Immune Checkpoint Inhibitor Adverse Events 2.0: 5 Pearls Segment

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ICI: immune checkpoint inhibitor

IRAE: immune related adverse event

Pearl 1: Pneumonitis

• Time to onset can range from 1.5 to 127 weeks; median time to onset: 34 weeks  
• Clinical presentation can range from asymptomatic to acute hypoxic respiratory failure. Signs/symptoms may include cough, dyspnea, chest pain, fever. 
• Ddx: heart failure, COPD, infection, pulmonary embolism, pneumonitis (radiotherapy, chemotherapy), malignancy, ILD flare, neuromuscular disorder, sarcoidosis.
• Evaluation: CT Chest with contrast (CXR insufficient). Infectious workup including sputum culture, respiratory viral panel, COVID-19, blood culture, urine legionella and strep pneumo antigen.  
• Further evaluation with fungal markers (B-glucan, galactomannan), endemic fungal antigens, TB or PJP is required if they are immunosuppressed with an appropriate clinical picture.
• CT chest often shows ground glass opacities in the lower lobes. Five different types of imaging findings have been identified: chronic obstructive pneumonia–like, ground-glass opacities, hypersensitivity type, interstitial type, and pneumonitis not otherwise specified.
• The role of bronchoscopy with BAL and specifically biopsy is widely debated in evaluating ICI pneumonitis. It can help to rule out infection or lymphangitic spread of tumor.  
• Use guidelines for treatment based on grade. For pneumonitis: 
  • Grade 1 (asymptomatic/affecting one lobe or <25% of lung): hold ICI and monitor; repeat imaging in 3-4 weeks. If improved, can re-trial ICI; if not improved, treat as grade 2. 
  • Grade 2 (symptomatic/involving more than one lobe of the lung or 25-50% of lung parenchyma): Hold ICI, give Prednisone 1-2mg/kg/day and taper over 4-6 weeks. If no improvement after 48-72 hours, treat as grade 3. Consider bronchoscopy with BAL +/- biopsy. 
  • Grade 3 (hospitalization for severe symptoms or oxygen requirement/all lung lobes involved or >50% of lung parenchyma) or Grade 4 (life-threatening respiratory compromise/intubation required): permanently discontinue ICI, give Methylprednisolone IV 1-2mg/kg/day and taper over 4-6 weeks. If no improvement in 48 hours, add an additional agent such as infliximab, mycophenolate mofetil, IVIG or cyclophosphamide. Consider bronchoscopy with BAL +/- biopsy.

• Decisions about empiric treatment with antibiotics and diuretics should be made on a case by case basis.  

Pearl 2: Colitis

• Time to onset can range from 1 to 107.5 weeks; median time to onset is 8 weeks
• Symptoms can include abdominal pain, nausea, diarrhea, blood or mucus in the stool, fever.
• Ddx: infectious colitis (bacterial, viral, parasitic), ischemic colitis, inflammatory bowel disease, radiation colitis, diverticulitis, drug-induced colitis (chemotherapy, tyrosine kinase inhibitors), graft vs host disease in transplant patients. 
• Evaluation: Bloodwork with CBC, CMP, TSH. Stool studies with culture, C. diff, ova and parasites, CMV, other viral tests like Norovirus, fecal inflammatory markers like lactoferrin and calprotectin. Review medication list (antibiotics, prolonged PPI use, NSAID). For patients who need biologics, obtain HIV, hepatitis A and B, TB. CT scan to evaluate for complications such as abscess.
• Endoscopy and colonoscopy with biopsy should be performed if grade 2 or positive inflammatory markers. Ulceration can be an early indication that biologics will be needed. 
• Upper GI toxicity is less common but presents with dysphagia, nausea, vomiting or epigastric pain and can be isolated or occur with lower GI toxicity.
• NSAID and prolonged PPI use has been associated with an increase in ICI colitis.
• CT findings often mimic inflammatory bowel disease and includes mesenteric vessel engorgement, bowel wall thickening, and fluid filled colon distension. 
• ICI colitis often involves the descending colon. 
• Use guidelines for treatment based on grade. For colitis:
  • Grade 1 (increase of <4 stools per day over baseline): Can continue ICI or hold temporarily until resolution of symptoms. Supportive care with hydration and medications such as loperamide if infection has been ruled out. 
  • Grade 2 (increase of 4-6 stools per day over baseline): Hold ICI until symptoms resolve to grade 1. Give prednisone 1mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks. If no improvement in 72 hours or there are high risk endoscopic features, then add infliximab or vedolizumab. 
  • Grade 3 (increase of > or =7 stools per day over baseline/hospitalization): Grade 2 recommendations apply. Can consider IV methylprednisolone especially if concurrent upper GI inflammation. Consider permanent discontinuation of CTLA-4 agents. 
  • Grade 4 (life threatening symptoms/urgent intervention required): Grade 2 and 3 recommendations apply. For steroid give IV methylprednisolone 1-2mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks. Permanently discontinue ICI. 

• Resume ICI if fecal calprotectin is less than 116 or if repeat endoscopy shows mucosal healing.

Pearl 3: Skin IRAE

• Time to onset can range from 2 to 150 weeks; median time to onset is 7 weeks
• Includes maculopapular rash, bullae, vitiligo, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, DRESS
• Symptoms: ranges from itch +/- rash to fever, skin sloughing, pustules, blisters or mucosal erosions
• Ddx: allergic or irritant contact dermatitis, atopic dermatitis, psoriasis, seborrheic dermatitis, infectious dermatitis (fungal, bacterial, viral), unrelated drug rash with eosinophilia and systemic symptoms (DRESS) 
• Evaluation: history and physical exam is very important including examination of oral mucosa, assessment of blisters and body surface area affected. Medication list should be reviewed. CBC and CMP should be obtained. Dermatology may obtain skin biopsy for further evaluation. 
• Vitiligo is associated with treatment response. 
• Use guidelines for treatment based on grade. For inflammatory dermatitis:
  • Grade 1 (rash<10% body surface area): Continue ICI and give topical emollients and/or mild-moderately potent topical steroids. 
  • Grade 2 (rash covering 10-30% BSA with or without symptoms): Consider holding ICI. Give topical emollients, oral anti-histamines and medium-highly potent topical steroids. Consider prednisone 0.5-1mg/kg and taper over 4 weeks. 
  • Grade 3 (rash >30% BSA with moderate or severe symptoms): Hold ICI and discuss with dermatology about timeline for restarting. Give topical emollients, oral antihistamines and highly potent topical steroids. Start oral prednisone 1mg/kg/day and taper over 4 weeks. If pruritus is present without rash, can try gabapentin or pregabalin. 
  • Grade 4 (severe symptoms requiring hospitalization): Hold ICI, hospitalize patient and give IV methylprednisolone 1-2mg/kg/day. Discuss with dermatology/oncology about appropriateness of restarting ICI.

Pearl 4: Endocrine IRAEs (thyroid)

• Time to onset for endocrine IRAEs is 1.5-130 weeks; median time to onset is 14.5 weeks
• Includes pituitary dysfunction, hypothyroidism, hyperthyroidism, adrenal insufficiency (nausea, vomiting, abdominal pain, weight loss, lightheadedness or orthostasis or syncope, and profound fatigue), T1DM (polyuria or polydipsia, nausea or vomiting, abdominal pain, and/or visual blurring).
• Symptoms
  • Primary hypothyroidism: cold intolerance, dry skin, constipation, weight gain, and/or fatigue
  • Thyrotoxicosis: palpitations, heat intolerance, insomnia, frequent bowel movements, or weight loss

• Ddx for primary hypothyroidism: Hashimoto’s thyroiditis, central hypothyroidism, post-viral subacute thyroiditis, induced by other drugs (lithium, amiodarone, anti-epileptics), induced by head and neck radiation. 
• Ddx for thyrotoxicosis: Grave’s disease, DeQuervain’s thyroiditis, medication induced (amiodarone), thyroid adenoma, secondary hyperthyroidism from pituitary adenoma. 
• Evaluation: TSH and free T4. T3 and TSH receptor antibody testing if suspicion for Graves' Disease (ophthalmopathy or thyroid bruit). 
• Low TSH and low free T4= central hypothyroidism (see hypophysitis below). High TSH and low free T4= primary hypothyroidism. 
• Use guidelines for treatment based on grade. For primary hypothyroidism:
  • Grade 1 (4.5<TSH<10 and asymptomatic): Continue ICI and monitor TSH every 4-6 weeks.
  • Grade 2 (TSH>10 and symptomatic): Can continue or hold ICI. Start levothyroxine and check TSH levels every 6-8 weeks until TSH is in reference range.
  • Grade 3-4 (severe symptoms): Hold ICI until symptoms resolve. Hospital admission if concern for developing myxedema (bradycardia, hypothermia, altered mental status). Discuss with endocrinology about IV levothyroxine and steroids. Thyroid supplementation per grade 2 recommendations. 
  • Consider referring to endrocrine at grade 2; should be referred grade 3 or higher.
• For thyrotoxicosis:
  • Grade 1 (asymptomatic or mild symptoms): Continue ICI. Beta blocker for symptoms. Monitor thyroid function 2-3 weeks to detect subsequent hypothyroidism (commonly occurs in transient subacute thyroiditis) in which case the patient should be treated for primary hypothyroidism.
  • Grade 2 (moderate symptoms): Consider holding ICI, give beta blocker for symptoms. If persistent >6 weeks, will need thyroid suppression. 
  • Grade 3-4 (severe symptoms, unable to perform ADLs): Hold ICI until symptoms resolve and give beta blockers for symptoms. Discuss with endocrine about medical therapies such as steroids, potassium iodide, methimazole, propylthiouracil or surgery. 
  • Refer to endocrine if thyrotoxicosis persists for more than 6 weeks.

Pearl 5: Endocrine IRAEs (pituitary)

• Hypophysitis is most commonly seen with ipilimumab. 
• Wide range of symptoms: can present with fatigue, loss of libido or mood changes, oligomenorrhea due to hormone imbalances or can present with headaches and visual changes.
• Evaluation: workup with AM cortisol, AM ACTH, TSH, free T4 and electrolytes. Need ACTH stimulation testing if AM cortisol results are indeterminate (between 3 and 15). Obtain hormone levels: LH, FSH, estrogen and testosterone. If visual changes, headache or diabetes insipidus is present, obtain MRI brain with and without contrast with sellar cuts to evaluate the pituitary gland. 
• Use guidelines for treatment based on grade. For hypophysitis:
  • Principles are somewhat different because hormone replacement is the mainstay of treatment instead of immunosuppression for endogenous hormone production recovery. 
  • Grade 1 (asymptomatic/mild symptoms): Consider holding ICI until patient stabilized on hormones. Steroid replacement for adrenal insufficiency if needed. Thyroid replacement if needed with free T4 goal in upper half of reference range. Testosterone or estrogen therapy if needed and no contraindications. 
  • Grade 2 (moderate symptoms): Consider holding ICI and hormone replacement as grade 1 recommendations. If MRI shows pituitary swelling or optic chiasm compression, treat with prednisone 1mg/kg/day and taper over 1-2 weeks to maintenance therapy dose. 
  • Grade 3-4 (severe symptoms/unable to perform ADLs): Hold ICI until stabilized on hormones. IV hydrocortisone 50-100mg q6-8 hours tapered down over 5-7 days or prednisone 1-2mg/kg/day tapered over 1-2 weeks to maintenance dose. Hormone replacement as grade 1 and 2. 

Contributors

Shreya Trivedi, MD, ACP Member – Host, Editor
Anuranita Gupta, MD – Host, editor, MOC questions
Benjamin Schlechter MD* - Guest
Allison Betof Warner MD * – Guest
Narjust Florez MD* - Guest

Reviewers

Meng Wu, MD, ACP Member
Elad Sharon, MD*

*Benjamin Schlechter, MD: Consultant: Agenus, Janssen

*Allison Betof Warner, MD: Consultant: BMS, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, Pfizer.

*Narjust Florez, MD: Consultant: AZ, BI, Daiichi Sankyo, Inivata, Inc., Janssen Biotech, Jazz Pharmaceuticals, Neogenomics, Novocure Inc., Pfizer, Regeneron Pharmaceuticals; Grant/Contract: Daiichi Sankyo, Genentech Foundation, Janssen Biotech.  Author and Honorarium: Ideology Health, MJH Life Sciences

*Elad Sharon, MD: Consultant: Mallinckrodt

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  January 8, 2025

Expiration Date: January 7, 2028

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