Uric Acid Mayhem and Other Cancer Derived Shenanigans
A brief overview of common pediatric hematologic malignancy emergencies
Case
An 8-year-old girl with past medical history of obesity presents with three weeks of intermittent fevers, joint aches, URI symptoms, abdominal pain, and decreased appetite. She had been treated for strep throat twice and had several visits with her primary care doctor to follow up. She was referred to the ED for blood work and evaluation because she developed a petechial rash on her torso and extremities. She had not had significant weight loss, night sweats, mucosal bleeding, or lymphadenopathy. She has been limping with ambulation, but her gait returned to normal with ibuprofen. On exam, she had no other focal findings other than scant petechial involving her entire body. The differential for this patient was broad and included recurrent viral illnesses, toxic synovitis, Henoch-Schonlein purpura, osteomyeltitis and occult malignancy. Unfortunately, shortly after her CBC was sent, the lab called and reported that her WBC count was 49,000 and abnormal cells were present; a hematologist confirmed that her peripheral blood contained 47% blasts.
Recognizing pediatric malignancies in the Emergency Department can be challenging as the presentations can be quite subtle. Once you diagnose a cancer, often other studies are required to ensure that there are not any other metabolic or physiologic complications resulting from the malignancy. In this blog post, we will focus on the oncologic emergencies in the pediatric patients that are not mechanical or mass related.
Tumor Lysis Syndrome
Description
Rapid cell destruction releases large amounts of intracellular contents. When the amount of material released overwhelms the ability of the kidneys to excrete it, this leads to metabolic derangements known as tumor lysis syndrome (TLS). Risk factors include chemotherapy induction, untreated acute leukemias (particularly ALL and high-grade non-Hodgkin lymphoma), chronic leukemia with blast crisis, or hyperleukocytosis, and hyponatremia. Malignant cells often contain a higher concentration of phosphorus than normal cells; the release of phosphorus causes the precipitation of calcium. Hyponatremia is often from SIADH. The hyperkalemia can be worsened by the development of acute kidney injury from the circulating uric acid [1].
Presentation
A high index of suspicion should be maintained to look for TLS as symptoms can be subtle (nausea, loss of appetite, muscle cramps, tetany, decreased urine output, altered mental status, convulsions, and arrhythmias). There is significant risk of morbidity and mortality if this diagnosis is not recognized and treated early (Howard et al.). Typical lab abnormalities include elevated uric acid (>8 mg/dl), hyperphosphatemia (>6.5 mg/dL), hypocalcemia (<7 mg/dL), hyperkalemia (>6 mEq/L). Typical treatment for hyperkalemia should be initiated to shift and eliminate excess potassium if there are EKG changes or the potassium is >7 mEq/L [1, 2].
Treatment
On all patients that are at risk for TLS, a uric acid level, BMP, ionized calcium, magnesium, phosphorus, and LDH level should be sent frequently to monitor for metabolic derangements. If TLS is present, then IV hydration at 2 – 4 times maintenance rate should be started. Agents to help decrease the uric acid level should also be initiated. Typical choices are IV allopurinol and rasburicase [1]. Allopurinol is a xanthine oxidase inhibitor which stops production of uric acid; it usually is used prophylactically during chemotherapy induction more than for TLS as it does not directly decrease uric acid level. Rasburicase is recombinant urate oxidase which converts uric acid into a metabolite that can be excreted; it usually decreases uric acid levels within hours [3]. While effective, this drug is relatively expensive (approximately $640 per mg of drug), which means it is often reserved for severe cases of tumor lysis syndrome [4]. Hypocalcemia should not be treated if it is asymptomatic as this can cause precipitation of calcium phosphate worsening renal injury. Fluid restriction for SIADH treatment is challenging given the insensible losses typical for patients undergoing chemotherapy and IV fluid requirements to treat other components of TLS. Hyperphosphatemia can be treated with aluminum hydroxide. If treatment is refractory to the above, then dialysis may be required to treat severe symptoms [1].
Neutropenic Fever
Description
Many patients on chemotherapy become neutropenic and some with active hematologic malignancies are functionally neutropenic as the abnormal cells prevent the formation of normal neutrophils. Patients with a lack of functional neutrophils are more susceptible to serious bacterial infections from all organisms but are particularly vulnerable to the following organisms: S. aureus, Enterococcus, S. viridens, S. pneumoniae, S. pyogenes, Coagulase-negative Staphylococcus, E. coli, Klebsiella, Enterobacter, Pseudomonas, Citrobacter, Acinetobacter, and Stenotrophomonas. Up to 80% of the time, bacterial infections are caused by normal flora organisms [5]. Also, they are at risk of typhlitis, which is a necrotizing colitis caused by invasive behavior by bacteria or fungi from the GI tract. Given this, a fever in this pediatric population must be reacted to aggressively [1].
Presentation and work-up
Often, these immunocompromised patients might not have associated symptoms with severe bacterial infections. Given this, patients require pan cultures (peripheral blood cultures, port cultures, urine culture, and an LP if headache or other neurologic symptoms are present) and chest X-ray. If there is any abdominal pain or tenderness, a CT scan of the abdomen should be considered. Any skin irritation or pain should be evaluated closely as surrounding erythema is often not present over abscesses [1, 5].
Treatment
In the pediatric population, both ceftriaxone and cefepime are acceptable choices for empiric treatment for antibiotic coverage. If patients are already on broad spectrum antibiotics, sometimes this coverage needs to be expanded to meropenem. The goal time for antibiotics is 30 – 60 minutes after arrival; it is recommended that you cover patients prior to the return of the CBC differential if there is a high suspicion that the patient is neutropenic [1].
Hyperviscosity Syndrome
Description
A variety of different processes related to different malignancies can result in an increase in the viscosity of the serum. In the adult population, the most common cause in from circulating proteins from paraproteinemias. However, in the pediatric population, this is more commonly caused by hematologic malignancies leading to hyperleukocytosis (WBC count greater than 100,000/mL) or polycythemia. It is more common in AML was myeloid blasts are larger than the lymphoid blasts in ALL, and thus more likely to “clog” arteries. The increase in viscosity leads to microvascular hypoperfusion from sluggish flow and prolonged bleeding time as platelet aggregation is disrupted. Hyperleukocytosis is a feature of approximately 20% of all pediatric leukemias and can trigger DIC due to a factor consumption and fibrinolytic proteases excreted by blasts [1, 6].
Presentation
The classic triad for hyperviscosity syndrome (HVS) is mucous membrane or skin bleeding, visual disturbance, and focal neurologic deficits. In addition to these symptoms, patients could also present with a variety of other symptoms including: altered mental status, focal neurologic deficits, priapism, pulmonary edema, and acute kidney injury. These end organ effects are caused by micro or macrovascular occlusion from the large white blood cell aggregates. On physical exam, the fundus can have dilated “sausage-like” retinal veins from the slowing of blood flow. Laboratory testing can confirm hyperviscosity; those with HVS have viscosity measurements greater than 3 times the upper limit of normal [6].
Treatment
Treatment begins with supportive measures such as intravenous fluids and can escalate to phlebotomy, plasmapheresis or leukopheresis in the case of leukemia, plasma exchange, and exchange transfusions as needed. Often, urgent chemotherapy can be initiated to help alleviate symptoms as well. Hydroxyurea can be used to help curb the production of WBCs [1, 6].
Case Resolution
After it was clear that her presentation was consistent with acute leukemia, screening labs for DIC and tumor lysis syndrome were sent. Her LDH was >3,600 IU/L and her uric acid was 13.5 mg/dl. Given this, she was started on aggressive hydration and given a dose of rasburicase. Her final pathology showed that she had Burkitt’s leukemia. She is now doing well and is in remission after several rounds of chemotherapy. Her course was complicated by epistaxis requiring transfusions from thrombocytopenia, hypertension, acute kidney injury, and several episodes of neutropenic fever. Luckily, the cure rate for Burkitt leukemia is very high (>90%) and the course of chemotherapy is usually 2 – 6 months. If remission is not achieved with this first round of treatment, then additional chemotherapy agents can be trialed followed by a stem cell transplant [7].
While the above does not provide a comprehensive list or description of all of emergencies that can occur in the pediatric patient with a hematologic malignancy, it can provide a starting point to make sure that key metabolic and infectious work-up and treatment occurs in a timely fashion in the emergency department.
Faculty Reviewer: Dr. Jane Preotle
References
- Prusakowski, MK and Cannon D. (2014). Pediatric Oncologic Emergencies. Emergency Medicine Clinics of North America; 32(3): 527-548.
- Howard SC, Jones DP, Pui CH. (2011). The tumor lysis syndrome. New England Journal of Medicine; 364:1844–54.
- Wagner, J and Arora, S. (2014). Oncologic Metabolic Emergencies. Emergency Medicine Clinics of North America; 32(3): 509-525.
- Rasburicase: drug information. (2018). Retrieved on April 20, 2018 from www.uptodate.com/contents/rasburicase-drug-information
- White, L and Ybarra, M. (2014). Neutropenic Fever. Emergency Medicine Clinics of North America; 32(3): 549-561.
- Khan, UA, Shanholtz, CB, and McCurdy, MT. (2014). Oncologic Mechanical Emergencies. Emergency Medicine Clinics of North America; 32(3), 495-508.
- Burkitt Lymphoma (2018). Dana-Farber Boston Children’s cancer and blood disorders center. Retrieved on April 20, 2018 from http://www.danafarberbostonchildrens.org/conditions/leukemia-and-lymphoma/burkitts-lymphoma.aspx