section name header

Info


A. Neutrophils [1]
[Figure] "Hematopoietic Lineages" navigator

  1. Derived from pleuripotent hematopoietic stem cells
  2. Stem cells are CD34+ and give rise to other hematopoietic as well as endothelial cells [23]
  3. Growth factors, stromal cell and matrix interactions critical for normal development
  4. Growth factors required for neutrophil development
    1. Interleukin 3 (IL3)
    2. Granulocyte-macrophage colony stimulating factor (GM-CSF)
    3. Granulocyte colony stimulating factor (G-CSF)
    4. Macrophage CSF may also play a role

B. Definition of Neutropenianavigator

  1. ANC is the absolute neutrophil count and 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

C. Epidemiology of Neutropenianavigator

  1. Prevalence ~1.2% overall in USA
  2. Prevalence in blacks 4.5%; in whites 0.9%; in Mexican-Americans ~0.4%
  3. Neutropenia more common in males and in children <5 years
  4. Smoking associated with higher leukocyte and neutrophil counts

D. Causes of Neutropenia [1]navigator

  1. Cancer Chemotherapy
  2. Non-Chemotherapy Agents [9,18]
    1. Carbamazapine (Tegretol®)
    2. Clozapine (Clozaril®)
    3. Ticlopidine (Ticlid®)
    4. Antithyroid agents: methimazole, carbimazole, propylthiouracil
    5. Sulfasalazine (Azulfidine®)
    6. Penicillin G
    7. Sulfa Antibiotics: Trimethoprim-Sulfamethoxazole (TMP/SMX; Bactrim®, Septra®)
    8. Inflammation suppression: methotrexate, azathioprine, dapsone, rituximab (Rituxan®)
    9. Immunological: quinidine, heparin, procainamide
    10. Chloramphenicol
    11. Ganciclovir and valganciclovir
    12. Dipyrione
  3. Cyclic Neutropenia [23]
    1. Automsomal dominant disorder with cyclic hematopoiesis
    2. More common in Black Persons
    3. Average cycle time in cyclic neutropenia is about 3 weeks
    4. Absolute neutrophil count (ANC) is usually >500/µL
    5. Very severe neutropenia (ANC <200/µL) occurs 3-6 days in each 21 day cycle
    6. Risk of infection only increased with neutrophil count <500/µL
    7. May be related to cyclic production of G-CSF
    8. Treatment with recombinant G-CSF (Filgrastim®) is effective
  4. Bone Marrow Infiltration
    1. Neoplastic / Leukemic Process
    2. Granulomatous Bone Marrow Disease
    3. Infectious Disease
  5. Infectious Diseases (mainly viral)
    1. Cytomegalovirus (CMV)
    2. HIV / AIDS
    3. Human herpesvirus 8 (HHV-8) - after solid organ or peripheral stem cell transplantation [24]
    4. Parvovirus B19 - usually anemia; neutropenia relatively uncommon
    5. MAI
  6. Vitamin B12, Folic Acid Deficiency
  7. Aplastic Anemia
    1. Acquired
    2. Congenital
  8. Severe Congenital Neutropenia [25]
    1. Kostmann (Morbus Kostmann) Syndrome
    2. Autosomal recessive causes arrest of granulocyte differentiation in the bone marrow
    3. Neutrophils have poor antibacterial activity and dysfunctional granules
    4. Neutrophils are deficient in cathelin-LL37 and have reduced alpha defensins [6]
    5. Salivary levels of LL37 are considerably reduced and may explane periodontal disease [6]
    6. Neutrophils have normal lactoferrin levels and normal oxidative burst
    7. Excellent response of most patients to recombinant G-CSF (Filgrastim®)
    8. However, the risk of leukemia transformation with G-CSF is not higher than untreated
    9. Therefore, G-CSF therapy is strongly recommended
    10. Allogeneic one marrow transplantation may be effective
  9. Collagen Vascular Disease
    1. Felty's Syndrome - Rheumatoid Arthritis with splenomegaly and neutropenia
    2. Systemic Lupus - antibodies to neutrophils lead to destruction
  10. Shwachman - Diamond Syndrome [25]
    1. Rare autosomal recessive disorder
    2. Exocrine pancreatic insufficiency
    3. Skeletal abnormalities
    4. Bone marrow dysfunction
    5. Recurrent infections due to cyclic or sustained neutropenia
  11. Cimetidine does not appear to cause neutropenia

E. Treatment navigator

  1. Treat underlying cause if possible
  2. Use of colony stimulating factors (CSFs) in Chemotherapy Induced Neutropenia [5,12]
    1. Reduces infection risk 3.8% versus 3.1% on placebo [5]
    2. Reduces febrile neutropenia from 40-44% to 22-25%
    3. Reduces hospital days and at least short-term mortality (5.7% to 3.4% on drug) [12]
  3. G-CSF (Neupogen®, Neulasta®) [36]
    1. Stimulates granulocytes well and is very well tolerated
    2. ~5µg/kg/d subcutaneous dosing of Neupogen®
    3. Neulasta® is given once per chemotherapy cycle (6mg for >45kg patients)
    4. Effective for chemotherapy induced neutropenia, reduces infections, febrile episodes [5]
    5. Reduces duration of neutropenia in afebrile patients without clinical benefits [7]
    6. No reduction in hospital admissions for febrile neutropenia in children with ALL [8]
    7. Beneficial in management of nonchemotherapy drug induced neutropenia in elderly [30]
    8. G-CSF administration to aplastic anemia patients does not increase malignancy risk [26]
  4. GM-CSF
    1. Higher incidence of severe side effects compared with G-CSF
    2. No apparent clinical benefit over G-CSF in neturopenia
    3. May be useful in certain stem cell applications
  5. Antiobiotic Prophylaxis [2]
    1. Usually instituted prophylactically in patients undergoing chemotherapy
    2. Overall, antibiotic prophylaxis reduced risk of death (versus placebo) 33%
    3. Meta-analysis showed fluoroquinolone antibiotics reduced risk of death 48% [2]
    4. Levofloxacin 500mg po qd reduced fever in patients with cancer and neutropenia by 25% (from 85% to 65%), reduced bacteremias 16%, did not affect mortality [3]
    5. Levofloxacin 500mg po qd reduced the incidence of any fever from 7.9% to 3.5% in and hospitalizations for infection in patients receiving chemotherapy [4]
    6. Antibiotic prophylaxis with a fluoroquinolone should be used in neutropenic patients
  6. Interleukin 11 (IL-11, Neumega®) [31]
    1. FDA approved for chemotherapy induced thrombocytopenia [32]
    2. Helps maintain gut epithelial integrity in setting of chemotherapy / neutropenia
    3. Also has immunostimulatory actions
    4. Administration on day -1 for 21 days reduces infection risk >50%
    5. Also reduces level of bacteremia
    6. Dose 50µg/kg sc daily should be considered in patients at high risk of infection
  7. Glucocorticoids may be effective in some conditions
  8. B12 and/or folic acid may improve counts
  9. Treatment of Febrile Neutropenic Patients (see below)

F. Fever and Neutropenia (F and N) navigator

  1. Specific guidelines have been developed
  2. High risk of death due to bacterial infections
    1. Main concern are gram negative (G-) enteric organisms
    2. G- organisms likely seed from gut due to microperforations
    3. Staphylococci and enterococci also concerning
    4. Prolonged neutropenia associated with fungal infections and also herpesvirus eruptions
  3. Requires rapid institution of antimicrobial therapy
    1. Intravenous antibiotics begun for any fever with ANC<500/µL
    2. Outpatient therapy with oral agents may be acceptable in some cases
    3. IL-11 may reduce gut microperforations (see above)
  4. Cultures most frequently negative (fever of unknown origin, FUO)
    1. Two or three sets of Blood Cultures
    2. Urine Culture
    3. Sputum Culture
    4. Consider throat culture
    5. Wound culture
  5. Common Organisms
    1. Gram negative rods, especially Pseudomonas species, E. coli
    2. Gram positive cocci, especially with indwelling catheters
    3. Anaerobes including Clostridial species
  6. Symptoms and signs of infection may be highly blunted with neutropenia
    1. Fever ± pain may be only symptom
    2. Erythema seldom occurs (no neutrophilic infiltrate)
    3. Purulence and/or swelling very unusual
    4. Rarely find infiltrates on radiograph until ANC returns
    5. Physical exam should include perirectal assessment but NO digital rectal examination
    6. Abdominal pain should prompt evaluation for neutropenic enterocolitis [13]
  7. Standard Initial Antibacterial Therapy
    1. Broad spectrum (especially Gram Negative) coverage empirically
    2. For "good risk" patients with fever and neutropenia, oral antibiotics may be sufficient
    3. Ofloxacin 400mg po bid for patients at low risk for destabilization is effective [14]
    4. Oral ciprofloxacin 750mg bid + amoxicillin-clavulanate (Augmentin®) 500mg po tid was as successful as intravenous ceftazidime [20]
    5. Ciprofloxacin 750mg po bid + Augmentin® 500mg po tid was as successful as intravenous ceftriaxone + amikacin and better tolerated [21]
    6. Mezlocillin 3gm q4 hours (renal dose) ± Gentamicin 2.0mg/kg load, then 1.5mg/kg q8-24°
    7. Piperacillin (Pip) ± tobramycin (Tob) are being increasingly used
    8. Pip + ciprofloxacin is as or more effective and safe as Pip + Tob [22]
    9. Many centers are moving away from combination therapy, use potent ß-lactam only [33]
    10. ß-lactam with ß-lactamase inhibitor probably sufficient initial monotherapy
    11. Mild allergy to penicillins: substitute ceftazidime 2gm q8° for mezlocillin
    12. Ceftazidime alone may be as or more effective than double antibiotic coverage
    13. Imipenem alone (500mg iv q6°) as effective as double coverage
    14. If (blood) cultures positive, double antibiotic coverage preferred in neutropenic patients
  8. G-CSF (filgrastim, Neupogen®)
    1. When initiated on admission for fever and neutropenia, lowers number of inpatient days for neutropenia from 4 to 3 days
    2. No change in number of days of fever
    3. No change in number of hospital days overall, but fewer patients stayed >11days
    4. Use of alternative antibiotics without change or slightly reduced
    5. Probably greatest benefit in patients with documented infection and ANC <100/µL
    6. Safe in patients with myelocytic leukemias with neutropenia [15]
  9. Pegfilgrastim (Neulasta®) [10]
    1. Pegylated version of G-CSF
    2. Single 6mg sc dose equivalent to 10-14 days of G-CSF
    3. Approved for management of chemotherapy related neutropenia in patients with non- myeloid malignancies who are receiving chemotherapy at >2 week intervals
  10. GM-CSF
    1. Effective post-chemotherapy for return of neutrophil accounts
    2. Addition of GM-CSF to antibiotics improved clinical responses but not survival [16]
  11. Other Infections
    1. Suspected cellulitis: add vancomycin 1gm every 12 hours (renal dosing required)
    2. Suspected abdominal source: add metronidazole 500mg q8 hrs
    3. Parenteral nutrition: yeasts (especially Candida) common
    4. Pneumocystis carinii pneumonia (PCP)
  12. Pneumocystis Pneumonia (PCP)
    1. Common in patients who have been on corticosteroids (not necessarily neutropenic)
    2. Not uncommon in solid tumor and leukemic patients (even without glucocorticoid use)
    3. Treatment with TMP/SFX (Bactrim®), iv pentamidine, dapsone, clindamycin
    4. Prednisone / Methylprednisolone should be added for hypoxic patients
  13. Neutropenic Enterocolitis (Typhlitis) [13]
    1. Inflammation of intestine following chemotherapy, usually in neutropenic patients
    2. Involves antineoplastic agent-induced damage to intestinal mucosa
    3. Usually occurs in the terminal ileum, ascending colon, and cecum
    4. Symptoms include pain, fever, bleeding; may mimic appendicitis
    5. Rapidly fatal unless treated
    6. Broad spectrum antibiotics and bowel rest for mild and moderate cases
    7. Persistance of pain, bleeding when no longer neutropenic may require surgical correction

G. Persistent Fever During Neutropenianavigator

  1. Defined as fevers Persisting >2 Days on Standard Therapy [28]
  2. Causes
    1. Fungal infections (45%)
    2. Typical bacterial infections (10%)
    3. Viral infections (5%)
    4. Atypical bacterial or toxoplasma infections (5%), undefined causes (25%)
    5. Also caused by graft-versus-host disease after transplantation (10%)
  3. Expanded Gram Positive Coverage: add vancomycin after 2 days
  4. Fungal Coverage [34]
    1. Antifungal therapy is typically added to coverage of fever with neutropenia if still febrile after >5 days of antibacterial coverage
    2. Amphotericin B (ABD), voriconazole, or caspofungin are reasonable alternatives
    3. ABD was previously the standard of care
    4. Liposomal ABD is as effective as, better tolerated and safer than conventional ABD [19]
    5. Voriconazole (Vfend®) is nearly as effective as and better tolerated than liposomal ABD in neutropenic patients with persistent fever [29]
    6. Caspofungin (Cancidas®) is clearly as (possibly more) effective as and is better tolerated than liposomal ABD in persistent fever and neutropenia [35]
    7. Itraconazole (Sporanox®) 200mg x 2 in first 24 hours, then 200mg daily, is as effective as, and far better tolerated than, standard ABD [27]
    8. Fluconazole (Diflucan®) is almost as effective as, is better tolerated and is safer than standard ABD [17]
    9. Given in vitro susceptibility profile, caspofungin and possibly voriconazole are reasonable replacements of liposomal ABD for initial therapy of persistent F and N [34]
  5. Viral Coverage: Acyclovir 5mg/kg q8 hrs (renal dose) if herpetic infection suspected
  6. Antimicrobials should in general be maintained until the patient is no longer neutropenic
    1. Non-neutropenic is defined as an ANC >500/µL for 2 consecutive days
    2. Neutrophil stimulating growth factors should be added if ANC < 100-200/µL

H. Granulomatous Bone Marrow Diseasenavigator

  1. Infectious (~38%)
    1. Histoplasmosis
    2. Tuberculosis
    3. Mononucleosis
    4. Other: brucellosis, CMV, Rickettsial, Tularemia
  2. Malignancy (~21%)
    1. Hodgkin's Disease
    2. Other lymphoproliferative disease
    3. Solid Tumors
  3. Drugs (~12%)
    1. Procainamide (Pronestyl®)
    2. Ibuprofen (Advil®)
    3. Others
  4. Sarcoidosis
  5. Collagen Vascular and Other Autoimmune Diseases

Resources navigator

calcAbsolute Neutrophil Count

References navigator

  1. Stock W and Hoffman R. 2000. Lancet. 355(9212):1351 abstract
  2. Gafter-Gvlli A, Fraser A, Paul M, Lelbovici L. 2005. Ann Intern Med. 142(12):679
  3. Bucaneve G, Micozzi A, Menichetti F, et al. 2005. NEJM. 353(10):977 abstract
  4. Cullen M, Steven N, Billingham L, et al. 2005. NEJM. 353(10):988 abstract
  5. Sung L, Nathan PC, Albitai SM, et al. 2007. Ann Intern Med. 147(6):400 abstract
  6. Putsep K, Carlsson G, Boman HG, Andersson M. 2002. Lancet. 360(9340):1144 abstract
  7. Hartmann LC, Tschetter LK, Habermann TM, et al. 1997. NEJM. 336(25):1777 abstract
  8. Pui CH, Boyett JM, Hughes WT, et al. 1997. NEJM. 336(25):1781 abstract
  9. Andersohn F, Konzen C, Garbe E. 2007. Ann Intern Med. 146(9):657 abstract
  10. Pegfilgrastim. 2002. Med Let. 44(1130):44 abstract
  11. Carratala J, Roson B, Fernandez-Sevilla A, et al. 1998. Arch Intern Med. 158(8):868 abstract
  12. Kuderer NM, Dale DC, Crawford J, Lyman GH. 2007. J Clin Oncol. 25(21):3158 abstract
  13. Thaler SJ and Compton CC. 1997. NEJM. 336(4):277 (Case Report)
  14. Malik IA, Khan WA, et al. 1995. Am J Med. 98(3):224 abstract
  15. Brugger W, Heimfeld S, Berenson RJ, et al. 1995. NEJM. 333(5):283 abstract
  16. Anaissie EJ, Vartivarian S, Bodey GP, et al. 1996. Am J Med. 100(1):17 abstract
  17. Malik IA, Moid I, Aziz Z, et al. 1998. Am J Med. 105(6):478 abstract
  18. van der Klauw MM, Goudsmit R, Halie MR, et al. 1999. Arch Intern Med. 159(4):369 abstract
  19. Walsh TJ, Finberg RW, Arndt C, et al. 1999. NEJM. 340(10):765
  20. Freifeld A, Marchigiani D, Walsh T, et al. 1999. NEJM. 341(5):305 abstract
  21. Kern WV, Cometta A, de Bock R, et al. 1999. NEJM. 341(5):312 abstract
  22. Peacock JE Jr, Herrington DA, Wade JC, et al. 2002. Ann Intern Med. 137(2):77 abstract
  23. Gunsillius E, Duba HC, Petzer AL, et al. 2000. Lancet. 355(9216):1688 abstract
  24. Luppi M, Barozzi P, Schulz TF, et al. 2000. NEJM. 343(19):1380 abstract
  25. Lekstrom-Himes JA and Gallin JI. 2000. NEJM. 343(23):1703 abstract
  26. Locasciulli A, Arcese W, Locatelli F, et al. 2001. Lancet. 357(9249):43 abstract
  27. Boogaerts M, Winston DJ, Bow EJ, et al. 2001. Ann Intern Med. 135(6):412 abstract
  28. Corey L and Boeckh M. 2002. NEJM. 346(4):222 abstract
  29. Walsh TJ, Pappas P, Winston DJ, et al. 2002. NEJM. 346(4):225 abstract
  30. Andres E, Kurtz JE, Martin-Hunyadi C, et al. 2002. Am J Med. 112(6):462
  31. Ellis M, Zwaan F, Hedstrom U, et al. 2003. Lancet. 361(9354):275 abstract
  32. Interleukin 11. 1998. Med Let. 40(1032):77 abstract
  33. Paul M, Soares-Weiser K, Grozinsky S, Leibovici L. 2003. ACP J Club. 138(2):45
  34. Klastersky J. 2004. NEJM. 351(14):1445 abstract
  35. Walsh TJ, Teppler H, Donowitz GR, et al. 2004. NEJM. 351(14):1391 abstract
  36. Kaushansky K. 2006. NEJM. 354(19):2034 abstract