Pediatric hematologic and oncologic emergencies are in 3 major categories: complications of hematologic disorders, emergencies associated with the new onset of cancers, and treatment-associated oncologic emergencies. The overall number of these patients remains low; however, the mortality associated with these diseases remains high despite significant advances in management. This article presents a review of the most commonly encountered pediatric hematologic and oncologic complications that emergency physicians and providers need to know.
Key points
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Hemoglobinopathies have a high risk of life-threatening complications, with which emergency providers must be comfortable identifying and appropriately managing.
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Bleeding disorders, although rare, can present with life-threatening bleeding, but the treatment of these varies depending on the disorder.
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Patients with new-onset cancer often present with nonspecific symptoms, and tumor lysis must be considered and be a part of the evaluation.
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The therapies used for patients with cancer can pose life-threatening risks to patients for which emergency providers must be prepared.
Introduction
Pediatric hematologic and oncologic emergencies are in 3 major categories: complications of hematologic disorders, emergencies associated with the new onset of cancers, and treatment-associated oncologic emergencies. Although the overall number of these patients remains low, the mortality associated with these diseases remains high despite significant advances in management. This article presents a review of the most commonly encountered pediatric hematologic and oncologic complications that emergency physicians and providers need to know.
Hematologic Disorders
Hematologic disorders affecting the pediatric population include hemoglobinopathies, platelet disorders, and bleeding disorders. The hemoglobinopathies encompass a broad range of disorders, including sickle cell disease (SCD), hereditary spherocytosis, and the thalassemias. Platelet and other bleeding disorders, such as von Willebrand disease and hemophilia, present as a spectrum from a mild disorder to severe disease with life-threatening bleeding. The most common pediatric bleeding disorder, immune thrombocytopenia (ITP), is discussed in this article.
New-onset Cancers
New malignancies in pediatric patients often present as a vague constellation of symptoms. Unlike in adult patients, many newly identified malignancies are admitted to the hospital for work-up and initiation of therapy. Tumor lysis syndrome is a common complication of lymphoproliferative disease treatment; it can also be a complication of pediatric solid organ tumors, although these masses more often present with compressive complications.
Cancers Undergoing Therapy
Patients who are undergoing therapy often have complications that are directly associated with therapy. Radiation has localizing effects, whereas chemotherapy can have a variety of targeted organ effects. This article briefly reviews the common drug side effects and explains the management of neutropenic fever and typhlitis in the pediatric patients with cancer.
Discussion
Sickle Cell Disease
Overview
The hemoglobinopathies encompass a broad range of disorders, including SCD, hereditary spherocytosis, and the thalassemias. SCD is the most common of these; it is a genetic autosomal recessive hemoglobin disorder that affects millions worldwide. There are multiple mutations that lead to variants of SCD and coinherited thalassemia with a range of clinical manifestations. The mutations cause abnormal hemoglobin polymerization, causing the red blood cells (RBCs) to take on an elongated and rigid morphology similar to a crescent, or sickle sword. The sickled erythrocytes cause microvascular and larger vessel occlusion as well as other cell and endothelial effects leading to acute and chronic complications. Although the sickling is reversible, these erythrocytes have a shorter half-life, which causes significant anemia. Hypoxia, dehydration, and other factors drive sickling, and thus compound a cycle of further ischemia and RBC sickling.
SCD complications leading to emergency department visits include vaso-occlusive episode (VOE)/crisis, acute chest syndrome (ACS), thromboembolic and hemorrhagic stroke, infection, and acute anemia. A more comprehensive listing of acute SCD complications is presented in Box 1 .
VOE (also known as vaso-occlusive crisis)
Acute anemia
Hemolysis
Aplastic crisis
Sequestration (splenic or hepatic)
ACS
Infection
Sepsis/bacteremia caused by encapsulated organisms
Septic arthritis
Osteomyelitis
Stroke (ischemic or hemorrhagic)
Pulmonary/venous thromboembolism
Solid organ infarction (renal, splenic, hepatic)
Avascular necrosis
Priapism
Prevalence/incidence/mortality
Globally, the prevalence of SCD varies greatly between regions but reaches 40% in some areas of sub-Saharan Africa, eastern Saudi Arabia, and central India. In developing areas, it is a disease that causes significant early childhood mortality despite improving access to medications such as hydroxyurea.
SCD affects approximately 100,000 Americans. A review of United States mortality data revealed that the mortality for pediatric patients with SCD decreased between 1979 and 2017, but the mortality increased for adults during the same period of time. The median age at death increased from 28 years to 43 years. Deaths during childhood trend toward acute complications as a cause, whereas adult deaths were more associated with chronic complications of SCD.
Clinical presentation
Acute complications of SCD leading to emergency department visits include VOE/crisis, ACS, thromboembolic and hemorrhagic stroke, venous thromboembolism (VTE), infection, and acute anemia. VOEs are the classic and most common type of acute SCD complication, occurring in isolation or in tandem with other complications.
VOE manifests as muscle and/or joint pain, most commonly in the back and lower extremities, and more specifically as dactylitis of the fingers and toes, especially in patients less than 2 years of age. In patients with SCD, pain crises are frequently recurrent in similar locations of the body, which typically includes long bones, and may also be present in the abdomen. It is important to characterize a current pain event in terms of onset, associated symptoms (such as fever), and comparison with prior pain events.
Patients presenting with chest pain, fever, tachypnea, cough, or wheezing must be evaluated for ACS, defined as those symptoms plus a new infiltrate on chest imaging. ACS is a leading cause of death in adults with SCD. Cardiopulmonary symptoms on presentation should also raise consideration for other SCD-related and non–SCD-related diagnoses, including myocardial infarction and pulmonary embolism. It is well established that adults with SCD have higher rates of VTE, and new data from a multicenter retrospective cohort analysis suggest a significant prevalence of VTE in pediatric patients with SCD (1.7%), with independent association of VTE with death (odds ratio [95% confidence interval]; P = 8.95 [3.55–22.56]; P <.0001).
Strokes in patients with SCD, similarly to other patients without SCD, present with sudden acute neurologic dysfunction. The lifetime prevalence of neurologic complications in patients with SCD (vasculopathy, territorial infarction, intracranial hemorrhage, or silent cerebral ischemia) is 25%, often occurring in early childhood. , Because children with SCD are at high risk for ischemic strokes, any focal neurologic symptoms or signs warrant further investigation.
Infection may present with constitutional symptoms with or without fever, and may also localize to a source; for example, pneumonia, joint infection, or elsewhere. Functional asplenia from intraparenchymal sickling leaves the patient at risk for life-threatening bacterial infection, especially from encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae type B. Pneumococcal conjugate vaccines and the implementation of penicillin prophylaxis have reduced the incidence of infection greatly.
Acute anemia is another potentially life-threatening complication of SCD. Patients present with symptoms suggestive of anemia, such as fatigue, shortness of breath, or exertional chest pain. The anemia can be induced by one of several distinct processes: (1) acute splenic or hepatic sequestration, (2) transient red cell aplasia (aplastic crisis), or (3) increased hemolysis. New or worsened jaundice suggests a hemolytic process, and new organomegaly may suggest splenic or hepatic sequestration.
Diagnostics
The sickle cell trait is routinely assessed in prenatal screening for expectant mothers. In the United States and other developed countries, SCD is typically diagnosed on newborn screening, with all 50 states plus the District of Columbia screening for SCD as part of the newborn screening program.
For patients presenting with VOE or other potential SCD-related complications, serum tests are indicated. Laboratory evaluation for patients presenting with concern for SCD complications should include a complete blood count (CBC) and comprehensive metabolic panel inclusive of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, lipase, prothrombin time (PT), partial thromboplastin time (PTT), reticulocyte count, and lactate dehydrogenase (LDH). In addition, any patient with SCD with a fever requires rapid assessment with a blood culture, and transfusion tests should be ordered if transfusion is anticipated. Table 1 provides a summary of recommended diagnostics.
| Diagnostic Test | Application |
|---|---|
| CBC | Assess hemoglobin level compared with baseline. White blood cell and platelet counts may be increased but nonspecific |
| Reticulocyte count | Very low count in setting of acute anemia suggests aplastic crisis |
| AST/ALT/alkaline phosphatase | Can suggest hepatobiliary complications, hemolysis |
| Direct bilirubin, LDH | Increase suggests hemolysis |
| Blood and/or urine culture | Assess for bacteremia or bacteriuria as a cause of fever/infection |
| Chest radiograph | Assess for infiltrates or pulmonary effusion |
| Computed tomography chest | Assess for pulmonary infiltrates or infarction; angiogram for assessment of pulmonary embolism |
Acute anemia is defined as a decrease of greater than 2 g/dL from baseline hemoglobin. A very low or nil reticulocyte count suggests an erythrocyte aplasia, whereas a normal or somewhat increased reticulocyte count in combination with increased indirect bilirubin, AST/ALT, and LDH levels suggests hemolysis and/or sequestration.
Note that, despite investigations into inflammatory markers and other laboratory tests, there are no diagnostic markers for vaso-occlusive pain. Pain assessment in the pediatric population is challenging, because the developmental stage in these patients may not be advanced enough to understand or describe their pain. Further, patients with chronic pain, such as those with SCD, experience pain in a more complex manner, often complicated further with anxiety.
In this chronically ill pediatric population, it is imperative to balance the risks of radiation exposure against the risk of delayed complication diagnosis. If the patient is afebrile and the pain is similar to prior events, imaging is likely to be of low yield. However, if the clinical presentation includes chest pain, hypoxia, shortness of breath, fever, or cough, a chest radiograph should be obtained immediately to assess for ACS. Computed tomography (CT) imaging may also be helpful, especially with angiography if pulmonary embolism (PE) is suspected. Several studies have shown increased D-dimer levels in patients with SCD and VOE, although there is currently no proposed threshold or clinical decision tool for PE assessment in patients with SCD. Neurologic deficits should be evaluated similarly to the general population, with the understanding that the threshold for work-up is low in this high-risk population. If osteomyelitis or avascular necrosis is suspected based on history or examination findings, further advanced imaging, such as MRI, is recommended.
Management
Pain control is an important factor that must be addressed in VOE. The American Society of Hematology (ASH) published updated guidelines in treatment of acute and chronic SCD pain in 2020. Among the recommendations pertaining to treatment of acute pain in children are:
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Rapid (within 1 hour of emergency department arrival) assessment and administration of analgesia with frequent reassessments (every 30–60 minutes)
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Tailored opioid dosing based on baseline opioid therapy and prior effective therapy: individualized care plans developed by acute care and SCD care providers
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Short course (5–7 days) of nonsteroidal antiinflammatory drugs in addition to opioids for acute pain management
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Steroids should not be used for acute pain management
The ASH guideline panel did not offer a recommendation for or against intravenous fluids in management of acute pain, but notes that the nonrecommendation does not preclude administration of fluids to patients with clinically significant dehydration.
For suspected ACS, patients should be managed with supplemental oxygen, pain control, and incentive spirometry to prevent splinting/hypoventilation, and empiric antibiotics to include coverage of encapsulated and atypical organisms. Hematology should be consulted early for consideration of exchange transfusion in the case of ACS, as well as in the case of ischemic stroke. If the patient is dehydrated or hypovolemic, isotonic solution and oral hydration should be administered with the goal of euvolemia. Overhydration or rapid hydration should be avoided, because complications of pulmonary edema may occur.
Undifferentiated fever must also be addressed with empiric antibiotics to cover encapsulated organisms. Patients with indwelling lines or ports should also receive adequate skin flora coverage against methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus (MRSA).
Simple blood transfusion may be considered in cases of acute symptomatic red cell aplasia. In the case of sequestration crisis, transfusion should only be used if the patient is hemodynamically unstable, because there is significant risk of hyperviscosity leading to stroke, ACS, and VOE from transfusion and/or release of sequestered RBCs back into circulation.
Patients with uncontrolled painful VOEs or concern for any of the discussed life-threatening complications should be admitted for continued management and hematology consultation.
Clinics care points
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Painful VOE can occur in isolation, but can also overlap with other complications; a thorough history and physical must be performed to exclude other complications
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Maintain a low threshold to obtain chest radiographs in the assessment of ACS, a life-threatening complication of SCD
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Children with SCD are at high risk of ischemic stroke, so prompt detection is key and management includes consideration of exchange transfusion
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Acute anemia is defined as a decrease of greater than 2 g/dL from baseline hemoglobin level; the physical examination, reticulocyte count, and hemolysis tests are key in assessing the cause
Immune Thrombocytopenia
Overview
ITP is the most common bleeding disorder diagnosed in children. ITP was previously referred to as idiopathic thrombocytopenic purpura, but the change in nomenclature reflects recognition that the disease process is caused by immune effects on platelets, and that most patients with the disease process do not have purpura.
Thrombocytopenia is defined as a platelet count less than 100 × 10 9 /L. Primary ITP is thought to be caused by immune destruction of platelets, and secondary ITP is associated with other underlying disorders. There is also mounting evidence that platelet production is impaired in ITP.
Prevalence/incidence/mortality
The incidence of ITP has trimodal peaks in childhood, young adulthood, and the geriatric years. From 2011 to 2016, the incidence of ITP for children less than 18 years old in the United States was 8.8 (95% confidence interval; 8.5–9.1) per 100,000 person-years.
Clinical presentation
ITP is often self-limiting, however one-quarter of cases become chronic. Bleeding associated with thrombocytopenia can be life threatening. Most adults and children do not present with purpura, which contributes to the reason for the change in nomenclature.
Common presenting symptoms include mucosal bleeding such as hemorrhagic mucosal blisters, gum bleeding, or epistaxis. Patients may be asymptomatic and thrombocytopenia incidentally discovered when tests are obtained for an unrelated reason.
Life-threatening bleeding is a feared but uncommon clinical presentation of ITP. A systematic review found the weighted proportion for intracerebral hemorrhage (ICH) in children with acute or chronic ITP is 0.4%. The same study found the weighted proportion for all other types of severe non-ICH bleeding was 20.8% in children, although the investigators acknowledge that the definition of severe bleeding was variable in the primary studies.
Diagnostics
The initial basic evaluation for patients presenting with potential ITP or other bleeding or clotting disorder includes a CBC with reticulocyte count and peripheral blood smear, as well as PT/PTT. Serum quantitative immunoglobulin panels can assist hematology consultants in the diagnostic work-up of ITP.
CT imaging of the head must be expedited in all patients with ITP or other bleeding disorders who are presenting with head trauma or atraumatic headache. In cases where the patient is altered or there is high suspicion for ICH, treatment should be initiated even before the expedited imaging. In patients with a prior history of ITP, commonly used clinical decision tools, such as the Pediatric Emergency Care Applied Research Network head injury algorithm, should be applied with caution.
Management
A hematologist should be consulted in the management of pediatric patients with ITP. An ASH panel published updated guidelines for adult and pediatric management of ITP in 2019, summarized later. The recommendations are based on symptoms rather than platelet count.
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In the case of severe, life-threatening bleeding, the cornerstones of treatment are platelet transfusion, corticosteroids, and intravenous immunoglobulin (IVIG).
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For non–life-threatening mucosal bleeding and/or patients with diminished health-related quality of life:
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First-line treatment: short course (7 days) of corticosteroids
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Second-line treatment: thrombopoietin receptor agonists
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Observation (without steroids, IVIG, or other treatments) is recommended regardless of the platelet count for patients with no or minor bleeding.
Clinics care points
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ITP can be incidentally diagnosed in asymptomatic children, or can present with minor to life-threatening bleeding
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Obtain CBC, reticulocyte count, and peripheral smear ± coagulation studies
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In all cases of head trauma or atraumatic headache, obtain expedited head imaging
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Treatment and disposition are based on symptoms rather than platelet count
New-onset Malignancies
Overview
The diagnosis of pediatric oncologic processes often occurs because of vague or persistent symptoms over time. Constitutional symptoms such as weight loss or poor weight gain for age, bone pain, fatigue, or unexplained persistent fevers should prompt evaluation ( Table 2 ). The most common pediatric cancers are leukemia, lymphoma, bone cancers, intracranial tumors, Wilms tumor, neuroblastoma, rhabdomyosarcoma, and retinoblastoma. There must be a high index of suspicion for these in order to identify the diagnosis. At times, these patients present in extremis. Presenting emergent conditions include superior vena cava syndrome, airway compromise caused by mass compression, clot or compression of the venous flow caused by abdominal masses, and stroke symptoms caused by hyperleukocytosis. Critically, patients may also present with tumor lysis syndrome. Although often a complication of initial therapy (specifically in lymphoproliferative diseases), this can also be a presenting diagnosis that requires rapid recognition and management.
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