EM@3AM: Immune-Related Adverse Event from Immune Checkpoint Inhibitors

Author: Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX) // Reviewed by: Alex Koyfman, MD (@EMHighAK)

Welcome to EM@3AM, an emDocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 43-year-old female with a history of breast cancer presents to the ED with diffuse abdominal pain and diarrhea for one week. She is experiencing over 12 episodes of non-bloody diarrhea daily. She denies fevers and nausea/vomiting, but she has felt generalized weakness due to the diarrhea. She is currently receiving Atezolizumab (also known as Tecentriq) for breast cancer.

Vital signs include BP 82/43, HR 121, T 98F oral, RR 22, SpO2 98% on RA. She appears tired, and her oral mucosa are dry. She displays diffuse abdominal tenderness to palpation, but there is no evidence of peritonitis. The rest of the exam is normal.

What is the patient’s diagnosis?


Diagnosis: Immune related adverse event from immune checkpoint inhibitor, specifically colitis

 

Background

  • A variety of cancer treatments are available. Immunotherapy encompasses several treatments that enhance, regulate, or supplement the immune system.
  • These therapies may be used in isolation or in combination with chemotherapy and radiation.
  • Immune checkpoint inhibitors (ICIs) are one such class of novel cancer therapy.
  • ICIs are used for several cancers (Table 1), with 7 having FDA approval by 2021.
  • Patients receiving ICI therapy may experience several adverse events due to T cell activation and immune system dysregulation.
  • These immune-related adverse events (irAEs) usually occur 3-6 months after initiation of therapy and affect organs with high cell turnover (dermatologic, GI, renal, endocrine). However, any system may be affected at any time after treatment.
  • The risk of irAE depends on the malignancy, medication, and use of other therapies.

 

Pathophysiology

  • T cells possess an important role in the immune system by recognizing and destroying abnormal cells (infected and malignant).
  • Several cancers suppress T cell function through activation of checkpoint signals. These signals normally result in activation of T cells to destroy abnormal cells (cancer).
  • ICIs prevent this suppression signal from malignant cells, which allows T cells to attack cancer cells.
  • ICIs include inhibitory ligands for the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), as well as programmed cell death ligand 1 (PD-L1).
    • CTLA-4 protein receptors are present on T cell surfaces and act as competitive receptor for CD28, responsible for cytokine production.
    • PD-1 is a receptor that stops T-lymphocyte proliferation, decreases proinflammatory cytokine production, and decreases T-lymphocyte survivability. Tumor cells take advantage of this by producing PD-L1.
  • Because of the disinhibition of the immune system, ICIs can result in organ injury, most commonly organs with rapid cell turnover. These are known as an immune related adverse event (irAE).
  • An irAE may occur in 60-90% of those on an anti-CTLA-4 medication and 20-70% of those on an anti-PD-1/PD-L1 medication.

 

Immune-Related Adverse Events

  • IrAEs are graded based on the National Cancer Institute (NCI) scale: mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening (grade 4), and death (grade 5).
    • Most patients experience grade 1 or 2 irAE, with < 10% experiencing grade 3 or worse.
  • Consultation with patient’s oncologist is recommended in those with suspected irAE. In most cases, consultation with the organ-specific specialist is recommended as well.

 

  • Dermatologic:
    • Occurs in up to 50% of patients, typically 2-3 weeks after treatment initiation.
    • Most common findings: non-severe rashes (e.g., maculopapular, lichenoid, psoriasiform, eczematous), pruritus, and vitiligo.
    • Bullous reactions and severe cutaneous adverse reactions (SCARs) including SJS, TEN, and DRESS are rare.
    • Grading:
      • Non-severe rashes: symptoms not affecting quality of life (grade 1), symptoms affecting quality of life requiring initiation of interventions (grade 2), failure of treatment for grade 2 toxicity (grade 3), and unmanageable or intolerable toxicity (grade 4).
      • Bullous diseases are primarily graded by body surface area (BSA) affected: <10% (grade 1), 10-30% (grade 2), >30% or limiting activities of daily living (ADL) (grade 3), and >30% with electrolyte or fluid status abnormalities (grade 4)
      • SCARs start at grade 2 with the following grades: non-sloughing maculopapular rash with 10-30% BSA and systemic symptoms (grade 2), sloughing of <10% BSA with mucosal involvement (grade 3), and sloughing of >10% BSA and/or systemic symptoms (grade 4).
    • Treatment:
      • Patients with non-severe rashes with grade 1 or 2 toxicities and bullous reactions of grade 1 toxicity can continue ICI therapy and treat symptoms with topical emollients and steroids.
      • Patients with grade 2 bullous reactions or grades 2-3 SCARs should be started on lower-dose systemic steroids with 0.5-1 mg/kg/day of prednisone or equivalent in addition to topical therapies.
      • Grade 3 or higher bullous reactions and grade 4 SCARs require high-dose systemic steroids at 1-2 mg/kg/day of prednisone or equivalent.  Any patient requiring systemic steroids or experiencing a SCAR of any grade should stop ICI therapy and receive a dermatology consultation. Patients with SCAR should be considered for transfer to burn center.

 

  • Pulmonary:
    • Occur in up to 19% of patients undergoing ICI therapy. Most common irAE is pneumonitis (also most common cause of death due to irAE).
    • Presents with dyspnea, chest pain, cough, decreased activity tolerance, hypoxia. Productive cough is uncommon. Symptoms usually begin 3 months after treatment initiation.
    • Grading: asymptomatic or limited disease (defined as only one lung lobe or <25% of parenchymal involvement) (grade 1); symptomatic or more extensive disease (defined as more than one lobe or up to 50% of parenchymal involvement) with mild hypoxemia (grade 2); severe symptoms, hypoxemia requiring hospitalization or oxygen supplementation, or severe disease (defined as all lung lobes or >50% of parenchymal involvement) (grade 3); and life-threatening complications or requirement for intubation (grade 4).
    • Imaging with x-ray or CT recommended. Evaluate for infection.
    • Treatment: Empiric antibiotics recommended in grade 2 severity or higher, with pulmonology consultation. Patients with grade 2 severity and higher require steroids 1-2 mg/kg/day of prednisone or equivalent. Patients with grades 3-4 may ultimately need non-ICI immunomodulators.

 

  • Gastrointestinal:
    • Hepatotoxicity and colitis most common. Colitis includes diarrhea and abdominal pain, while hepatotoxicity involves asymptomatic mild elevations in liver function tests, with severe cases including jaundice, weakness, and fever.
    • Typically starts 8-12 weeks after beginning therapy.
    • Colitis:
      • Occurs in up to 33% of patients. Chronic diarrhea with steatorrhea is one of the most common manifestations.
      • Grading: up to 3 additional stools from baseline or mild increase ostomy output (grade 1); 4-6 additional stools from baseline or moderate increase ostomy output (grade 2); 7 or more additional stools from baseline, severe increase in ostomy output, or requiring hospitalization (grade 3); and life-threatening complications associated with colitis (grade 4).
      • Evaluation includes fecal studies such as cultures, infectious stool polymerase chain reaction panels, if available, and fecal leukocytes. Obtain CBC, lipase, renal and liver function, electrolytes.
      • CT can assist in evaluating for severity of irAE and complications.
      • Treatment: Grade 1 – hold ICI; grade 2: start steroids; grade 3 or higher: other immunomodulators.
      • Severe colitis: surgery consultation and antibiotics.
    • Hepatotoxicity:
      • Occurs in up to 7% of patients.
      • Hepatoxicity grading: asymptomatic with AST/ALT levels up to 3 times the ULN or total bilirubin up to 1.5 times the ULN (grade 1); asymptomatic with AST or ALT 3-5 times the ULN or total bilirubin 1.5-3 times the ULN (grade 2); symptomatic liver toxicity, AST/ALT 5-20 times the ULN, or total bilirubin 3-10 times the ULN (grade 3); and decompensated liver failure (e.g., synthetic dysfunction, metabolic encephalopathy, ascites), AST/ALT greater than 20 times the ULN, or total bilirubin greater than 10 times the ULN (grade 4).
      • Evaluation includes LFTs, ruling out causes of liver enzyme abnormalities, imaging with ultrasound of liver, biliary tract, gallbladder.
      • Treatment: Grade 1 – hold ICI; grade 2: start steroids; grade 3 or higher: other immunomodulators.

 

  • Renal:
    • Affects up to 29% of patients receiving immunotherapy.
    • Includes AKI, interstitial nephritis, glomerulonephritis, and IgA nephritis.
    • ICI-associated renal injury commonly presents as hematuria, pyuria, worsening hypertension, or rising serum creatinine levels, with most cases having an onset of symptoms within the first 2-3 months.
    • Grading: increase of >0.3 mg/dL or 1.5-2.0 times above baseline (grade 1); creatinine 2.0-3.0 times above baseline (grade 2); creatinine >3.0 times above baseline, creatinine value of  >4.0 mg/dL, or hospitalization (grade 3); and any life-threatening complications or need for dialysis (grade 4).
    • Evaluation: CK to evaluate for rhabdomyolysis and myositis, electrolytes, renal and liver function, CBC and blood smear to evaluate for microangiopathic anemias, and urinalysis.  Urinalysis can be normal but may show sterile pyuria, microscopic hematuria, mild proteinuria, and granular casts. Obtain renal ultrasound.
    • Treatment: avoidance of nephrotoxic agents and cessation of ICI therapy, with permanent discontinuation for severity grade 3 or higher. When grade 2 or higher ICI-induced renal toxicity is suspected, administer steroids.

 

  • Endocrine:
    • Occurs in up to 17% of patients.
    • Includes hypophysitis, or pituitary gland inflammation, both hyper- and hypothyroidism, adrenal insufficiency (AI), and diabetes mellitus (DM).
    • Hypophysitis ranges from 2-3 months, thyroid dysfunction ranges from 2 weeks to 5 months, and DM ranges from 1 week to 1 year after therapy initiation.
    • Hypophysitis:
      • Symptoms are often vague, including headache, blurry vision, generalized weakness, fatigue, mood changes, dizziness, and loss of libido.
      • Graded in terms of ADLs: asymptomatic or mild symptoms (grade 1), moderate symptoms but still able to perform ADLs (grade 2), severe symptoms causing life-threatening conditions or inability to perform ADLs (grades 3-4).
      • Evaluation typically includes CBC, renal and liver function, TSH, FT4, electrolytes, morning cortisol, and ACTH. Neuroimaging with brain MRI is recommended.
      • Treatment of hypophysitis includes holding ICI therapy for all grades, initiation of replacement hormone therapy depending on which pituitary axis is affected, and endocrinology consultation. Patients with secondary AI or grades 3-4 toxicity should receive systemic steroids at a dose of 1-2 mg/kg/day of prednisone or equivalent.
    • Thyroid:
      • Patients with symptomatic hyperthyroidism can present with weight loss, fatigue, palpitations, anxiety, heat intolerance, and increased bowel movements.  Patients with hypothyroidism can present with nonspecific symptoms including weakness, fatigue, dizziness, weight change, and mood changes.
      • Hypothyroidism grading also includes TSH levels with a TSH <10 mIU/L for grade 1 and a TSH  >10 mIU/L for grade 2.
      • Treatment: Patients with grade 1 toxicities for both hyper- and hypothyroidism can continue ICI therapy.  Patients with grade 2 or higher hyperthyroidism should have ICI therapy held and begin treatment with beta-blockers and consideration for methimazole or propylthiouracil.  Grades 3 or 4 hyperthyroidism also require systemic steroids at a dose of 1-2 mg/kg/day of prednisone or equivalent.  Patients with grade 2 or higher hypothyroidism should have ICI therapy held and initiate thyroid replacement therapy, which should include intravenous therapy in grades 3-4.
    • Diabetes:
      • DKA is a common presentation.
      • Evaluation: basic metabolic panel, ketone levels, venous blood gas,, and the addition of DM autoantibody levels (if available).
      • Grading: asymptomatic or mild symptoms (e.g., polyuria, polydipsia) and a fasting blood glucose (FBG) >160 mg/dL without evidence of ketosis (grade 1), moderate symptoms with a FBG >160-250 mg/dL or ketosis (grade 2), and severe symptoms with life-threatening complications with a FBG >250-500 mg/dL (grade 3) or FBG > 500 mg/dL (grade 4).
      • Treatment: patients with grade 2 toxicity or higher should have the ICI therapy held until blood glucose is controlled with initiation of insulin therapy for grades 3-4. Treatment of DKA is similar to patients without ICI therapy.
    • Adrenal insufficiency:
      • Very rare, with case reports.
      • Presents with fatigue, dehydration, nausea, vomiting, and weight loss, though distributive shock can be present in adrenal crisis.
      • Grading of AI is the same as the grade for hypophysitis and includes ADLs.
      • Treatment will include steroids.

 

  • Neurologic:
    • Occurs in up to 6%.
    • Headaches, sleep disturbances, psychiatric symptoms most common.
    • The more severe neurologic complications associated with ICI therapy (e.g., myasthenia gravis, non-infectious encephalitis, Guillain-Barre syndrome [GBS], aseptic meningitis, transverse myelitis) are much less frequent.
    • Myasthenia gravis and non-infectious encephalitis have a reported mortality rate of up to 20%.

 

  • Cardiac:
    • Rare overall, occurring in less than 1%.
    • Includes myocarditis, pericarditis, coronary artery disease, heart failure, and arrhythmias.
    • Evaluate with ECG, renal and liver function, electrolytes, troponin, BNP, imaging.

 

  • Hematologic:
    • Rare overall.
    • Includes drug-induced hemolytic anemia, immune thrombocytopenia, lymphopenia, acquired hemophilia, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS).

 

Disposition:

  • Consult the patient’s oncologist to assist with evaluation, management, and disposition.
  • Admit those with neurologic toxicity, cardiac toxicity, toxicity above grade 2 of any organ system, or patients requiring the initiation of high-dose systemic steroids. These patients require coordination of further evaluation and irAE-specific therapy, steroid tapering, electrolyte trending, close monitoring for progression to higher grade toxicities, and consideration of continued ICI treatment.
  • Outpatient management for grade 1-2 toxicities may be reasonable in coordination with oncology, specialists based on the affected organ system(s), and assessment of the patient’s clinical trend in the ED.
  • Disposition decisions may also be influenced by time from ICI induction, duration of symptoms, stability of symptoms, comorbid conditions, social support, and access to care.

 

Take Home Points:

  • ICIs are a mainstay in cancer treatment, and the indications have significantly broadened. These medications are used in a wide range of malignancies as both single medications and combination therapies.
  • ICI therapy is typically well tolerated. However, ICIs can cause significant toxicities requiring their cessation, initiation of systemic steroids, and potentially additional immunosuppressant medications.
  • Each organ system and irAE possesses its own toxicity grading and associated treatment recommendations, making the approach to patients on ICI drugs challenging. 

References

  1. Twomey JD, Zhang B. Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics.AAPS J. 2021;23(2):39.
  2. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.J Immunother Cancer. 2017;5(1):95.
  3. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade.N Engl J Med. 2018;378(2):158-168.
  4. 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.
  5. 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. 2018;29(Suppl 4):iv264-iv266.
  6. Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ. Management of Immune Checkpoint Inhibitor Toxicities: A Review and Clinical Guideline for Emergency Physicians.J Emerg Med. 2018;55(4):489-502.
  7. El Majzoub I, Qdaisat A, Thein KZ, et al. Adverse Effects of Immune Checkpoint Therapy in Cancer Patients Visiting the Emergency Department of a Comprehensive Cancer Center.Ann Emerg Med. 2019;73(1):79-87.

 

Leave a Reply

Your email address will not be published.