists and intensivists to master a new category of immune-mediated diseases. Early recognition, prompt immunosuppression, and multidisciplinary coordination are the cornerstones of successful irAE management. As ICI use expands, proficiency in managing these toxicities becomes essential for all physicians caring for cancer patients.

The key to success lies in maintaining high clinical suspicion, acting quickly when irAEs are suspected, and partnering closely with oncology colleagues to optimize both cancer outcomes and patient safety.

References

Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related 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.
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.
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.
Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391(10124):933.
Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126.
Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Netw. 2020;18(3):230-241.
Suresh K, Naidoo J, Lin CT, Danoff S. Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities. Chest. 2018;154(6):1416-1423.
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51-60.
Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49.
Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563-580.

Monday, June 23, 2025