EM@3AM: Leukopenia

Answer: Leukopenia

Overview

• Leukopenia is defined as total WBC count < 4000/mm³ 
  • Neutropenia is the most common subset of leukopenia and is defined on absolute neutrophil count:¹
    • Mild (1.0–1.5 × 10^9/L)
    • Moderate (0.5–0.9 × 10^9/L)
    • Severe (< 0.5 × 10^9/L)
  • Generalized leukopenia (i.e. a decrease in all WBC lines) and lymphopenia (a decrease in lymphocytes) are less common²
• Leukopenia can be acute or chronic³
• Common causes of leukopenia include¹
  • Medications
  • Infection
  • Nutritional deficiency
  • Malignant disease
  • Autoimmune disease
• Management should target underlying cause of leukopenia

Epidemiology

• The prevalence and incidence of leukopenia depends largely on global region as well as inciting etiology⁴
  • Global: 2.8%
  • Most common causes of leukopenia
    • Infections: 36.4%
    • Medications: 25.6%
    • Autoimmune Disorders: 10.9%
    • Bone Marrow Disease: 9.5%
  • Specific Pathologies:
    • HIV Infection: 6.1%-34.2% (before treatment)^{5, 6}
    • Systemic Lupus Erythematosus: 22%-60%⁷
    • Post Transplant: 14.1%-43.4%^{8, 9}

Pathophysiology^10-12

• Stem cells in the bone marrow divide to make immature white blood cells which further mature and differentiate
• Leukocytes play a key role in the immune system
• The main types of white blood cells (leukocytes) are basophils, eosinophils, lymphocytes, monocytes, and neutrophils^{10, 11}
  • Basophils – release substances to mediate inflammation and allergic reactions
  • Eosinophils – mediate parasitic infections as well as chronic inflammation and allergic reactions
  • Lymphocytes – differentiate into B cells (make antibodies) and T cells (attack tumor cells and infected cells)
  • Monocytes – differentiate into osteoclasts, macrophages, etc. in tissue to help fight infection
  • Neutrophils – first line defense. Destroy bacteria by phagocytosis
• Leukopenia can be caused by:¹²
  • Suppression or dysfunction of the bone marrow (as seen in aplastic anemia)
  • Immune-mediated or drug damage of leukocytes (as seen in alkylating agents)
  • Splenic sequestration
  • Infection

Differential Diagnosis

• Leukopenia is often a consequence of an underlying acute or chronic illness, or a complication of medical therapy. Causes of leukopenia include:^{13, 14}

 Clinical Presentation

• Often leukopenia is an incidental finding in an asymptomatic patient
• When symptomatic, patient’s presentation is dependent on the underlying etiology and thus can be highly variable

ED Evalaution

• Workup should be focused on identifying the etiology with emphasis on identifying an infectious etiology, underlying malignancy or medication/therapy effect.
  • History and physical exam are key in helping to identify underlying causes
    • Signs and symptoms of UTI, URI, pneumonia, etc.
    • Splenomegaly
    • Often vague, such as general malaise and fatigue
  • Complete medication history
    • Specifically chemotherapy medications such as carboplatin but also a variety of other medications such as chloramphenicol and clozapine
  • Social history for nutritional deficiencies, exposures, etc
  • Labs to evaluate for infection: CBC, CMP, urinalysis, blood cultures, viral swabs, HIV screen
  • Imaging to evaluate for infection: Chest X-Ray, CT Abdomen/Pelvis (if indicated by history or exam)

Treatment and Management

• Treat underlying etiology
• Supportive Care:
  • Fluid Resuscitation – 30 cc/kg Normal Saline or Lactated Ringers for septic patients with dehydration, otherwise as clinically indicated
• If concomitant anemia or thrombocytopenia:
  • Consider PRBC / Platelet Transfusion as indicated
• If infection is present or suspected:
  • If febrile, antipyretics – 1000 mg acetaminophen every 6 hours, NSAIDS, plus/minus cooling blanket
  • If hypothermic – warmed blanket, warmed fluids
  • Antibiotics (as indicated) targeted to specific infection:
    • Pneumonia, Urinary Tract Infection, Cellulitis, etc.
  • Specific Considerations:
    • Neutropenic Fever:¹⁵
      • Definition: Absolute Neutrophil Count <500 or <1000 with predicted nadir of <500 in 48 hours AND Fever ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period
      • Treatment:
        • Inpatient:
          • Cefepime 2g IV q8hrs OR Meropenem 1g IV q8hrs OR Piperacillin/Tazobactam 4.5g IV q6hrs.
          • Vancomycin 15-20mg/kg loading dose
            • Consider when:
              • MRSA / Gram Positive Colonization Concern
              • Catheter / Line Infections
              • Hypotension
          •  Outpatient:
            • Ciprofloxacin 750mg PO q12 hours AND Amoxicillin/Clavulanate 875mg PO q12 hours OR Clindamycin 450mg PO q8 hours
    •  New HIV Diagnosis¹⁶
      • If well appearing and without otherwise complicating infection (i.e PCP Pneumonia, Sepsis) can be discharged with initiation of Antiretroviral Therapy in consultation with Infectious Disease (ID) physician with full ID evaluation outpatient.
      • Others with systemic illness, meeting sepsis criteria, or concerning for immunocompromised infection should be admitted
    • New Leukemia Diagnosis
      • Consult Hematology / Oncology
        • Patients may be admitted for bone marrow biopsy, further inpatient testing.
•  Consultants to consider:
  • Hematology / Oncology if etiology is suspected to be related to bone marrow suppression or dysfunction, splenic sequestration, malignancy, or idiopathic
  • Infectious disease if etiology is suspected to be infectious or if a superimposed infection is present
  • Toxicology if etiology is suspected to be drugs/pharmaceuticals

Disposition

• Depends largely on overall presentation, age, medical history and other risk factors.
• Young and healthy patients can be considered for discharge with close primary care/consultant evaluation outpatient, especially in cases of:
  • Suspected acute viral illness
  • Well appearing, reliable patient
• Patients may require admission in cases of:
  • Older patients
  • Complex medical history / comorbidities
  • Active Chemotherapy / Radiation treatment
  • Abnormal Vitals in setting of infection
  • Neutropenic Fever
  • High Suspicion for chemotherapy induced etiology
  • New malignancy diagnosis (ie. Leukemia)

Pearls

• Leukopenia is not an uncommon laboratory finding, and can have multiple etiologies.
• Approach to leukopenia in the ED should be focused on identifying the inciting etiology with emphasis on evaluation for infection, malignancy, and/or toxin/drug mediated effect.
• Management is directed based on underlying etiology, but consider fluid resuscitation, antipyretics, and antibiotics as indicated.
• Disposition is based on overall clinical presentation, inciting etiology, and consultant evaluation.