Neutropenia

TOC | HEME Neutropenia (Resource: Outline Medicine on Physician Online 2000)

Bacterial Infection Risk of Neutropenia
In otherwise healthy persons, the risk of bacterial infections is low if the neutrophil count is >500/mm³.
The risk of infection, however, is greater when neutropenia develops after myelotoxic chemotherapy or when there are other abnormalities in a patient's host defenses. These conditions include lymphocytopenia, monocytopenia, hypogammaglobulinemia, HIV infection, disruptive mucosal or cutaneous barriers, and the administration of corticosteroids. Infection by mixtures of aerobic and anaerobic organisms of the oropharynx frequently causes gingivitis, pharyngitis, and sinusitis with neutropenia. Gram-negative bacilli often invade the blood from the GI tract in these patients. Antibiotic therapy, particularly therapy involving broad-spectrum antibiotics and protracted treatments, leads to colonization by resistant bacteria and to fungal infections.

Definition of Neutropenia
Neutropenia is generally defined as a neutrophil count of less than 1, 800/mm³. In some populations (e.g., Africans, African-Americans, and Yemenite Jews), neutrophil counts as low as 1,000/mm³ are probably normal.
1. The absolute neutrophil count is used to grade neutropenia
2. Mild Neutropenia: <1000 Neutrophils / µL, also called Grade III neutropenia
3. Moderate: <500/µL (Grade IV neutropenia)
4. Severe: <200/µL
5. Risk of infection increases substantially as counts drop below the 200-500/µL range

Evaluation of neutropenia

1. A good history & physical exam, including
- a good family history of neutropenia
- Drug history. Drug-induced neutropenia and viral infections should always be among the first considerations; any medications should be discontinued if they can be implicated as causes of the neutropenia.
- History and severity of infections, including oral ulcers, gingivitis, cellulitis, and more serious problems.
- any splenomegaly or signs of collagen diseases.

2. A complete blood count will reveal whether the neutropenia is isolated or associated with other hematologic abnormalities.

3. Serologic testing for infectious mononucleosis, hepatitis, and HIV; also ANA and rheumatoid factor titers.

4. A bone marrow biopsy and aspirate are indicated if there is any question of myelodysplasia or a hematologic malignancy.

5. Broader immunologic assessments (i.e., lymphocyte subtypes and immunoglobulin levels) are warranted if the history suggests a susceptibility to infections by viruses, parasites, or bacteria or to detect clonal proliferation of lymphocytes and to diagnose the large granular lymphocyte syndrome. Neutrophil mobilization with corticosteroids and demargination tests with epinephrine are rarely helpful.

Differential Diagnosis or Causes of Neutropenia

1. Drug-induced Neutropenia, as chemotherapy Non-chemotherapy agranulocytosis_drugs.pdf
- probably the most common cause of neutropenia in adults
- most patients recover from drug-induced neutropenia; the time for recovery can vary from 2 days to 2 weeks or more
- Medications: Ganciclovir, Carbamazapine (Tegretol®), Ticlopidine (Ticlid®), Clozapine (Clozaril®), Inflammation suppression: methotrexate, cyclophosphamide, azathioprine; chloramphenicol
- Many cancer chemotherapy drugs, some of which are also used as cytotoxic immunosuppressive agents (e.g., cyclophosphamide, methotrexate, azathioprine), predictably cause dose-dependent neutropenia.
- Other drugs cause neutropenia idiosyncratically. Many of these reactions probably occur because drugs can act as immunogens or as haptens, causing immunologic injury to neutrophils and their precursors. Other mechanisms of drug-induced neutropenia may involve direct toxicity of marrow cells in susceptible persons.
- Most patients recover from drug-induced neutropenia; the time for recovery can vary from 2 days to 2 weeks or more.

2. Nutritional Deficiency Neutropenia: Vit. B12, Folate

3. Hematologic Disease Neutropenia
Aplastic Anemia: Acquired, Congenital
Leukemia: especially in myeloid malignancies
Chronic idiopathic neutropenia
Cyclic Neutropenia: More common in Black Persons; Absolute neutrophil count (ANC) is nearly always >500/µL; Average cycle time in cyclic neutropenia is about 3 weeks; Risk of infection only increased with neutrophil count <500/µL

4. Infection-associated Neutropenia
- Viral infections, especially HIV-associated neutropenia (AIDS)
- Bacterial severe infections - neutropenia occurs as a consequence of endotoxemia.
- Parasitic infections associated with splenomegaly, such as kala-azar and acute malaria, presumably as a result of splenic trapping of the cells.

5. Autoimmune Neutropenia
- This diagnosis requires specific antineutrophil antibody tests. Because these tests are not widely available, it is often difficult to distinguish autoimmune neutropenia from cases otherwise categorized as idiopathic neutropenia.
- In patients with Evans' syndrome, it is associated with immune thrombocytopenia and hemolytic anemia.

6. Neutropenia of collagen vascular disease (SLE, RA, Sjogren's syndrome, and Felty's syndrome - Rheumatoid Arthritis with splenomegaly and neutropenia

7. Diseases with splenomegaly
As in sarcoidosis, cirrhosis, and congestive splenomegaly of diverse causes, Gaucher's disease.

8. Bone Marrow Infiltration / Invasion with malignancy, granulomatous disease, etc.: Neoplastic / Leukemic Process; Granulomatous Bone Marrow Disease; Infectious Disease - CMV, Parvovirus B19 (usually anemia; neutropenia uncommon), MAI

9. Idiopathic Neutropenia

10. Severe Congenital Neutropenia: Kostmann's Syndrome, Due to arrest of granulocyte differentiation in the bone marrow; Excellent response of most patients to recombinant G-CSF; This therapy may lead to G-CSF mutations and leukemia transformation

Treatment of Neutropenia
Treatments vary with the severity of neutropenia and the pattern of susceptibility to infection. With few exceptions, use of corticosteroids, immunosuppressive drugs, g-globulin injections, androgens, and splenectomy is rarely helpful. The neutropenia in Felty's syndrome often responds to splenectomy as well as to weekly doses of methotrexate.

Granulocyte colony stimulating factor (G-CSF)
Granulocyte-macrophage colony stimulating factor (GM-CSF)

1. Treat underlying cause if possible

2. G-CSF: Filgrastim (Neupogen)
- For febrile neutropenia: Adults dosage is 5—10 µg/kg IV or SC once daily is sufficient to support the Absolute Neutrophil Count during an episode of febrile neutropenia.
- For the treatment of congenital, idiopathic, and cyclic neutropenia and hastens the recovery of marrow from neutropenia after cancer chemotherapy: the usual dose of 1 to 5 ug/kg/day, is of proven benefit .

3. GM-CSF: Sargramostim (Leukine) : Higher incidence of severe side effects compared with G-CSF; No apparent clinical benefit over G-CSF.

4. Glucocorticoids may be effective in some conditions

5. B12 and/or folic acid may improve counts

6. Treatment of Febrile Neutropenic Patients: Specific guidelines have been developed (see below) ; Main concern are gram negative (G-) enteric organisms; G- organisms likely seed from gut due to microperforations; Staphylococci and enterococci also concerning; Prolonged neutropenia associated with fungal infections and also herpesvirus eruptions

Fever and Neutropenia

1.Requires rapid institution of antimicrobial therapy

a. High risk of death due to gram negative infections
b. Intravenous antibiotics begun for any fever with ANC<500/µL
c. Outpatient therapy with oral agents may be acceptable in some cases

2.Cultures most frequently negative (fever of unknown origin, FUO)

a. Two or three sets of Blood Cultures
b. Urine Culture
c. Sputum Culture
d. Consider throat culture
e. Wound culture

3. Common Organisms

a. Gram negative rods, especially Pseudomonas ssp., E. coli
b. Gram positive cocci, especially with indwelling catheters
c. Anaerobes including Clostridial ssp.

4. Symptoms and signs of infection may be highly blunted

a. Fever ± pain may be only symptom
b. Erythema seldom occurs (no neutrophilic infiltrate)
c. Purulence and/or swelling very unusual
d. Rarely find infiltrates on radiograph until ANC returns
e. Physical exam should include perirectal assessment but NO digital rectal examination
f. Abdominal pain should prompt evaluation for neutropenic enterocolitis

5. Standard Initial Antibiotic Therapy

Broad spectrum (especially Gram Negative) coverage empirically
Mezlocillin 3gm q4 hours (renal dose) + Gentamicin 2.0mg/kg load, then 1.5mg/kg q8-24°
Piperacillin and tobramycin combinations may be used as well
Mild allergy to penicillins: substitute ceftazidime 2gm q8° for mezlocillin
Ceftazidime alone may be as or more effective than double antibiotic coverage
Single agent ceftazidime also appears to have fewer side effects than double coverage
Imipenem alone (500mg iv q6°) as effective as double coverage
Ofloxacin 400mg po bid for patients at low risk for destabilization is effective [12,14]
However, use of oral agents in setting of Fever and Neutropenia is still experimental
If (blood) cultures positive, double antibiotic coverage preferred in neutropenic patients

6. G-CSF / Filgrastim (see above)

When initiated on admission for fever and neutropenia, lowers number of inpatient days for neutropenia from 4 to 3 days
No change in number of days of fever
No change in number of hospital days overall, but fewer patients stayed >11days
Use of alternative antibiotics without change or slightly reduced
Probably greatest benefit in patients with documented infection and ANC <100/µL
Appears to be safe in patients with myelocytic leukemias with neutropenia [15]

7. GM-CSF / Sargramostim

Effective post-chemotherapy for return of neutrophil accounts
Addition of GM-CSF to antibiotics improved clinical responses but not survival

8. Other Infections

Suspected cellulitis: add vancomycin 1gm every 12 hours (renal dosing required)
Suspected abdominal source: add metronidazole 500mg q8 hrs
Parenteral nutrition: yeasts (especially Candida) common
Pneumocystis carinii pneumonia (PCP)

9. Pneumocystis Pneumonia (PCP)

a. Common in patients who have been on corticosteroids (not necessarily neutropenic)
b. Not uncommon in solid tumor and leukemic patients (even without glucocorticoid use)
c. Treatment with TMP/SFX (Bactrim®), iv pentamidine, dapsone, clindamycin
d. Prednisone / Methylprednisolone should be added for hypoxic patients

10. Neutropenic Enterocolitis (Typhlitis)

Inflammation of intestine following chemotherapy, usually in neutropenic patients
Involves antineoplastic agent-induced damage to intestinal mucosa
Usually occurs in the terminal ileum, ascending colon, and cecum
Symptoms include pain, fever, bleeding; may mimic appendicitis
Rapidly fatal unless treated
Broad spectrum antibiotics and bowel rest for mild and moderate cases
Persistance of pain, bleeding when no longer neutropenic may require surgical correction

11. Still Spiking Fevers after 2-7 days on standard therapy

Add vancomycin after 2 days
Cover fungi: fluconazole may be as effective as and is safer than amphotericin B
Add acyclovir 5mg/kg q8 hrs (renal dose) if suspect herpetic infection

12. Antibiotics should in general be maintained until the patient is no longer neutropenic

Non-neutropenic is defined as an ANC >500/µL for 2 consecutive days
Neutrophil stimulating growth factors should be added if ANC < 100-200/µL

Granulomatous Bone Marrow Disease

1. Infectious (~38%): Histoplasmosis, Tuberculosis, Mononucleosis, Other: brucellosis, CMV, Rickettsial, Tularemia

2. Malignancy (~21%) : Hodgkin's Disease, Other lymphoproliferative disease, Solid Tumors

3. Drugs (~12%): Procainamide (Pronestyl®), Ibuprofen (Advil®), Others

4.Sarcoidosis

5.Collagen Vascular and Other Autoimmune Diseases

References: Outline Medicine on Physician Online 2000