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Granulocytopenia, Emergency Medicine

Basics

Description

- A significant decrease in the number of granulocytes in the peripheral blood. - 3 classes of granulocytes: - Neutrophils or polymorphonuclear (PMN) cells and bands - Eosinophils - Basophils

- 4 basic mechanisms cause granulocytopenia: - Decreased production - Ineffective granulopoiesis - Shift of circulating PMN cells to vascular endothelium - Enhanced peripheral destruction.

- Most common in patients undergoing myelosuppressive drug therapy or radiation treatment for neoplasms. Most common 5-10 days after chemo. - Adverse reaction to drugs is the 2nd most common cause: - Excludes cytotoxic drugs and requires at least 4 wk of administration prior to the onset of granulocytopenia - Discontinuation usually results with correction within 30 days. - Drugs with the highest risk: - Antipsychotic: Clozapine - Antibiotic: Sulfasalazine - Antithyroid: Thioamides

- Antiplatelet agents - Antiepileptic drugs - NSAIDs

- Parasitic infections: - Rickettsial infections: - Rickettsialpox - Ehrlichiosis - Rocky Mountain spotted fever

- Congenital neutropenia: - Neutropenia with abnormal immunoglobulins - Reticular dysgenesis - Severe congenital neutropenia or Kostmann syndrome - Cyclic neutropenia

- Signs of pancytopenia: - Fatigue - Pallor - Petechiae - Epistaxis and other spontaneous bleeding

  • A significant decrease in the number of granulocytes in the peripheral blood.
  • 3 classes of granulocytes:Neutrophils or polymorphonuclear (PMN) cells and bandsEosinophilsBasophils
  • As PMN cells predominate, the term neutropenia is often used interchangeably with granulocytopenia, as almost all granulocytopenic patients are neutropenic.
  • Granulocytes are a key component of the innate immune system.
  • The clinical risks resulting from granulocytopenia are best defined by the level of the absolute neutrophil count (ANC):ANC = WBC — percentage (PMN + bands)Modern automated instruments often calculate and report ANC.
  • Neutropenia: ANC <1,500 cells/mm3:Mild: Between 1,000 and 1,500Moderate: Between 500 and 1,000Severe: <500Agranulocytosis: <100Patients with a count <1,000 that has recently or rapidly fallen are at greater risk for infection than those with a count <500 but rising.Patients with myelodysplastic syndromes should be considered granulocytopenic with higher counts because of defective neutrophils.
  • 4 basic mechanisms cause granulocytopenia:Decreased productionIneffective granulopoiesisShift of circulating PMN cells to vascular endotheliumEnhanced peripheral destruction.
  • Mortality of fever and neutropenia is as high as 50% if untreated:Mortality correlates with the duration and severity of the neutropenia and the time elapsed until the 1st dose of antibiotics.
  • 21% of patients with cancer and neutropenic fever develop serious complications.
  • Newborn infants have a physiologically elevated ANC in the 1st few days of life and may be granulocytopenic with levels >1,500/μL.
  • Children >3 mo without underlying immunodeficiency or a central venous catheter unexpectedly found to have isolated moderate neutropenia are not at high risk of serious bacterial infection.

Etiology

  • Most common in patients undergoing myelosuppressive drug therapy or radiation treatment for neoplasms. Most common 5-10 days after chemo.
  • Adverse reaction to drugs is the 2nd most common cause:Excludes cytotoxic drugs and requires at least 4 wk of administration prior to the onset of granulocytopeniaDiscontinuation usually results with correction within 30 days.Drugs with the highest risk:Antipsychotic: ClozapineAntibiotic: SulfasalazineAntithyroid: ThioamidesAntiplatelet agentsAntiepileptic drugsNSAIDs
  • Drugs that suppress the bone marrow:MethotrexateCyclophosphamideColchicineAzathioprineGanciclovir
  • Chemicals
  • Bacterial infections:TyphoidShigella enteritisBrucellosisTularemiaTuberculosis
  • Parasitic infections:
  • Rickettsial infections:RickettsialpoxEhrlichiosisRocky Mountain spotted fever
  • Viral infections
  • Postinfectious neutropenia:Most severe and protracted following HIV, hepatitis B, and Epstein-Barr viral infections
  • Immune-related:Primary immune neutropenia:Due to antineutrophil antibodiesCrohns diseaseSystemic lupus erythematosusRheumatoid arthritisGoodpasture diseaseWegener granulomatosisThymomaCompliment activation
  • Bone marrow infiltration
  • Transfusion reaction
  • Alcoholism
  • Vitamin deficiency (B12/folate/copper)
  • Chronic idiopathic neutropenia
  • Pure white cell aplasia
  • Congenital neutropenia:Neutropenia with abnormal immunoglobulinsReticular dysgenesisSevere congenital neutropenia or Kostmann syndromeCyclic neutropenia
  • Chronic benign neutropenia
  • Neonatal isoimmune neutropenia
  • Shwachman-Diamond syndrome
  • Cartilage-hair hypoplasia
  • Dyskeratosis congenita
  • Barth syndrome
  • Ch ©diak-Higashi syndrome
  • Myelokathexis
  • Lazy leukocyte syndrome
  • Cohen syndrome
  • Hermansky-Pudlak syndrome type 2

Diagnosis

Signs and Symptoms

  • Signs of bacterial or fungal infection:FeverLocalized erythema or fluctuance
  • Signs of pancytopenia:FatiguePallorPetechiaeEpistaxis and other spontaneous bleeding

History

  • Medical list should be reviewed for causative drugs.
  • Family history of granulocytopenia in neonates and children
  • Records of past ANC levels to assess for chronicity
  • Question the patient carefully about fever, chills, dizziness, and vomiting as indicators of an underlying serious infection.
  • Ask about localizing signs of infection such as cough; shortness of breath; chest pain; dysuria; urinary retention, urgency, or frequency; abdominal pain; and rectal pain.

Physical Exam

Focus on finding signs of infection:

  • Oral exam: Thrush, ulcers, periodontal disease, mucositis
  • Lungs: Rales, rhonchi
  • Abdominal: Splenomegaly
  • Skin: Rashes, ulcers, abscesses
  • Perirectal: Although the rectal exam is relatively contraindicated until antibiotics are started, check for abscesses and mucosal lesions.
  • Evaluate indwelling catheter sites

Essential Workup

Complete physical exam:

  • Detailed exam of oral mucosa and perianal area
  • Palpation of skin
  • Location of fluctuance or tenderness
  • Careful lung exam and abdominal
  • Rectal exam after antibiosis if symptoms suggest perirectal abscess

Diagnosis Tests & Interpretation

Lab

  • CBC with differential:
  • LFTs
  • Blood culture before antibiosis from 2 different sites, with 1 from IV catheter site if present
  • Urinalysis and urine culture:May not show WBCs or leukocytes esterase OR may be normal
  • Sputum Cx if applicable
  • Stool Cx if applicable
  • Culture indwelling catheters
  • Cerebrospinal fluid analysis for altered mental status/signs of meningitis

Imaging

CXR even in absence of lung findings

Differential Diagnosis

  • Lab error
  • Neoplasm and chemotherapy
  • Medication reaction
  • Chemical exposure
  • Infections (viral/bacterial/rickettsial)
  • Autoimmune syndrome
  • Genetic etiology
  • Transfusion reaction
  • Nutritional deficiency
  • Tumor lysis syndrome
  • Hypersplenism
  • African Americans may have a lower but normal ANC value of 1,000 cells/mm3

Treatment

Initial Stabilization/Therapy

For patients presenting in shock:

  • Administer 1 L 0.9% NS IV fluid bolus (peds: 20 cc/kg).
  • Initiate pressors as needed to stabilize BP if no response to IV fluids.
  • Consider starting goal-directed therapy.

Ed Treatment/Procedures

  • Strict isolation in a negative airflow room if possible
  • Administer broad-spectrum combination antibiotics after cultures for suspected or documented infection:Imipenem/cilastatin or fluoroquinoloneCeftazidime alone or with aminoglycoside (amikacin, tobramycin, gentamicin)
  • Cefepime alone
  • Aminoglycoside + antipseudomonal β-lactam (mezlocillin, piperacillin, or ticarcillin)
  • Vancomycin if patient is at risk to be carrier of MRSA

Medication

  • Amikacin: 15 mg/kg/24 h (peds: 15-30 mg/kg/24 h) div. q8-12h IV
  • Cefepime: 0.5-2 g q12h
  • Ceftazidime: 1-2 g (peds: 30-50 mg/kg q8h) q8-12h IV
  • Gentamicin: 1 mg/kg (peds: 2-2.5 mg/kg) q8h or 5 mg/kg q24h
  • Imipenem/cilastatin: 250-1,000 mg q6-8h
  • Levofloxacin: 500 mg IV QID
  • Mezlocillin: 3 g q4h over 30 min
  • Tobramycin: 1 mg/kg q8h IV (peds: 2-2.5 mg/kg q8h IV)
  • Vancomycin: 15 mg/kg q8-12h IV

Follow-Up

Disposition

Risk Stratification

MASCC Score: Identifies febrile neutropenic patients who are at a lower risk of complications.

Admission Criteria

  • Signs of infection
  • Unreliable patient
  • Close follow-up unavailable

Discharge Criteria

  • Previously diagnosed granulocytopenia
  • Completely asymptomatic
  • Close follow-up ensured
  • Reliable patient

Issues for Referral

All patients with granulocytopenia should be referred to their physician or a hematologist.

Follow-Up Recommendations

  • Patient should return immediately to the ED with fever.
  • Follow-up within 48 hr with the patients physician

Pearls and Pitfalls

  • Usual signs of infection may be masked because of the impaired immune response in patients with granulocytopenia.
  • Rectal exams and rectal temperatures are relatively contraindicated in neutropenic patients but should be performed once antibiotics are started to avoid missing a perirectal abscess.
  • Patients with fever and an ANC <500 requires immediate and aggressive therapy with broad-spectrum antibiotics and IV fluids.
  • Hepatosplenic candidiasis: Complication of resolving neutropenia. Abscess formation as ANC rises. Treat with amphotericin B.

Additional Reading

  • Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52:e56-e93.
  • Kaufman DW, Kelly JP, Levy M, et al. The Drug Etiology of Agranulocytosis and Aplastic Anemia. New York, NY: Oxford University Press; 1991.
  • Melendez E, Harper MB. Risk of serious bacterial infection in isolated and unsuspected neutropenia. Acad Emerg Med. 2010;17:163-167.
  • Mushlin SB, Greene HL. Decision Making in Medicine: An Algorithmic Approach. 3rd ed. Boston, MA: Elsevier Inc.; 2010.
  • Perrone J, Hollander JE, Datner EM. Emergency Department evaluation of patients with fever and chemotherapy-induced neutropenia. J Emerg Med. 2004;27(2):115-119.
  • Segel GB, Halterman JS. Neutropenia in pediatric practice. Pediatr Rev. 2008;29:12-23.

Codes

ICD9

  • 288.00 Neutropenia, unspecified
  • 288.03 Drug induced neutropenia
  • 288.09 Other neutropenia
  • 288.01 Congenital neutropenia
  • 288.02 Cyclic neutropenia
  • 288.04 Neutropenia due to infection
  • 288.0 Neutropenia

ICD10

  • D70.1 Agranulocytosis secondary to cancer chemotherapy
  • D70.8 Other neutropenia
  • D70.9 Neutropenia, unspecified
  • D70.0 Congenital agranulocytosis
  • D70.2 Other drug-induced agranulocytosis
  • D70.3 Neutropenia due to infection
  • D70.4 Cyclic neutropenia
  • D70 Neutropenia

SNOMED

  • 417672002 granulocytopenic disorder (disorder)
  • 425229001 chemotherapy-induced neutropenia (disorder)
  • 303011007 Neutropenic disorder (disorder)
  • 89655007 Congenital neutropenia (disorder)
  • 191347008 Cyclical neutropenia (disorder)
  • 46359005 Neutropenia associated with infectious disease (disorder)