Oncologic Emergencies: Immune-Based Cancer Therapies and Complications

vasculitis, atopic/contact viral exanthem, drug toxicity,


Pulmonary
Pneumonitis is the predominant irAE of the pulmonary system, ranging from no or mild symptoms to respiratory failure requiring intubation and ventilatory support. [1][2][3][4][5] Pneumonitis is the most common irAE requiring discontinuation of checkpoint inhibitor therapy, as well as the most common cause of death related to irAE. [63][64][65] Dyspnea, cough, fever, and chest pain may be present, with dyspnea occurring in 53% and cough in 35% of patients. 40,[63][64][65] Productive cough is rare and suggests another diagnosis. 40 The differential includes infection (opportunistic infection, pneumonia), heart failure (myocarditis), pulmonary embolism, extension of the malignancy, underlying interstitial lung disease or obstructive disease, diffuse alveolar hemorrhage, neuromuscular disease, or pneumonitis due to other therapies.
Laboratory assessment includes CBC, electrolytes, blood cultures, and urine testing for pneumococcal and legionella antigens. Sputum cultures and gram stain are also recommended, although these can be obtained in the critical care unit. 40,[63][64][65] If the patient presents during influenza season, testing for viral upper respiratory infections is recommended. Neuromuscular weakness should be assessed with negative inspiratory force and forced vital capacity. 65,66 Regarding imaging, chest radiograph demonstrates a sensitivity of approximately 75% for diagnosis of pneumonitis. [63][64][65][66] Computed tomography (CT) is recommended with contrast. The findings on CT vary, including ground glass opacities (37%), cryptogenic organizing pneumonia, interstitial infiltrates, and pneumonitis not otherwise specified. 65,66 If an infiltrate is present but the patient is asymptomatic, the patient does not require therapy beyond discontinuing the checkpoint inhibitor and obtaining oncology follow-up. Patients with critical illness or grade 3-4 irAEs require other therapies. [63][64][65] In the patient with severe respiratory symptoms, empiric therapy with antimicrobials is recommended, as grade 3-4 pneumonitis will not be immediately diagnosable. Procalcitonin can be used in the critical care setting to determine whether antibiotics should be continued, but this laboratory assessment should not be used in isolation for determining need for initial antibiotics. [1][2][3][4][5] Pneumocystis jirovecii (PJP) can cause similar clinical and radiographic findings, and empiric treatment with trimethoprimsulfamethoxazole is recommended if the patient is at high risk with corresponding radiographic findings. 63 Table 2. Immune-related adverse effects on the organs of cancer patients undergoing immunotherapy. [35][36][37][38][39][40][41][42]48,49 therapy is reasonable in the intensive care unit (ICU) if patients do not improve despite use of other therapies. Regarding pneumonitis, 1-2 mg/kg/day of prednisone or methylprednisolone is recommended. Over 80% of patients will improve in several days if an irAE is present. 67,68 However, up to 14% of patients will not respond to corticosteroid therapy. 37,67 Higher doses can be attempted (4 mg/kg/day), as well as other agents including infliximab or mycophenylate. 37

Long et al.
Oncologic Emergencies: Immune-Based Cancer Therapies and Complications Oncologic Emergencies: Immune-Based Cancer Therapies and Complications Long et al.
Patients with grades 3-4 pneumonitis or critical illness will require ICU admission. Bronchoscopy may be needed; however, there is no specific finding on bronchoscopy that definitely diagnoses pneumonitis due to checkpoint inhibitor toxicity, and it is not associated with improved survival. 56,57,[66][67][68] Bronchoscopy can be used to evaluate for infection as the etiology. 56,57 The decision for bronchoscopy is ultimately left to the pulmonologist and critical care physician.

Gastrointestinal Presentations
GI presentations of irAE typically include diarrhea and colitis, which can occur in up to 40% on ipilimumab. [1][2][3][4] These most often occur 6-7 weeks after initiation of therapy. [1][2][3][4]40 In the ED, differentiating mild-moderate symptoms from severe diarrhea and colitis is vital, as well as considering the wide differential including infectious diarrhea, enteritis, inflammatory bowel disease, and perforation. Nausea and vomiting may be present with upper GI tract involvement. Colitis tends to present with pancolitis, diverticulosis and segmental colitis, or isolated rectosigmoid colitis but no diverticulosis. 70 Severe colitis with fever, peritonitis, and perforation is rare but may occur. 57,58,71 Stool testing is recommended based on the grade of severity to include bacterial pathogens, viral etiologies, and Clostridium difficile. 57,58,70,71 Imaging with CT of the abdomen/pelvis is recommended in patients with critical illness to evaluate disease severity and complications and may demonstrate thickening of the bowel wall, mesenteric fullness, stranding, and/or perforation. [70][71][72][73] Colonoscopy for patients with severe illness may be used to evaluate for alternative diagnoses and guide management. Upper endoscopy may be needed during admission if CT does not reveal findings of colitis but the patient has diarrhea. 72,73 Volume-depleted patients require fluid resuscitation. Opioids and medications such as loperamide should be avoided, if possible. Corticosteroids are recommended for patients with > 6 stools, patients who are admitted for colitis, and other complications, with prednisone at doses of 1-2 mg/ kg/day. 37,57,58,73,74 Patients with severe disease may require infliximab. 37,57 Patients with perforation or toxic megacolon require surgical consultation. Empiric antibiotics are recommended for those with severe illness.

Hepatitis
Patients with hepatitis due to an irAE are usually asymptomatic and detected by routine liver function assessments, although patients may present with fever, jaundice, and abdominal pain. 37,75 Immune-related adverse events affecting the liver typically occur 6-14 weeks after beginning therapy. [35][36][37]75 Liver function tests including aspartate transaminase and alanine aminotransferase, as well as bilirubin, are increased, and the symptoms and levels of elevation determine the severity. 37,75 Fulminant hepatic failure and death are rare. Evaluating for other conditions is recommended, such as alcoholic hepatitis, acetaminophen toxicity, viral hepatitis, chronic hepatitis reactivation, biliary obstruction, shock liver, liver metastases, or vascular occlusion. Laboratory assessment should include viral hepatitis panel and autoimmune hepatitis panel (anti-smooth muscle antibodies, antinuclear antibody, liver-kidney microsomal antibody). Ultrasound of the liver, gallbladder, and biliary tract with doppler examination is needed to evaluate for liver and/ or biliary disease. 37,75 Treatment includes stopping medications that may result in hepatoxicity. Those with grade 2 disease or higher should receive corticosteroids. Infliximab may result in hepatotoxicity, limiting its use in hepatitis due to irAE. 2,35-37

Nephritis
Acute tubulointerstitial nephritis is the most common form of renal toxicity, although glomerulonephritis can also occur. 2,[35][36][37][38][39][40] Patients are typically asymptomatic, with laboratory abnormality the only finding. Renal failure can present with uremic encephalopathy, volume overload, and electrolyte abnormalities. 2,76,77 As renal injury due to irAE is rare, evaluation for other causes of renal failure is recommended to include CBC and blood smear (microangiopathic hemolytic anemias), CK (myositis and rhabdomyolysis), and urinalysis are recommended. Urinalysis may be normal or include sterile pyuria, mild proteinuria, microscopic hematuria, and granular casts. 76,77 Renal ultrasound is recommended with vascular studies. If no other cause is found for renal injury, biopsy is recommended. Corticosteroids should be initiated if the renal injury is due to irAE. Other immunosuppressant medications may be needed if the patient does not improve. Hemodialysis is recommended for grade 4 irAEs. 2,[35][36][37][38][39][40]76,77 Endocrinopathies Endocrinopathy affects approximately 10% of patients; it can be either central involving the pituitary gland, or peripheral involving the thyroid or adrenal glands. 2,48 Immune-related adverse events affecting the endocrine system are difficult to diagnose, and clinicians should consider these conditions in patients with non-specific symptoms such as fatigue, weakness, headache, nausea, and vomiting. 2,40,48,54 These complications typically arise 9-10 weeks after initiation of therapy. Endocrinopathies differ from other irAEs with organ dysfunction, as treatment with corticosteroids is not typically used, and organ dysfunction is often persistent due to disruption of the adrenal axis. 2,[35][36][37][38][39][40]61 Thus, treatment typically involves hormone replacement on a long-term basis.
Primary hypothyroidism is the most common endocrinopathy and may present with fatigue, cold intolerance, weight gain, constipation, and depression. 2,37,48,78 Diagnosis involves elevated TSH and low free T4, and treatment includes thyroid hormone replacement. Hyperthyroidism comes in two forms: thyroiditis and Graves' disease. Symptoms of hyperthyroidism include heat intolerance, diaphoresis, dyspnea, diarrhea, palpitations, tremor, and weight loss, although Graves' disease can present with ophthalmopathy. 2,40,48,79 Thyroiditis presents with mild symptoms of hyperthyroidism in the acute phase, followed by

Long et al.
Oncologic Emergencies: Immune-Based Cancer Therapies and Complications chronic hypothyroidism due to gland destruction. Graves' disease is much less common and presents with persistent, more severe hyperthyroidism. 2,48,79 Diagnosis includes reduced TSH and elevated free T4. TSH-receptor antibody can be used as well. Treatment includes a thionamide and endocrinology consult for those with mild-moderate symptoms. 2,37,40 Severe symptoms require therapy for thyrotoxicosis and thyroid storm if present, as well as corticosteroids. 37 Adrenal insufficiency can present with fatigue and weight loss or with adrenal crisis and distributive shock. Electrolytes, renal and liver function, cortisol, adrenocorticotropic hormone (ACTH), and CT of the abdomen/pelvis are recommended. Treatment includes hydrocortisone, with dosing dependent on patient hemodynamic status and symptoms. Adrenal crisis requires hydrocortisone 100 mg IV, as well as evaluation for infection, broad-spectrum antibiotics, and IV fluids with glucose. 2,[35][36][37][38][39][40]48 Pituitary dysfunction, or hypophysitis, typically presents with symptoms of hypothyroidism but may also present with arthralgias, vision changes, hypogonadism, hypothyroidism, diabetes insipidus, and/or adrenal insufficiency. 2,[35][36][37][38][39][40]48,54,79 Headache occurs in 85% of patients. 40 Electrolytes, cortisol, ACTH, TSH, free T4, luteinizing hormone, folliclestimulating hormone, and either testosterone/estrogen level are recommended, as well as central nervous imaging with brain MRI. [37][38][39][40] Diagnosis is based on at least one hormone deficiency plus MRI abnormality, or > 2 hormone deficiencies with headache. [37][38][39][40] Treatment is based on patient presentation, symptoms, and laboratory results. 37,40 Insulin-dependent diabetes is another irAE. 2,37,80 Treatment focuses on insulin and management of diabetic ketoacidosis if present. 37
A dangerous hemolytic irAE is acquired thrombotic thrombocytopenic purpura (TTP) or atypical hemolytic uremic syndrome (aHUS). 2,3,40,92,97 Both conditions can present with non-palpable purpura, fever, abdominal pain/vomiting, and renal failure. TTP tends to present with neurologic abnormalities. Lactate dehydrogenase, haptoglobin, coagulation panel, fibrinogen, ADAMTS13 activity and inhibitor titer, complement, and urinalysis are recommended, along with the other common laboratory assessments for anemia. If diarrhea is present, testing for bacterial pathogens is recommended. Treatment depends on the diagnosis. Prednisone or methylprednisolone can be used, but for TTP, plasma exchange is recommended, while for aHUS eculizumab is recommended. 2,3,40,92,97 Acquired hemophilia can occur due to inhibition of factor VIII. 97,101,102 Mixing studies and quantification of inhibitor levels are used to make the diagnosis. Treatment includes prednisone and/or other immunosuppressive therapies. 37,97

Rheumatologic
Myalgias and arthralgias are present in 2-12% of patients, most commonly in those receiving anti-PD-1 agents. 37,40,91 However, vasculitis, myositis, and giant cell arteritis may occur. Patients with mild to moderate symptoms can be treated with acetaminophen and/or non-steroidal anti-inflammatory drugs. Prednisone can also be used. Severe symptoms should be treated with high-dose corticosteroids, with consultation with oncology and rheumatology. 2,3,37,40,91

Ocular
Ocular toxicity is rare, occurring in 1% of patients. 2,3,103 These are divided into ocular inflammation including keratitis, uveitis and orbital inflammation, and retinal/choroidal disease. Patients may present with eye pain and vision changes. Treatment requires ophthalmology consultation with topical corticosteroids for episcleritis or anterior uveitis. Systemic corticosteroids are recommended for severe inflammation. 2,3,103
Oncologic Emergencies: Immune-Based Cancer Therapies and Complications associated with IL-6 production 117,124-127 However, CRP cannot differentiate between CRS and infection. [124][125][126][127] While not typically obtained in the ED, ferritin is often elevated in CRS, similar to that seen in macrophage activation syndrome. [104][105][106]128 Management of CRS requires symptomatic care and cytokine inhibition. Depending on signs, symptoms, and patient hemodynamic status, patients may require IV fluids, vasopressors, and broad-spectrum antibiotics, as sepsis is possible (Table 4). [104][105][106]117,118 Management of CRS focuses on two medications: corticosteroids and tocilizumab, a humanized immunoglobulin that prevents IL-6 binding to other receptors and further cell signaling. [104][105][106] Literature suggests tocilizumab is an effective therapy for severe CRS, with improvement within hours of infusion. [129][130][131] Corticosteroids are generally avoided in CRS and should only be used in conjunction with oncology consultation, as these medications can adversely affect antitumor effects. This differs from checkpoint inhibitor therapy, in which corticosteroids do not affect the therapeutic effects on the malignancy. 117,132,133 However, if evidence of adrenal crisis is present, stress-dose corticosteroids are recommended. Patients with CRS require admission and consultation with oncology due to the potential severe nature of the condition. [104][105][106] Differentiating CRS from infection and sepsis is difficult, as patients will typically meet systemic inflammatory response syndrome criteria and have greater than two points on the sequential organ failure assessment score. 118,121 One study found that 23% of patients developed infection in the first month of CAR T-cell therapy, with many infections occurring with onset of CRS. 118 Bacterial infections predominate, primarily of the respiratory tract. Thus, patients should be presumed to have infection, and antibiotics and resuscitation are recommended in the ED. [104][105][106] Cytokine storm is due to nonspecific activation of T cells, usually rapidly after CAR T-cell infusion. 119,120 This condition is a separate entity from CRS, although the presentation is similar. Tumor necrosis factor and interferon gamma are the predominant factors resulting in cytokine storm. [104][105][106]119,120 As opposed to CRS, the primary therapy for cytokine storm includes corticosteroids with resuscitation. However, corticosteroids should only be initiated with oncologist consultation, as steroids can deplete CAR T-cells. [104][105][106] Neurologic complications from CAR T-cell therapy present in a wide range, from mild headache to severe altered mental status and seizures. 104,120 Neurotoxicity is the second most common major adverse event with CAR T-cell therapy, officially known as CRES. 104-106 CRES does not always coincide with CRS, and symptoms can occur before, during, or after CRS. 104 A mechanism has not been definitely determined, although IL-1 may play a role. Tocilizumab is not effective in CRES as it does not cross the blood-brain barrier; however, anakinra, which blocks IL-1 receptors, may be beneficial. 105 Patients with severe neurologic symptoms should be managed with corticosteroids, primarily dexamethasone 10 mg IV due to its ability to cross the blood-brain barrier. 104,134 What's the Emergency Physician to Do?
While irAEs from checkpoint inhibitors and complications of CAR T-cell therapy can be severe, physicians must consider several other causes of the patient's symptoms. Patients may be experiencing acute illness unrelated to the malignancy and therapy, complications of the malignancy itself (disease progression or other complication such as tumor lysis syndrome), complications of more traditional cancer therapies including chemotherapy and radiotherapy (radiation pneumonitis, opportunistic infections/neutropenic fever), and complications of the immune-based therapy itself (irAEs, underlying rheumatologic disorder, immune reconstitution syndrome). [1][2][3]12,[35][36][37][38][39][40] With this wide differential of potentially dangerous conditions, patients may require emergent resuscitation.
Obtaining history of immune-based therapy is vital in the consideration of irAEs, CRS, or CRES. In the ED, biomarkers  Table 4. Grading cytokine release syndrome to guide treatment. [104][105][106] Oncologic Emergencies: Immune-Based Cancer Therapies and Complications Long et al.
such as interleukin levels are not readily available. Laboratory assessment should include CBC with differential, renal function and electrolytes, coagulation studies, liver function testing, cortisol, TSH, and urinalysis. Inflammatory markers such as CRP and ESR may be beneficial but cannot definitively diagnose the condition or exclude infection. Suspicion of an infectious etiology requires blood cultures and antibiotics. Bedside echocardiography can assist in assessment of the cardiopulmonary system. [1][2][3][4]12,[35][36][37][38][39][40] Management focuses on the specific organ involved, with resuscitation and antibiotics. For severe, critical illness, the checkpoint inhibitor should be discontinued if an irAE is likely. Early initiation of a corticosteroid improves prognosis with irAEs due to checkpoint inhibitors, except for those with endocrinopathies, and most patients improve within 2-3 days. If patients do not improve, there are other immunosuppressive agents that can be used. [1][2][3]71 Recurrence of an irAE can be seen with corticosteroid tapering and checkpoint inhibitor reinitiation. [1][2][3]12,37 Regarding CRS related to CAR T-cell therapy, patients should be admitted to the ICU for tocilizumab, and CRES requires ICU admission and corticosteroids. [35][36][37][38][39][40]

CONCLUSION
Immune-based therapies consist of immune stimulators, checkpoint inhibitors, and adoptive immunotherapy. These therapies differ in mechanism compared to other anticancer therapies, namely chemotherapy and radiation. Complications include irAEs, CRS, autoimmune toxicity, and CRES. Immunerelated adverse events, most commonly encountered with checkpoint inhibitors, may result in dermatologic complications, pneumonitis, colitis/diarrhea, hepatitis, and endocrinopathies. Less common irAEs include nephritis, myocardial injury, neurologic toxicity, ocular diseases, and musculoskeletal complications. Cytokine release syndrome and CRES are more commonly associated with CAR T-cell therapy. Cytokine release syndrome may present with flu-like illness, but severe myocardial and pulmonary disease may occur. Critically ill patients require resuscitation, broad-spectrum antibiotics, and hematology/ oncology consultation.

ACKNOWLEDGMENTS
BL, EB, and AK conceived the idea for this manuscript and contributed substantially to the writing and editing of the review. This manuscript did not use any grants or funding, and it has not been presented in abstract form. This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, Brooke Army Medical Center, or SAUSHEC EM Residency Program.