CONTENTS

• Rapid reference 🚀
• Introduction to checkpoint inhibitors
• Core principles of immunotherapy-related adverse events
• Immune-related adverse events in the ICU
• Specific organ-system involvement
  • Cardiac
  • Pneumonitis
  • Colitis
  • Hepatitis
  • Nephritis
  • Endocrine
  • Neurologic
  • Hematologic
  • Dermatologic
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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basic tests to consider in critically ill patient s/p checkpoint inhibitor (more)

• Labs:
  • CBC with differential, electrolytes.
  • Coagulation studies (INR, PTT).
  • Liver function tests.
  • TSH and free T4.
  • Cortisol level (if adrenal insufficiency possible).
• Imaging:
  • POCUS to evaluate for myocarditis.

differential considerations may include:  

• Disease process totally unrelated to cancer.
• Infection, including opportunistic (if on chemotherapy or neutropenic).
• Venous thromboembolic disease.
• Checkpoint inhibitor immune-related toxicity.
• Complication from other cancer therapy (e.g., chemotherapy, radiotherapy, surgery).
• Progression of malignancy (e.g., metastases).
• Paraneoplastic process (e.g., hypercalcemia, encephalitis).

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introduction to checkpoint inhibitors

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agents & mechanism of action of checkpoint inhibitors

Cancer cells may up-regulate suppressive signaling to T-cells via CTLA-4 and PD1/PD1-ligand, in order to evade the immune anti-tumor response.  Checkpoint inhibitors block these inhibitory signals, thereby re-activating the immune response to cancer cells.(28031719)  Three subsets of checkpoint inhibitors block different targets (as listed below), although two of them interrupt the same cell-signaling pathway (PD-1 inhibitors and PD-Ligand 1 inhibitors).

• PD-1 inhibitors:
  • Nivolumab.
  • Pembrolizumab.
  • Cemiplimab.
• PD-Ligand 1 (PD-L1) inhibitors:
  • Atezolizumab.
  • Avelumab.
  • Durvalumab.
• CTLA-4 inhibitors:
  • Ipilimumab.
  • Tremelimumab.

common indications for checkpoint inhibitors

• Melanoma, squamous-cell carcinoma of head and neck.
• Lung cancer (both non-small cell and small-cell carcinomas).
• Renal cell carcinoma, urothelial carcinoma.
• Hepatocellular CA, Colorectal carcinoma, Gastric adenocarcinoma.
• Hodgkin's lymphoma.
• Head and neck squamous cell carcinoma.
• Cervical cancer.

rapidly expanding world of checkpoint inhibitors

• The number of indications for these drugs is currently exploding on a monthly basis.
• Most studies have extensive exclusion criteria (often excluding patients with a history of rheumatologic disorders; see example below).
• When utilized broadly among a more diverse patient population in actual practice, the incidence of toxicity of checkpoint inhibitors will increase.  Combination therapy (two checkpoint inhibitors together, or a checkpoint inhibitor plus traditional chemotherapy) may also increase toxicity.
• There are no RCTs evaluating the treatment of checkpoint inhibitor toxicity, so ideal treatment remains unknown.

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core principles of immune-related adverse events

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immune-related adverse events (irAEs)

• Checkpoint inhibitors lead to dysregulated, hyperactive immune responses which mimic autoimmune diseases (e.g., inflammatory bowel disease, interstitial lung disease).
• These events are usually discrete, involving only one organ.  However, some tend to occur together
  • Myositis, myasthenia gravis, and myocarditis are frequently seen together and may cause a high mortality rate.(34172516)
• Any organ can be involved, with the most common sites being the skin, colon, adrenals, lungs, and liver.
• Events usually develop within the first few weeks to months after treatment initiation, but can occur at any time.(29320654)  They may even occur months to years after the discontinuation of therapy.(29162153)

differential diagnosis, in broad strokes:  

• Acute illness totally unrelated to malignancy.
• Complications of the malignancy itself:
  • Direct progression of disease (e.g., compression of spinal cord, superior vena cava).
  • Indirect complications from malignancy (e.g., venous thromboembolic disease).
• Complications of conventional chemotherapy/radiotherapy in patients exposed to this:
  • Drug toxicity (e.g., radiation pneumonitis).
  • Opportunistic infections.
• Complications of immunotherapy:
  • Immune-related adverse events.
  • Flare of any underlying rheumatologic disease.
  • Immune reconstitution inflammatory syndrome (IRIS) causing previously latent tuberculosis to manifest clinically.(29427804)

basic evaluation

• Lab panel:  consider, depending on the clinical presentation:
  • CBC with differential, electrolytes.
  • Coagulation studies (INR, PTT).
  • Liver function tests.
  • Cortisol level.
  • TSH & free T4.
  • Urinalysis.
• Physical examination may include:
  • Bedside echocardiography to evaluate for myocarditis or pericardial effusion.
  • Lung ultrasonography (bilateral B-lines with spared areas in between may suggest pneumonitis).

treatment

• ⚠️ Treatment of a checkpoint inhibitor-induced disorder may have important differences compared to treatment of the same disorder when it occurs spontaneously.
• Treatment varies, depending on the organ involved, but the general rubric is as follows.
• Immune checkpoint inhibitor should be discontinued for any critically ill patient with possible immune-related adverse event.
• 1st line therapy is usually corticosteroid.
  • This doesn't appear to impair the anti-tumor effect of these drugs.(30245744)
  • Early initiation of steroid generally carries a favorable prognosis (e.g. ~1-2 mg/kg/day IV methylprednisolone or oral equivalent).(29250474)  Most patients will respond to steroids within 48-72 hours.
• 2nd line treatment is unclear.
  • There is evidence is available regarding this.
  • Various immunosuppressives are used, most often anti-TNF therapy (infliximab).(29250474, 26282644)
• For each organ involved, the severity may be graded in order to determine management.  The general scheme tends to look something like this:

outcome

• Most immune-related adverse events appear to be reversible, with the exception of endocrine side effects (which may require chronic hormone supplementation).
• Steroid is generally required for a long time (e.g., tapered down over several weeks).  This places patients at risk for opportunistic infections, so prophylaxis against pneumocystis jiroveci may be considered.
• Recurrence can occur during steroid taper, even without re-exposure to checkpoint inhibitors.

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disorders frequently encountered in ICU

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The likelihood of encountering an immune-related adverse event in the ICU is a function of two probabilities:

1. The frequency of the immune-related adverse event.
2. The likelihood that the immune-related adverse event will require ICU admission.

The most common cause of ICU admission is probably pneumonitis, a topic that intensivists should be very familiar with.(33064239)  Other more frequent causes of ICU admission are neurologic complications (including myasthenia, encephalitis, and seizure) as well as endocrinologic derangements (including diabetic ketoacidosis and thyroid abnormalities).

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cardiac involvement

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clinical presentations vary, including the following: 

• Myocarditis causing new-onset systolic heart failure, cardiogenic shock.
• Takotsubo cardiomyopathy.
• Arrhythmias (heart block, supraventricular or ventricular tachycardias).
• Pericarditis, myopericarditis.

differential diagnosis includes: 

• Dyspnea due to pneumonitis.
• Arrhythmia due to hyperthyroidism.
• Shock due to adrenal or pituitary dysfunction.
• The combination of simultaneous myasthenia gravis, myositis, and myocarditis is described.  The presence of any one of these three should prompt evaluation for all three disorders.(34172516)

evaluation

• EKG.
• Echocardiography (may see reduced RV or LV function, with global or regional abnormalities).
• TSH, free T4, cortisol levels.
• Troponin (only ~50% sensitive for any cardiac involvement, but 94% sensitive for myocarditis).(30191849, 34172516)
• Creatinine kinase (cardiomyopathy may associate with generalized myositis).
• Cardiac MRI.
• Cardiac catheterization.

treatment

• Steroid therapy may be used for patients with myocarditis or ventricular arrhythmias.  Mild-moderate illness can be treated with prednisone 1-2 mg/kg/day.  However, if severe or not rapidly prednisone-responsive, consider early institution of pulse-dose steroid (methylprednisolone 1 gram daily) and either mycophenolate mofetil, infliximab, or antithymocyte globulin.
• Additional treatments depend on the clinical presentation, for example:
  • Treatment of heart failure with usual therapies.📖
  • Treatment of conduction disease may require pacemaker insertion.
  • Pericardial tamponade may require drainage.

more information

• ASCO 2018 guidelines, page 43: myocarditis

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pneumonitis

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clinical presentation

• Severity ranges from subclinical to frank respiratory failure.
• Timing ranges from 9 days to over 19 months after treatment initiation, with a median onset of 3 months.(31584861)
• Symptoms include dyspnea (53%), cough (35%), fever (12%), and chest pain (7%)(27646942)
• Productive cough usually doesn't occur, so this might suggest an alternative diagnosis.(29162153)
• Pneumonitis is most common with PD-1 inhibitors or multiple checkpoint inhibitors, less common with PD-L1 inhibitors, and rare in patients  treated with anti-CTLA-4 agents.(32541313, 31584861)

differential diagnosis includes: 

• Heart failure (e.g. checkpoint inhibitor induced myocarditis).
• Infection (including opportunistic infection, if immunosuppressed by steroid or chemotherapy).
• Pulmonary embolism (both malignancy and checkpoint-inhibitors increase risk).
• Pneumonitis due to other therapies (e.g. radiotherapy, chemotherapy).
• Extension of malignancy (lymphangitic infiltration of the lung, lung metastases, or pulmonary tumor emboli).
• Flare of underlying interstitial lung disease.
• Neuromuscular weakness (e.g., checkpoint-inhibitor induced myasthenia gravis, myositis, or Guillain-Barre Syndrome).
• Diffuse alveolar hemorrhage (if severe chemotherapy-induced thrombocytopenia).

imaging features

• Chest X-ray has a sensitivity of only ~75%.(27646942)
• CT scan is required.  Consider using contrast to evaluate for pulmonary embolism.
• Radiographic and pathological patterns are variable, mimicking an array of interstitial diseases as shown below.
• Inflammation may cause tumor present in the lungs to enlarge (which can mimic progression of malignancy).
• Some features aren't commonly seen (cavitation, pleural effusion).  These should arouse suspicion for an alternative diagnosis.

most common radiographic patterns 🌊

• Organizing pneumonia pattern is most common.
  • Bilateral peribronchovascular and subpleural ground-glass and airspace opacities.
  • Mid-lung to lower-lung predominance.
  • May also see:  Reversed halo or atoll sign, pulmonary nodules/masses.
  • (Ddx:  Progression of malignancy, infection including fungi, cryptogenic organizing pneumonia.)
• Nonspecific interstitial pneumonitis (NSIP) pattern.
  • Relatively symmetric ground-glass and reticular opacities with basilar predominance.
  • Immediate subpleural sparing may be somewhat specific, if seen.
  • (Ddx:  Other causes of NSIP, infection.)
• Hypersensitivity pattern (HP)
  • Diffuse or centrilobular ground-glass nodules with a mid-to-upper lobe predominance.
  • Air trapping may occur.
  • (Ddx:  Exposure-related hypersensitivity pneumonitis, follicular bronchiolitis, atypical infection.)
• Acute Interstitial Pneumonitis-ARDS
  • Patchy or diffuse ground-glass or consolidative opacities.
  • Majority or entire lung involvement can occur.
  • Interlobular septal thickening with a crazy-paving pattern may be present.
  • (Ddx:  Cardiogenic pulmonary edema, ARDS due to other etiologies, pulmonary hemorrhage, infection including PJP.)
• Bronchiolitis
  • Centrilobular nodules with tree-in-bud nodularity.
  • May visualize adjacent ground-glass opacities and/or consolidation (but this shouldn't be the predominant finding).
  • (Ddx:  Aspiration, infection.)
• Radiation recall
  • Ground-glass or consolidative opacities confined to prior radiation field.
  • (Ddx: Acute radiation pneumonitis.)

basic evaluation

• Chest CT scan (see above).
• Echocardiography to evaluate for myocarditis.
• Blood cultures, sputum culture & gram stain, procalcitonin, urine pneumococcal and legionella antigens, PCR for relevant viruses (e.g., COVID, influenza).
• If concern for fungal infection:  Beta-D-glucan serum assay, antigens for endemic fungi (e.g., histoplasma, blastomycosis, cryptococcus neoformans).
• If concern for neuromuscular weakness, check negative inspiratory force (NIF) and forced vital capacity (FVC).

bronchoscopy

• The utility of bronchoscopy in checkpoint-inhibitor-associated respiratory failure is currently unknown.(30189190)  While some authors promote the use of bronchoscopy, others report treating patients empirically without bronchoscopy.(26865455)
• There is no finding on bronchoscopy that proves the diagnosis of checkpoint inhibitor pneumonitis.
• The role of bronchoscopy is primarily to exclude infection (especially pathogens that require specific antibiotic therapy:  fungus, tuberculosis, or pneumocystis jiroveci).  Thus, bronchoscopy is most important among patients with immunocompromise or imaging features suggestive of fungal/mycobacterial infection (e.g. nodular infiltrates, cavitation).
• Should unstable patients be intubated solely to facilitate bronchoscopy?
  • Some patients are encountered who are doing OK, yet are too unstable for bronchoscopy (e.g. on 60-80% FiO2 via high-flow nasal cannula).  A classic conundrum is whether to intubate such patients in order to facilitate bronchoscopy.
  • For each patient, the benefits of bronchoscopy must be weighed against the risks of intubation and mechanical ventilation.  This should involve an informed discussion with the patient including risks/benefits of various strategies.
  • From an evidentiary standpoint, bronchoscopy has never been shown to improve mortality (not even among immunosuppressed pneumonia patients).  Meanwhile, intubation of critically ill patients has repeatedly been demonstrated to carry a small, yet real mortality of ~2%.(22174463)  Intubation also increases the risk of delirium and ventilator-associated pneumonia.  This makes intubation solely for the purpose of bronchoscopy difficult to justify.
  • A reasonable compromise may be to initiate empiric therapy and consider delayed bronchoscopy after 1-2 days (by which point the patient will often have improved).  Delaying bronchoscopy will reduce the yield for bacterial pathogens, but pneumocystis and fungal studies are likely to remain positive.  Sometimes lab tests will return within this time frame, which make bronchoscopy unnecessary (e.g. positive urine pneumococcal antigen).

treatment overview

Patients with asymptomatic radiographic abnormalities may not require any therapy (aside from discontinuing the checkpoint inhibitor and closely monitoring).  The remainder of this section refers to patients admitted to the hospital with respiratory failure (Grade 3-4 toxicity).

treatment:  antimicrobial

• It is rarely possible to be entirely certain of the diagnosis of pneumonitis immediately, so patients will often be covered with antibiotics.  As laboratory tests return and the diagnosis becomes clear, these antibiotics should be discontinued.
• 1) Antibacterial therapy
  • Most patients will be treated initially to cover pneumonia (e.g. ceftriaxone/azithromycin).
  • If procalcitonin and other microbiologic studies are negative, antibiotics can generally be discontinued.
• 2) Pneumocystis jiroveci (PJP) therapy
  • PJP can cause radiographic patterns that look exactly like checkpoint-inhibitor pneumonitis (e.g. diffuse, patchy, ground-glass opacification).
  • Empiric therapy with trimethoprim-sulfamethoxazole may be reasonable if the patient is at risk for PJP and has a CT scan which is consistent with PJP.
• 3) Antifungal therapy (e.g., histoplasma, blastomycosis, cryptococcus neoformans)
  • Checkpoint inhibitor pneumonitis with a cryptogenic organizing pneumonia (COP) pattern may resemble fungal pneumonia (with dense nodules and patchy consolidation; image above).
  • For patients at risk for fungal pneumonia (due to immunosuppression or exposure) and with a CT scan consistent with fungal pneumonia, empiric coverage with isavuconazonium is reasonable while awaiting microbiologic studies.  Isavuconazonium is a newer anti-fungal agent which lacks the toxicity of amphotericin.

treatment:  immunomodulatory

• The mainstay of therapy is 1-2 mg/kg/day of prednisone or methylprednisolone.
  • 86% of patients will respond to this within a few days.(30189190)
  • Pneumonitis may recur following rapid steroid taper, so a minimum treatment duration of 4-6 weeks may be beneficial.(29162153)
• 14% of patients respond poorly to steroid.
  • Ideal treatment for these patients is unknown.  Historically they tend to do poorly.(30189190)
  • Recommended steroid doses vary between articles.  In the absence of any solid data, it's possible that higher steroid doses (e.g., 4 mg/kg/day) could be attempted in patients refractory to lower doses. (30189190)
  • Other options include infliximab 5-10 mg/kg, IV immunoglobulin, mycophenolate mofetil, or tocilizumab

sarcoidosis-mimic

• Less common than pneumonitis, checkpoint inhibitor pneumonitis may mimic sarcoidosis.  Beyond pulmonary involvement, this may involve other organs (ocular, myocardial, neurologic, hypercalcemia).(29162153)

more information

• ASCO 2018 guidelines, page 15 pneumonitis

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colitis

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presentation

• Diarrhea is generally the first symptom.  While often mild, this may progress to colitis with pain, fever, and mucus in stool.  Bloody diarrhea is uncommon.(32541313)
• Upper gastrointestinal tract involvement can occur, with nausea and vomiting.
• Toxic megacolon and perforation occur in ~1% of patients.(29442540)

evaluation

• Stool testing for bacterial pathogens, clostridioides difficile, and norovirus.  May also consider testing for shiga toxin (considering E. coli O157:H7), listeria, aeromonas, yersinia, and vibrio.
• CT scan of the abdomen to evaluate distribution and exclude perforation.  Checkpoint inhibitor colitis tends to have one of three patterns:  pancolitis, segmental colitis with diverticulosis, or isolated rectosigmoid colitis without diverticulosis.(30231401)
• Colonoscopy with biopsies may be used to exclude alternative diagnoses (e.g., CMV or ischemic colitis) and guide therapy (if ulceration is seen, this predicts steroid-refractory disease requiring infliximab; some guidelines recommend early initiation of infliximab in this situation).(34172516)
• In cases of diarrhea without CT findings of colitis, upper endoscopy with biopsies may also be considered to evaluate for gastric or duodenal involvement.

treatment

• Fluid resuscitation as needed for volume depletion.
• Avoid agents that reduce gut motility (e.g., opioids, loperamide).
• Steroid:
  • Indicated if >6 stools per day, hospitalization required due to colitis, or more serious complications.
  • Dose equivalent to 1-2 mg/kg/day prednisone, depending on severity.  Remember to taper slowly over 5-6 weeks.
• Surgical consultation if there is perforation or toxic megacolon.
• For severe disease that doesn't respond to steroid within 3-5 days, infliximab 5-10 mg/kg or vedolizumab may be added.(34172516)  Mycophenolate mofetil can be considered, and occasionally surgery is necessary.

more information

• ASCO 2018 guidelines, page 10: colitis

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hepatitis

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clinical findings

• Usually asymptomatic, but may cause fever and jaundice.
• Mostly elevated AST/ALT, but bilirubin can be increased.
• Rarely can lead to fulminant hepatic failure and death.(30447917)

differential diagnosis includes: 

• AST/ALT elevation due to myositis.
• Hepatitis due to other medications (especially acetaminophen).
• Alcoholic hepatitis.
• Viral hepatitis.
• Reactivation of chronic hepatitis (e.g., autoimmune hepatitis).
• Budd-Chiari syndrome.
• Liver metastases.
• Shock liver due to myocarditis.
• Biliary obstruction.

evaluation

• Obtain alcohol history.
• Review drug history for potential hepatotoxins (including over-the-counter drugs containing acetaminophen, supplements, and chemotherapeutic agents).
• Review other medications and supplements for potential hepatotoxins.
• Evaluate perfusion & vital signs, echocardiogram if needed (exclude shock liver).
• Creatinine kinase level (to evaluate for myositis as a cause of AST/ALT elevation).
• PT/INR.
• Labs for viral hepatitis (including HAV, HBV, HCV, and HSV), autoimmune hepatitis (ANA, anti-smooth muscle antibodies, liver-kidney microsomal antibody, antimitochondrial antibody).
• Hepatic ultrasound, including doppler (to exclude Budd-Chiari syndrome, biliary obstruction)

treatment

• Discontinue all potentially hepatotoxic medications.
• Immunosuppressive therapies are shown in the table below.  Resolution usually takes about two months.(30231401)

more information

• ASCO 2018 guidelines, page 13:  hepatitis

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nephritis

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The most common form of renal toxicity is acute tubulointerstitial nephritis (ATIN), which is what the remainder of this section explores.  However, some cases of glomerulonephritis have also been reported.  Additionally, checkpoint inhibitor-induced microangiopathic hemolytic anemia can cause renal failure (more on this in the hematology section below).

presentation

• Usually asymptomatic laboratory abnormality.
• Can present with manifestations of renal failure, for example:
  • Accumulation of renally cleared medications.
  • Uremic encephalopathy, poor appetite
  • Volume overload, electrolyte abnormalities

evaluation

• In most cases, renal failure isn't the result of checkpoint inhibitor toxicity.(34172516)  Thus, these patients require a thorough evaluation to exclude other causes of renal failure (e.g., obstruction, other nephrotoxic medications, volume depletion).
• CBC and blood smear should be performed to exclude microangiopathic hemolytic anemia (checkpoint inhibitors can cause thrombotic thrombocytopenic purpura or hemolytic uremic syndrome).
• Creatinine kinase should be measured to exclude checkpoint inhibitor-induced myositis causing rhabdomyolysis.
• Urinalysis may be entirely normal.(28105370)  Abnormalities that may be seen include mild proteinuria (<1 gram/day), sterile leukocyturia, microscopic hematuria, and granular casts.(27832664)  A spot protein:creatinine ratio should be performed to quantify proteinuria.  
• Renal biopsy isn't needed if there is no alternative cause of kidney injury.
• Review for any other medications which could be causing tubulointerstitial nephritis (e.g., NSAIDs, proton pump inhibitors, some antibiotics).(34172516)

treatment

• Prompt steroid initiation may prevent further kidney injury.
• Initial treatment is shown below.  If this treatment fails, then additional immunosuppression may be considered (e.g. mycophenolate mofetil).
• Supportive care for management of renal failure.📖

more information

• ASCO 2018 guidelines, page 28:  nephritis

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endocrinopathies

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Endocrinopathies occur in ~10% of patients on checkpoint inhibitors.(29442540)  The possibility of either central (pituitary) failure or peripheral (thyroid/adrenal) failure makes this especially complex.  Endocrine toxicity is distinct from most other organ toxicities for two reasons:

1. Treatment with steroids usually isn't used.  Treatment focuses on managing the patient clinically (e.g. with hormone replacement), rather than trying to save the endocrine gland.
2. Organ dysfunction is often persistent, requiring chronic hormone replacement.

pituitary dysfunction (hypophysitis)

• Epidemiology
  • Incidence is 3% with ipilimumab, or 6% with ipilimumab plus another agent (anti-PD1/PD-L1 monotherapy rarely causes hypophysitis).(32487905)
• Symptoms
  • Usually present with adrenal insufficiency, but can also present with elements of hypothyroidism, diabetes insipidus, and hypogonadism.
  • Headache (85%).(29162153)
  • Visual field deficits can result from optic chiasm compression.
• Evaluation (pituitary dysfunction causes all hormone levels to be decreased)
  • AM cortisol and ACTH levels (noting that frequent steroid use with chemotherapy may affect these).
  • TSH and free T4.
  • Luteinizing hormone, follicle-stimulating hormone, and either testosterone/estrogen level.
  • Brain MRI may show swelling and enhancement of the pituitary gland (while excluding other abnormalities such as brain metastases).(32487905)
• Treatment
  • (1) Glucocorticoid replacement if needed (same as for primary adrenal insufficiency below).  Make sure to start glucocorticoid replacement before thyroid replacement, to avoid precipitating adrenal crisis.
  • (2) Thyroid replacement if needed (same as for primary hypothyroidism above).
  • (3) High-dose steroids aren't recommended unless there are visual field symptoms due to marked swelling of the pituitary.  Regardless of steroid dosing, pituitary function is rapidly and irreversibly lost.(32487905)  Checkpoint inhibitor therapy may be resumed.
  • (4) Endocrinology consultation, sex hormone replacement PRN.

primary hypothyroidism 📖

• Symptoms are those of hypothyroidism (e.g. fatigue, weight gain, cold intolerance, constipation, depression).
• Diagnosed on the basis of elevated TSH and low free T4.
• Evaluation should also include AM cortisol and ACTH levels, to identify concurrent adrenal insufficiency or hypophysitis.(34172516)
• Treatment:  Thyroid hormone replacement as clinically indicated.

hyperthyroidism

• Two forms
  • 1) Thyroiditis is more common – usually causing milder hyperthyroidism.  Over several weeks this destroys the gland, leading to permanent hypothyroidism.
  • 2) Graves' disease is much less common.  Antibodies stimulate thyroid activity, leading to more persistent and severe hyperthyroidism.
• Symptoms
  • Hyperthyroidism (e.g. weight loss, heat intolerance, dyspnea, diarrhea, tremor, palpitations).
  • Graves disease may cause additional symptoms:  ophthalmopathy and digital clubbing.
• Diagnosis
  • Hyperthyroidism is diagnosed on basis of reduced TSH and elevated free T4.
  • Thyroiditis may be differentiated from Graves disease based on serologies (e.g., thyroid stimulating hormone receptor antibody) and radioactive iodine uptake by the thyroid.
• Treatment
  • Mild-moderate symptoms:  Consult endocrinology, may consider thionamide (steroid not usually needed).
  • Severe symptoms:  Prednisone 1-2 mg/kg/day plus additional therapies as needed to treat thyroid storm.📖

primary adrenal insufficiency

• Symptoms range from chronic adrenal insufficiency (e.g., fatigue, weight loss) to adrenal crisis (distributive shock).
• Evaluation:
  • AM cortisol & ACTH levels (should see low cortisol and elevated ACTH level).
  • If urgent situation or persistent diagnostic confusion:  an ACTH stimulation test.
  • CT scan to evaluate for adrenal metastases/hemorrhage.
• Differential diagnosis:  Must sort this out from pituitary dysfunction based on ACTH level (see below).
• Treatment:
  • Mild symptoms:  Start hydrocortisone replacement at usual dose (e.g. 10-20 mg in the morning and 5-10 mg in the afternoon).
  • Moderate symptoms:  Start hydrocortisone at twice normal dose (e.g. 20-30 mg in the morning and 10-20 mg in the afternoon).
  • Severe symptoms:  Start steroid without delay (either hydrocortisone 100 mg IV q8hr, or 4 mg dexamethasone if the diagnosis is uncertain).  More on the treatment of adrenal crisis.📖

type-I diabetes

• Checkpoint inhibitors may cause new-onset, autoimmune type-I diabetes – which can present in the form of diabetic ketoacidosis (DKA).📖  Less severe presentations may include a constellation of weight loss, hyperglycemia, polydipsia, and polyuria.
• The differential diagnosis here often centers around type-II diabetes versus type-I diabetes.  Serologies may help sort this out (anti-glutamic acid decarboxylase, anti-islet cell, or anti-insulin autoantibodies).  For immediate clinical management, however, this doesn't matter.

more information

• ASCO 2018 guidelines, page 17:  endocrine toxicities

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neurologic

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myasthenia gravis – see chapter on myasthenia gravis 📖 

encephalitis – see chapter on autoimmune encephalitis 📖

Guillain-Barre syndrome

• Symptoms:
  • Often begins early, usually within the first two months of therapy.(32487905)
  • Often starts with sensory symptoms or neuropathic pain in legs.
  • Progressive, ascending, symmetric muscle weakness may eventually involve respiratory and bulbar muscles.  This is accompanied by areflexia.
  • May cause dysautonomia, facial weakness, and extraocular movement impairment.(32487905)
• Differential diagnosis includes
  • Myositis.
  • Spinal cord compression.
  • Leptomeningeal carcinomatosis.
• Evaluation
  • Creatinine kinase, aldolase (to evaluate for myositis).
  • MRI of the spine (and brain in cases of cranial neuropathy) may be normal, or may show leptomeningeal enhancement.(32487905)
  • Lumbar puncture:  typically, elevated protein occurs along with a lymphocytic pleocytosis (unlike classic Guillain-Barre syndrome, which usually causes albuminocytologic dissociation).
  • Serum antiganglioside antibody tests for Guillain-Barre syndrome.
  • Electrodiagnostic studies may show a demyelinating polyneuropathy, or an axonal pattern.(32487905)
• Treatment
  • IVIG (0.4 grams/kg/day for five days) or plasmapheresis.
  • Methylprednisolone 2-4 mg/kg/day.

myositis

• Symptoms:
  • Myalgia is usually an early sign that precedes weakness.
  • Weakness may involve the proximal extremities, difficulty swallowing/speaking, ocular weakness, or ptosis.  This may resemble myasthenia gravis (with involvement of eyelids, neck muscles, and diaphragm).(32487905)
  • In severe cases, may cause rhabdomyolysis.
• Differential diagnosis includes:
  • Myositis, myocarditis, and myasthenia gravis may tend to occur together.
  • Steroid-induced myopathy.
  • Drug-induced rhabdomyolysis.
• Evaluation:
  • Creatinine kinase often is markedly elevated (but not always).
  • Check troponin to evaluate for myocarditis (+/- echocardiogram).
  • EMG may show muscle fibrillations.
• Treatment:
  • Steroid is the cornerstone of therapy.
    • If creatinine kinase is elevated more than three times normal, start prednisone at 0.5-1 mg/kg.
    • Consider 1-2 mg/kg methylprednisolone if severe compromise (e.g., weakness limiting mobility or respiration).
  • Plasmapheresis or IVIG also may be considered in steroid-refractory or life-threatening situations.(34172516)

transverse myelitis

• Symptoms:  Acute or subacute weakness or sensory changes bilaterally, often with increased deep tendon reflexes (unlike Guillain-Barre syndrome, which causes reduced reflexes).
• Differential diagnosis includes:  Guillain-Barre syndrome, myasthenia gravis, myositis, abscess, malignancy.
• Evaluation:  MRI spine, lumbar puncture.
• Treatment:
  • Methylprednisolone (either 2 mg/kg/day or strongly consider a pulse dose of 1 gram/day for 3-5 days).
  • Strongly consider IVIG.

other neurologic complications:

• Posterior reversible encephalopathy syndrome (PRES).
• Temporal lobe epilepsy.(33896532)
• Classic paraneoplastic neurologic syndromes (e.g., ANNA-1 limbic encephalitis).
• Optic neuritis, flare of underlying multiple sclerosis.
• Aseptic meningitis.
• Peripheral neuropathy, cranial neuropathy, autonomic neuropathy.

more information

• ASCO 2018 guidelines, page 30:  nervous system toxicities

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hematologic

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autoimmune hemolytic anemia

• Symptoms:  Weakness, pallor, jaundice, dark urine.
• Differential diagnosis includes:  Hemorrhage, marrow-toxic medication, aplastic anemia
• Evaluation
  • CBC, blood smear.
  • Reticulocyte count.
  • Hemolysis labs (LDH, haptoglobin).
  • DIC panel (INR, PTT, fibrinogen).
  • Direct agglutinin test.
• Treatment
  • Prednisone 1-2 mg/kg/day.
  • Conservative transfusion strategy (target 7 mg/dL).
  • Folic acid supplementation.
  • If steroid-refractory, start other immunosuppressives (e.g., rituximab, IVIG, cyclosporin A, mycophenolate mofetil).

immune thrombocytopenia

• Symptoms:  Petechiae, bleeding.
• Differential diagnosis includes:  Drug-induced marrow toxicity; post-viral; disseminated intravascular coagulation; aplastic anemia; thrombotic thrombocytopenic purpura; atypical hemolytic uremic syndrome
• Evaluation
  • CBC with differential, blood smear.
  • Testing for HIV, HCV, HBV.
  • Reticulocyte count, direct agglutinin test to exclude Evan's syndrome (concurrent autoimmune hemolytic anemia and thrombocytopenia)
  • Bone marrow aspiration (if other cell lines decreased and there is concern for aplastic anemia).
• Treatment
  • Prednisone 1-2 mg/kg/day is indicated for substantially reduced platelet count (e.g., <75).(34450397)
  • IVIG 1 gram/kg one-time dose, if a more rapid increase in platelet count is required.  Alternatively, 2021 SITC guidelines recommend IVIG at 0.5 gram/kg/day for five days.(34172516)  

lymphopenia

• Symptoms
  • May lead to opportunistic infections similar to those seen in AIDS (e.g. pneumocystis jirovecii pneumonia).   Note that CD4+ T-cells are a subset of lymphocytes, so the CD4 count must always be lower than the lymphocyte count.
• Differential diagnosis includes:  Lymphocyte-depleting therapy (e.g. anti-thymocyte globulin, cytotoxic chemotherapy, radiation exposure).
• Evaluation
  • CBC with differential, peripheral smear (lymphopenia defined as <1,500 lymphocytes/mm3).
  • Chest x-ray for evaluation of thymoma.
  • Tests for HIV, CMV.
  • CD4+ T-cell count.
• Treatment
  • If lymphocyte count <250/mm3, start prophylaxis for pneumocystis jirovecii and mycobacterium avium complex.
  • There is no clear role for systemic steroids.(34450397)

aplastic anemia

• Symptoms:  May cause failure of all cell lines (anemia, thrombocytopenia, neutropenia).
• Differential diagnosis includes:  Marrow failure due to medications, radiation, toxin, or recent viral infection.
• Evaluation
  • CBC, reticulocyte count.
  • Viral studies including CMV, HHV6, EBV, parvovirus.
  • B12 level.
  • Bone marrow aspiration.
• Treatment
  • Erythrocyte transfusion as needed (should be irradiated and filtered).
  • Platelet transfusion as indicated.
  • If severe:  Anti-thymocyte globulin and cyclosporine.

acquired thrombotic thrombocytopenic purpura (TTP) -OR- atypical hemolytic uremic syndrome (aHUS)

• Checkpoint inhibitors can cause either TTP or aHUS.  These can look similar, but the treatment is different.
• Symptoms
  • Both TTP and aHUS:  non-palpable purpura, renal failure, fever, abdominal pain and vomiting.
  • More suggestive of TTP:  neurologic abnormalities (e.g., seizure, hemiplegia, visual disturbances).
• Differential diagnosis includes
  • Disseminated intravascular coagulation.
  • Intracranial hemorrhage.
  • Renal failure due to acute tubulointerstitial nephritis.
  • Microangiopathic hemolytic anemia due to other drugs (e.g. chemotherapy, cyclosporine, tacrolimus).
• Evaluation
  • CBC with differential and peripheral blood smear.
  • Hemolysis labs (LDH, haptoglobin).
  • DIC panel (INR, PTT, fibrinogen).
  • ADAMTS13 activity level and inhibitor titer.
  • Complement testing:  C3, C4, CH50.
  • Urinalysis.
  • If diarrhea:  test for bacterial pathogens (shigella, E. coli 0157:H7).
• Treatment
  • Steroid:  Either prednisone 1 mg/kg/day or pulse dose steroid (methylprednisolone 1 gram IV for 3 days) depending on severity.
  • TTP:  Plasma exchange.
  • aHUS:  Eculizumab 900 mg weekly.

hemophagocytic lymphohistiocytosis (HLH) 📖

• May occur, a median of a month after starting therapy.(34172516)

acquired hemophilia A

• Symptom:  Bleeding, due to antibody which inhibits Factor VIII.
• Evaluation:  CBC, Coagulation studies (INR, PTT, thrombin time, fibrinogen), Mixing study, Quantification of inhibitor level.
• Treatment
  • Prednisone 1-2 mg/kg/day +/- rituximab.
  • Factor replacement and transfusion support.

more information

• ASCO 2018 guidelines, page 35:  hematologic toxicities

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dermatologic

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presentations are numerous, may include:

• Maculopapular rash.
• Maculopustular rash, bullae.
• Vitiligo.
• Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis.
• Drug reaction with eosinophilia and systemic symptoms (DRESS).

investigation

• Review medication list to evaluate for any other potential causes (e.g. drugs linked to Steven Johnson Syndrome / Toxic Epidermal Necrolysis).
• Consult dermatology, consider skin biopsy if nature of rash is unclear.

treatment

• Mild rashes may be managed with antihistamines and topical steroid.
• Steroid is indicated for more severe involvement, with a dose roughly proportional to the severity of the rash.  For example:
  • Blistering involves 10-30% body surface area:  Prednisone 1 mg/kg/day
  • Signs of Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis:  Prednisone 2 mg/kg/day.
• Consider antibiotics if signs of secondary cellulitis.

more information

• ASCO 2018 guidelines, page 4:  dermatitis

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Remember that checkpoint inhibitor reactions can occur months after initiation of treatment (or even after stopping the checkpoint inhibitor entirely).
• Maintain a broad differential diagnosis, including disorders related to the checkpoint inhibitor, complications of the malignancy itself, toxicity related to other interventions (e.g. chemotherapy, radiotherapy), as well as the possibility of entirely unrelated new diseases.
• Diagnosis of an immune-related adverse reaction from a checkpoint inhibitor may be difficult to make with 100% certainty.  In many situations, empiric steroid may be required while continuing to sort out the situation (and sometimes while providing concomitant antibiotic therapy).

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
•  = Link to supplemental media.

Going further

• Best source: ASCO/NCCN 2018 guidelines