Neutropenia Clinical Presentation
- Author: Christopher D Braden, DO; Chief Editor: Emmanuel C Besa, MD more...
Patients with neutropenia often present with infection. Other sequelae may reflect concurrent pancytopenia, such as anemic symptoms (eg, fatigue, weakness, dyspnea on exertion) and manifestations of thrombocytopenia (eg, petechiae, purpura, epistaxis). For further information on pancytopenia, refer to Bone Marrow Failure.
Common presenting symptoms of neutropenia include the following:
Gingival pain and swelling
Recurrent sinusitis and otitis
Symptoms of pneumonia (eg, cough, dyspnea)
Perirectal pain and irritation
Patients with agranulocytosis usually present with the following:
Sudden onset of malaise
Sudden onset of fever, possibly with chills and prostration
Stomatitis and periodontitis accompanied by pain
Pharyngitis, with difficulty in swallowing
Determine if a fever is present, because the physician must be aware of a possible life-threatening infection. Obtaining a history of infections may aid in the current diagnostic workup. A history of periodically recurring infections is suggestive of cyclic neutropenia. A strong family history of recurrent infections, usually beginning in childhood, is strongly indicative of a genetic defect. Congenital neutropenia is suggested by a personal history of lifelong infections, family history of recurrent infections, documentation of longstanding neutropenia since childhood or adolescence, and absence of any other blood abnormality.
A family history of infections or sudden death may be an indication of inherited disorders. The maternal medical history (in neonatal neutropenia) may indicate inherited disorders or adverse effects of maternal medications. Records of past complete blood counts (CBCs) establish the chronicity of the neutropenia. Determining the age at onset aids in the differential diagnosis.
A patient with agranulocytosis may have experienced a recent viral infection, although such infections are rarely associated with severe neutropenia. Certain bacterial infections may also precede agranulocytosis.
Chronic, benign familial neutropenia is suggested by a history of long-standing neutropenia without an increased risk of infection. These patients do not generate increased leukocyte counts with infection, but they have fevers and other symptoms, such as tachycardia, when infected.
A history of autoimmune diseases may be associated with antineutrophil antibodies. Such antibodies may also be the only manifestation of autoimmune disease. A number of test methods are available, but none is widely used.
Primary immune neutropenia is uncommon. Secondary immune neutropenia may be associated with systemic lupus erythematosus, rheumatoid arthritis, and Felty syndrome.[2, 45, 14]
Obtaining a careful drug history may reveal the offending agent and spare the patient from an extensive diagnostic workup. Patients often report a history of a new drug being used or a recent change in medication. However, the offending medication may no longer be in use; therefore, the inquiry should extend back for some time. A history of occupational or accidental exposure to chemicals or physical agents (eg, ionizing radiation) may be noted.[46, 47]
If treatment is not promptly instituted, the infection progresses to generalized sepsis, which may become life threatening.
Go to Pediatric Autoimmune and Chronic Benign Neutropenia for complete information on this topic.
Physical examination of a patient with neutropenia should focus on finding signs of an infection. The skin examination focuses on rashes, ulcers, or abscesses. The oral mucosa examination assesses for aphthous ulcers, thrush, or periodontal disease. Lymphadenopathy is a possible indication of a disseminated infection or, possibly, malignancy. For perirectal infections, look for abscesses or mucous membrane abnormalities. For perineal infections, look for rashes, abscesses, or lymphadenopathy. Lung infections are usually bacterial or fungal pneumonias.
Physical findings on examination of a patient with neutropenia may include the following:
Splenomegaly (see the image below)
Associated petechial bleeding
In agranulocytosis, fever (often 40°C or higher) may be present. Rapid pulse and respiration may be evident. Hypotension and signs of septic shock may be apparent if infection has been present. Painful aphthous ulcers may be found in the oral cavity. Swollen and tender gums may be present. Usually, purulent discharge is not present, because not enough neutrophils exist to form pus. Skin infections are associated with painful swelling, but erythema and suppuration are usually absent.
Jacobson CA, Berliner N. Neutropenia. Greer JP, Arber DA, Glader B, et al, eds. Wintrobe’s Clinical Hematology. 13th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2014. 1279-89.
Smith CW. Production, Distribution, and Fate of Neutrophils. Kaushansky K, Lichtman MA, Prchal JT, et al. Williams Hematology. 9th ed. New York, NY: McGraw-Hill; 2016.
Schimpff SC. Empiric antibiotic therapy for granulocytopenic cancer patients. Am J Med. 1986 May 30. 80(5C):13-20. [Medline].
Schwarzinger M, Sagaon-Teyssier L, Cabaret O, Bretagne S, Cordonnier C, Pautas C, et al. Performance of serum biomarkers for the early detection of invasive aspergillosis in febrile, neutropenic patients: a multi-state model. PLoS One. 2013. 8(6):e65776. [Medline].
[Guideline] Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, 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 Feb 15. 52(4):e56-93. [Medline]. [Full Text].
Bodey GP. Managing infections in the immunocompromised patient. Clin Infect Dis. 2005 Apr 1. 40 Suppl 4:S239. [Medline].
[Guideline] National Comprehensive Cancer Network. Prevention and Treatment of Cancer-Related Infections Version 2.2015. NCCN. Available at http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed: February 26, 2016.
Kern WV, Cometta A, De Bock R, Langenaeken J, Paesmans M, Gaya H. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med. 1999 Jul 29. 341(5):312-8. [Medline].
Bow EJ, Mandell LA, Louie TJ, Feld R, Palmer M, Zee B, et al. Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group. Ann Intern Med. 1996 Aug 1. 125(3):183-90. [Medline].
Finberg RW, Talcott JA. Fever and neutropenia--how to use a new treatment strategy. N Engl J Med. 1999 Jul 29. 341(5):362-3. [Medline].
Freifeld A, Marchigiani D, Walsh T, Chanock S, Lewis L, Hiemenz J, et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med. 1999 Jul 29. 341(5):305-11. [Medline].
Mulcahy N. New ASCO Guideline on Neutropenia and Fever. Medscape Medical News. Jan 16 2013. Available at http://www.medscape.com/viewarticle/777736. Accessed: January 22, 2013.
[Guideline] Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2013 Jan 14. [Medline].
Formiga F, Mitjavila F, Pac M, Moga I. Effective splenectomy in agranulocytosis associated with systemic lupus erythematosus. J Rheumatol. 1997 Jan. 24(1):234-5. [Medline].
Palmblad J, Nilsson CC, Höglund P, Papadaki HA. How we diagnose and treat neutropenia in adults. Expert Rev Hematol. 2016 Feb 16. Vol 2:1-9. [Medline].
Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count?. J Lab Clin Med. 1999 Jan. 133(1):15-22. [Medline].
Mustafa MM, McClain KL. Diverse hematologic effects of parvovirus B19 infection. Pediatr Clin North Am. 1996 Jun. 43(3):809-21. [Medline].
Rodriguez A, Yood RA, Condon TJ, Foster CS. Recurrent uveitis in a patient with adult onset cyclic neutropenia associated with increased large granular lymphocytes. Br J Ophthalmol. 1997 May. 81(5):415. [Medline]. [Full Text].
Bar-Joseph G, Halberthal M, Sweed Y, Bialik V, Shoshani O, Etzioni A. Clostridium septicum infection in children with cyclic neutropenia. J Pediatr. 1997 Aug. 131(2):317-9. [Medline].
Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe’s Hematology. 10th ed. Baltimore, Md: William and Wilkins; 1999. 1836-88.
Boxer LA. Immune neutropenias. Clinical and biological implications. Am J Pediatr Hematol Oncol. 1981 Spring. 3(1):89-96. [Medline].
Welte K, Dale D. Pathophysiology and treatment of severe chronic neutropenia. Ann Hematol. 1996 Apr. 72(4):158-65. [Medline].
Young NS. Agranulocytosis. JAMA. 1994 Mar 23-30. 271(12):935-8. [Medline].
Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology Am Soc Hematol Educ Program. 2004. 63-79. [Medline].
Sifton DW, Murray L, Kelly GL, Reilly S, eds. Physicians’ Desk Reference. 55th ed. Montvale, NJ: Medical Economics Company, Inc.; 2001. 551-6, 847-60, 1275-80, 1396-9, 1793-5, 1998-2002, 3068-71.
American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 1994 Nov. 12(11):2471-508. [Medline].
Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol. 1996 Jun. 14(6):1957-60. [Medline].
Vial T, Gallant C, Choqu-Kastylevsky G, Descotes J. Treatment of drug-induced agranulocytosis with haematopoietic growth factors: a review of the clinical experience. BioDrugs. 1999 Mar. 11(3):185-200. [Medline].
D'Angelo G. Ethnic and genetic causes of neutropenia: clinical and therapeutic implications. Lab Hematol. 2009. 15(3):25-9. [Medline].
Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008 Oct 8. CD003189. [Medline].
D'Souza A, Jaiyesimi I, Trainor L, Venuturumili P. Granulocyte colony-stimulating factor administration: adverse events. Transfus Med Rev. 2008 Oct. 22(4):280-90. [Medline].
Carlsson G, Aprikyan AA, Ericson KG, Stein S, Makaryan V, Dale DC, et al. Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Haematologica. 2006 May. 91(5):589-95. [Medline].
Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009 Nov. 147(4):535-42. [Medline]. [Full Text].
Goulenok T, Fantin B. Antimicrobial Treatment of Febrile Neutropenia: Pharmacokinetic-Pharmacodynamic Considerations. Clin Pharmacokinet. 2013 Jun 27. [Medline].
Andersen CL, Tesfa D, Siersma VD, Sandholdt H, Hasselbalch H, Bjerrum OW, et al. Prevalence and clinical significance of neutropenia discovered in routine complete blood cell counts: a longitudinal study. J Intern Med. 2016 Jan 21. [Medline].
Mueller EL, Croop J, Carroll AE. Fever and neutropenia hospital discharges in children with cancer: A 2012 update. Pediatr Hematol Oncol. 2016 Feb 22. 1-10. [Medline].
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. [Medline].
Grann VR, Bowman N, Joseph C, Wei Y, Horwitz MS, Jacobson JS, et al. Neutropenia in 6 ethnic groups from the Caribbean and the U.S. Cancer. 2008 Aug 15. 113(4):854-60. [Medline].
Pathak R, Giri S, Aryal MR, Karmacharya P, Bhatt VR, Martin MG. Mortality, length of stay, and health care costs of febrile neutropenia-related hospitalizations among patients with breast cancer in the United States. Support Care Cancer. 2015 Jan 4. [Medline].
Meisel A, von Felten S, Vogt DR, Liewen H, de Wit R, de Bono J, et al. Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial. Eur J Cancer. 2016 Jan 29. 56:93-100. [Medline].
Jansen RR, Biemond BJ, Schinkel J, Koekkoek SM, Molenkamp R, de Jong MD, et al. Febrile neutropenia: significance of elaborated screening for respiratory viruses, and the comparison of different sampling methods, in neutropenic patients with hematological malignancies. Virol J. 2013 Jun 27. 10(1):212. [Medline].
Hellmich B, Schnabel A, Gross WL. Treatment of severe neutropenia due to Felty's syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor. Semin Arthritis Rheum. 1999 Oct. 29(2):82-99. [Medline].
MacVittie TJ. Therapy of radiation injury. Stem Cells. 1997. 15 Suppl 2:263-8. [Medline].
Mac Manus M, Lamborn K, Khan W, Varghese A, Graef L, Knox S. Radiotherapy-associated neutropenia and thrombocytopenia: analysis of risk factors and development of a predictive model. Blood. 1997 Apr 1. 89(7):2303-10. [Medline].
[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Myeloid Growth Factors v 1.2015. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf. Accessed: February 24, 2016.
[Guideline] Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011 Jan. 47 (1):8-32. [Medline].
Wang XJ, Tang T, Farid M, Quek R, Tao M, Lim ST, et al. Routine Primary Prophylaxis for Febrile Neutropenia with Biosimilar Granulocyte Colony-Stimulating Factor (Nivestim) or Pegfilgrastim Is Cost Effective in Non-Hodgkin Lymphoma Patients undergoing Curative-Intent R-CHOP Chemotherapy. PLoS One. 2016. 11 (2):e0148901. [Medline].
Massey E, Paulus U, Doree C, Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2009 Jan 21. CD005341. [Medline].
Dranitsaris G, Rayson D, Vincent M, Chang J, Gelmon K, Sandor D, et al. Identifying patients at high risk for neutropenic complications during chemotherapy for metastatic breast cancer with doxorubicin or pegylated liposomal doxorubicin: the development of a prediction model. Am J Clin Oncol. 2008 Aug. 31(4):369-74. [Medline].
Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999 Mar 11. 340(10):764-71. [Medline].
Curnutte J, Coates T. Disorder of phagocyte function and number. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000. 720-62.
Douglas D. Antifungals cut risk of invasive infections in neutropenic patients. Reuters Health Information. September 9, 2013. [Full Text].
Pechlivanoglou P, Le HH, Daenen S, Snowden JA, Postma MJ. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother. 2013 Aug 23. [Medline].
Chustecka Z. Biosimilar Filgrastim Recommended for Approval in US. Medscape Medical News. January 7, 2015. Available at http://www.medscape.com/viewarticle/837725.
|Cyclic neutropenia||Autosomal dominant||ELA2||Alternate 21-day cycling of neutrophils and monocytes|
|Kostmann syndrome||Autosomal recessive||Unknown||Stable neutropenia, no MDS or AML|
|Severe congenital neutropenia||Autosomal dominant||ELA2 (35-84%)||Stable neutropenia, MDS or AML|
|Autosomal dominant||GFI1||Stable neutropenia, circulating myeloid progenitors, lymphopenia|
|Sex linked||Wasp||Neutropenic variant of Wiskott-Aldrich syndrome|
|Autosomal dominant||G-CSFR||G-CSF–refractory neutropenia, no AML or MDS|
|Hermansky-Pudlak syndrome type 2||Autosomal recessive||AP3B1||Severe congenital neutropenia, platelet dense-body defect, oculocutaneous albinism|
|Chediak-Higashi syndrome||Autosomal recessive||LYST||Neutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function|
|Barth syndrome||Sex linked||TAZ||Neutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria|
|Cohen syndrome||Autosomal recessive||COH1||Neutropenia, mental retardation, dysmorphism|
|Source: Modified from Berliner et al, 2004.
AML = acute myeloid leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplastic syndrome.