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
- 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 1,500
- Moderate: Between 500 and 1,000
- Severe: <500
- Agranulocytosis: <100
- Patients 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 production
- Ineffective granulopoiesis
- Shift of circulating PMN cells to vascular endothelium
- Enhanced 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 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
- Drugs that suppress the bone marrow:
- Methotrexate
- Cyclophosphamide
- Colchicine
- Azathioprine
- Ganciclovir
- Chemicals
- Bacterial infections:
- Typhoid
- Shigella enteritis
- Brucellosis
- Tularemia
- Tuberculosis
- Parasitic infections:
- Rickettsial infections:
- Rickettsialpox
- Ehrlichiosis
- Rocky 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 antibodies
- Crohns disease
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Goodpasture disease
- Wegener granulomatosis
- Thymoma
- Compliment activation
- Bone marrow infiltration
- Transfusion reaction
- Alcoholism
- Vitamin deficiency (B12/folate/copper)
- Chronic idiopathic neutropenia
- Pure white cell aplasia
- Congenital neutropenia:
- Neutropenia with abnormal immunoglobulins
- Reticular dysgenesis
- Severe congenital neutropenia or Kostmann syndrome
- Cyclic 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:
- Fever
- Localized erythema or fluctuance
- Signs of pancytopenia:
- Fatigue
- Pallor
- Petechiae
- Epistaxis 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 fluoroquinolone
- Ceftazidime 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)