Neutropenia natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]


Neutropenia is a frequent finding on blood differential. When identified, attention must be placed on identifying underlying medication toxicities, autoimmune disorders or hematological malignancies, or various infections. While most patients with mild neutropenia recover quickly and without complications, severe medication-related neutropenia can be fatal in up to 10%.[1] Close attention must be given to identifying poor prognostic indicators, early signs of infection, and any cyclic pattern to this hematologic abnormality to avoid potentially fatal complications.

Febrile neutropenia is an often fatal complication of severe neutropenia, with fever often being the only presenting symptom of an underlying infection.

Natural History

Neutropenia is a frequent finding related to various infections, cytotoxic chemotherapies or medication toxicities, autoimmune disorders, hematological malignancies, and certain ethnic groups. It is often asymptomatic and the neutropenia often normalizes quickly and without complications, however evaluation for an underlying cause is necessary when the neutropenia is severe or there are associated findings to prevent complications that can often be fatal.

For those without severe neutropenia and without clinical, serological, or radiographic evidence of underlying diseases contributing to neutropenia, regular blood count monitoring up to a few times each week is recommended to monitor the course of neutropenia. During this time, particular attention should be paid to any symptoms of infection or malignancy and any contributing medications as infectious complications carry a mortality rate of up to 10%.[1]

A small fraction of neutropenic patients are found to have cyclic neutropenia, where 4-6 day periods of neutropenia occur approximately every 3 weeks and, like other forms of severe neutropenia, predispose the patient to complicated infections. Screening these individuals requires serial monitoring of neutrophil counts a minimum of 3 times per week for a minimum of 6 weeks to reveal the 3 week cycles.[2]

Neutropenia is classified as "chronic" when lasting for greater than 3 months.


There are no intrinsic complications of neutropenia itself, however neutropenia is a complication of many cytotoxic medications and chemotherapy and other conditions described and can increase the risk of infections. Neutropenic fever is a potentially life-threatening condition associated with neutropenia that is described in detail in its own chapter and reviewed briefly below.

Febrile Neutropenia

In patients with severe neutropenia, the neutrophil-mediated inflammatory process in the setting of infection is often blunted. Fever can be the sole presenting symptom. The risk of infection increases with the degree and duration of neutropenia with prolonged neutropenia defined as >7 days.

Per 2002 IDSA [3] and 2013 ASCO [4] guidelines, febrile neutropenia requires both of the following criteria:
  1. Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour
  2. Severe neutropenia: ANC< 500 cells/microliter

Despite prompt and thorough evaluation, a source of infection is identified in less than 1/3 of patients. Bacteremia, present in up to 25%, often serves as the only source of positive culture data. [3] As such, rapid risk stratification and appropriate empiric treatment is necessary.


Prognosis for low risk neutropenia is excellent - >90% probability of complete resolution without complications - however, high risk patients have >40% risk of complications. Risk assessment for patients with neutropenia is defined as below.

Low risk: typically patients with solid tumors on chemotherapy plus the following:

  • Anticipated neutropenia (ANC<500 cells/microliter) <7 days
  • No significant hepatic or renal dysfunction
  • No significant comorbidities**
  • MASCC Risk Score >21 (PPV 91%, specificity 68%, sensitivity 71%)

High risk

  • Anticipated neutropenia (ANC<500 cells/microliter) >7 days
  • Significant hepatic or renal dysfunction
  • Significant comorbidities**
  • Disease progression
  • MASCC Risk Score <21 (PPV 91%, specificity 68%, sensitivity 71%)

**Significant comorbidities: Hemodynamic instability, mucositis, GI symptoms, acute neurological changes, intravascular catheters, pulmonary infiltrates, or underlying chronic lung disease.


  1. 1.0 1.1 Andrès E, Maloisel F. (2008). "Idiosyncratic drug-induced agranulocytosis or acute neutropenia". Curr Opin Hematol. 15 (1): 15–21. PMID 18043241.
  2. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. (2008). "Congenital neutropenia: diagnosis, molecular bases and patient management". Orphanet J Rare Dis. 19 (6): 26. PMID 21595885.
  3. 3.0 3.1 Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. (2011). "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. 52 (4): e56–95. PMID 21258094.
  4. Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD (2013). "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". 31 (6): 794–810. PMID 23319691.

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