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neutropenia

Neutropenia is defined as < 2000 neutrophils + bands/uL in the peripheral blood. It is classified: 1) severe: < 500/uL 2) moderate: 500-1000/ mL 3) mild: 1000-2000 Etiology: 1) increased destruction/ peripheral margination a) drugs esp chemotherapy (see pharmaceutical agents implicated in neutropenia) b) autoimmune disorders - rheumatoid arthritis, Felty's syndrome - systemic lupus erythematosus - anti-neutrophil antibodies - Wegener's granulomatosis c) sepsis syndrome d) splenomegaly e) hemodialysis f) cardiopulmonary bypass 2) decreased production a) drugs (neutropenia may be associated with pancytopenia) (see pharmaceutical agents implicated in neutropenia) b) hematologic diseases - aplastic anemia - leukemia - lymphoid - myeloid - lymphoma - Hodgkin's lymphoma - non-Hodgkin's lymphoma - metastatic solid tumors - myelodysplasia - myelofibrosis - congenital neutropenia - congenital hypoplastic neutropenia (Kostmann's syndrome) - glycogen storage disease 1b - cyclic neutropenia (rare) - chronic idiopathic neutropenia (benign ethnic neutropenia) - subpopulations of suppressor T-cells that suppress granulopoiesis have been described - more common in African-Americans c) malnutrition - folate deficiency - vitamin B12 deficiency - alcoholism - bulimia - anorexia nervosa d) infectious - virus - HIV1 infection - bunyaviruses - arboviruses - phleboviruses - measles - Epstein-Barr virus - viral hepatitis - cytomegalovirus - parvovirus - bacterial - tuberculosis - typhoid fever - tularemia - brucellosis - parasitic - malaria - leishmaniasis - fungal - histoplasmosis - rickettsial - ehrlichiosis - Rocky Mountain spotted fever 3) peripheral pooling, sequestration & margination (transient neutropenia) a) acute bacterial endotoxemia b) hemodialysis c) cardiopulmonary bypass 4) idiopathic Epidemiology: - mild congenital neutropenia is common among blacks, Yemenite Jews & Jordanian Arabs - prevalence of transient neutropenia - in pediatric patients 4.9% - in adults 1.9% - prevalence of chronic neutropenia - in pediatric patients 0.06% - in adults 0.10% [13] Pathology: 1) when neutrophil count falls below 1000/uL, there is a progressively increased susceptibility to bacterial & fungal infections 2) infections are uncommon in patients with neutrophil counts > 500/uL 3) most serious infections associated with neutropenia occur in patients with neutrophil counts < 100/uL 4) infections: a) common pathogens in neutropenic patient 1] bacteria a] gram-negative bacilli 1} Pseudomonas aeruginosa & other Pseudomonas spp 2} Escherichia coli 3} Klebsiella 4} Enterobacter 5} Serratia 6} Acinetobacter 7} Citrobacter b] gram-positive cocci 1} Staphylococcus aureus 2} Staphylococcus epidermidis 3} alpha-Streptococcus c] gram-positive bacilli 1} diphtheroids 2} JK bacillus 2] fungi a] Candida species b] Aspergillus species b) most likely source of bacteremia in neutropenic patient without indwelling catheter is endogenous flora of the mouth or gastrointestinal (GI) tract c) other sites of infection are skin & lung Clinical manifestations: 1) symptoms are usually associated with infection a) FEVER in a neutropenic patient is a MEDICAL EMERGENCY b) odynophagia c) painful defecation d) respiratory distress e) inflammation f) lethargy 2) lymphadenopathy 3) oral thrush 4) skin lesions: abscesses 5) tachycardia 6) postural hypotension 7) digital rectal exams are contraindicated in neutropenic patients Laboratory: 1) complete blood count (CBC) a) white blood cell differential b) increased MCV suggests Vitamin B12 or folate deficiency 2) peripheral smear a) left-shift, toxic granulation, Dohle bodies suggests response to infection or marrow in recovery phase b) absence of immature forms suggests toxic insult 3) bone marrow aspiration & biopsy a) gold standard b) marrow infiltration (myelophthisis) 1] leukemia 2] lymphoma 3] metastatic tumors 4] granulomatous infections c) paucity of myeloid precursors in toxic insult d) myeloid hyperplasia in peripheral destruction & margination 4) serum vitamin B12 5) serum folate 6) anti-granulocyte antibody a) Felty's syndrome b) systemic lupus erythematosus (SLE) 7) chromosome studies 8) body fluid cultures in febrile patients a) blood cultures are essential in patients with neutropenia & fever b) culture sputum, urine & other fluids as indicated Complications: - 3.7% of pediatric patients later diagnosed with viral infections, 0.5% were diagnosed with acute lymphoblastic leukemia [13] - 2.1% of adults later diagnosed with viral infections (HIV, hepatitis), 2.6% were diagnosed with hematological diseases, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) [13] - positive predictive value of severe neutropenia for a hematological malignancy in adults is 40%, 90% of adults with AML or MDS with multiple cytopenias or pancytopenia [13] Management: 1) treat underlying etiology - mild congenital neutropenia does not require therapy [2] 2) eliminate potential offending pharmacologic agents if feasible 3) growth factors - granulocyte colony-stimulating factor (G-CSF or Neupogen) - granulocyte-macrophage colony stimulating factor (GM-CSF or sargramostim [Leukine, Prokine]) - used for autoimmune neutropenia & neutropenia due to chemotherapy [2] - can decrease severity & duration of neutropenia, but benefit is modest & pharmaceuticals expensive [2] - reserve for patients at high risk for neutropenia-associated infection [2] 5) consult hematologist 6) febrile neutropenia is a medical emergency a) hospitalization, unless 1] no significant comorbidities (pneumonia, hypotension) 2] neutropenia expected to resolve within 7 days b) culturing of body fluids c) pathogens 1] gram negative aerobic bacteria 2] penicillin-resistant viridans Streptococci: ARDS 3] fungi in patients with neutropenia > 7-10 days a] Candida krusei b] Candida glabrata c] Candida parapsilosis d] Aspergillus d) empiric intravenous (IV) antibiotics 1] first line agents a] ceftazidime b] ceftazidime plus aminoglycoside c] imipenem cilastatin d] cefepime e] piperacillin tazobactam (Zosyn) [3] 2] vancomycin should be added within 48 h a] if patient fails to respond to initial therapy b] if gram positive cocci are cultured from blood 3] metronidazole or clindamycin should be added for: a] perirectal abscess b] odontogenic infection c] severe, acute abdominal pain suggesting typhlitis 4] empiric therapy for fungal infections in patients who fail antibacterial therapy after 3-7 days -> amphotericin B is drug of choice 5] antibiotic therapy should be continued at least until the neutrophil count rises above 500/uL 6] 7 days of therapy adequate for gram-negative sepsis & neutropenia due to hematologic malignancy or hematopoietic stem cell transplantation [14] 7) low bacteria diet in patients with prolonged neutropenia a) avoidance of fresh fruits & vegetables b) may not improve outcomes [7] 8) patients should avoid individuals with known communicable diseases 9) prophylaxis against aerobic gram negative bacilli in patients expected to be neutropenic (< 100/uL) > 1 week a) fluoroquinolones reduced mortality (RR 0.52) [6,7] b) acute myeloid leukemia (AML), myelodysplastic syndrome or c) fluoroquinolone prophylaxis not recommended for most patients with solid tumors 10) air filtration for bone marrow transplant patients

Related

granulocyte transfusion neutrophil count pharmaceutical agents implicated in neutropenia

Useful

filgrastim [G-CSF] (Neupogen, Lenograstim, Granulokine) sargramostim [GM-CSF] (Leukine, Prokine, Leucomax)

Specific

chronic idiopathic neutropenia; benign ethnic neutropenia familial neutropenia febrile neutropenia HIV-associated neutropenia

General

leukopenia sign/symptom

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 587-89
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 332
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 540
  5. Journal Watch 23(14):111-112, 2003 Paul M et al, BMJ 326:1111, 2003 http://bmj.com/cgi/content/full/326/7399/1111
  6. Journal Watch 25(17):136, 2005 Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005 Jun 21;142(12 Pt 1):979-95. PMID: 15968013
  7. Gardner A et al, Randomised comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol 2008, 26:5684 PMID: 18955453
  8. Bucaneve G, Micozzi A, Menichetti F et al Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005 Sep 8;353(10):977-87. PMID: 16148283 - Cullen M, Steven N, Billingham L et al Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med. 2005 Sep 8;353(10):988-98. PMID: 16148284 - Baden LR. Prophylactic antimicrobial agents and the importance of fitness. N Engl J Med. 2005 Sep 8;353(10):1052-4. PMID: 16148291
  9. Dale DC, Link DC. The many causes of severe congenital neutropenia. N Engl J Med. 2009 Jan 1;360(1):3-5 PMID: 19118300
  10. Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med. 2007 Apr 3;146(7):486-92 PMID: 17404350
  11. Gibson C, Berliner N How we evaluate and treat neutropenia in adults. . Blood. 2014 Aug 21;124(8):1251-8; PMID: 24869938 Free Article
  12. ARUP Consult: Neutropenia The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/neutropenias
  13. Palmblad J et al. Age-related prevalence and clinical significance of neutropenia - isolated or combined with other cytopenias. Am J Hematol 2020 Feb 13; PMID: 32052479 https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25756
  14. Ranganath N et al. Evaluating antimicrobial duration for Gram-negative bacteremia in patients with neutropenia due to hematologic malignancy or hematopoietic stem cell transplantation. Transpl Infect Dis 2023 Jun 6; [e-pub]. PMID: 37279240 https://onlinelibrary.wiley.com/doi/10.1111/tid.14085