Neutropenia natural history, complications and prognosis: Difference between revisions
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==Complications== | ==Complications== | ||
= | ===Febrile Neutropenia=== | ||
===Diagnosis | '''Diagnosis''' | ||
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. | 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. | ||
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Per 2002 IDSA <ref name="PMID21258094">{{cite journal |author=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. |title=Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america|journal=Clin Infect Dis. |volume=52 |issue=4 |pages=e56-95 |year=2011 |pmid=21258094 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/21258094}}</ref> and 2013 ASCO <ref name="PMID23319691">{{cite journal |author=Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD |title=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. |volume=31 |issue=6 |pages=794-810 |year=2013 |pmid=23319691 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/23319691}}</ref> guidelines, febrile neutropenia requires both of the following criteria: | Per 2002 IDSA <ref name="PMID21258094">{{cite journal |author=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. |title=Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america|journal=Clin Infect Dis. |volume=52 |issue=4 |pages=e56-95 |year=2011 |pmid=21258094 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/21258094}}</ref> and 2013 ASCO <ref name="PMID23319691">{{cite journal |author=Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston AA, Marr KA, Rolston KV, Ramsey SD |title=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. |volume=31 |issue=6 |pages=794-810 |year=2013 |pmid=23319691 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/23319691}}</ref> guidelines, febrile neutropenia requires both of the following criteria: | ||
#Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour | |||
#Severe neutropenia: ANC< 500 cells/microliter | |||
'''Pathogenesis''' | |||
#Damage to the immune system and/or mucosal barriers by an underlying malignancy. | |||
#Damage to the immune system and/or mucosal barriers by chemotherapy. | |||
The majority of cases of neutropenic fever are attributed to chemotherapy-induced mucositis, which permits endogenous bacterial and fungi to seed the bloodstream. Defects in neutrophilic phagocytosis, as well as antibody production, immune complex clearance, and T-cell mediated cytotoxic killing by hematologic malignancies or immunosuppressive chemotherapies predispose to infection by encapsulated and intracellular organisms. | The majority of cases of neutropenic fever are attributed to chemotherapy-induced mucositis, which permits endogenous bacterial and fungi to seed the bloodstream. Defects in neutrophilic phagocytosis, as well as antibody production, immune complex clearance, and T-cell mediated cytotoxic killing by hematologic malignancies or immunosuppressive chemotherapies predispose to infection by encapsulated and intracellular organisms. | ||
'''Common pathogens | '''Common pathogens''' | ||
''Gram-positive bacteria'' | ''Gram-positive bacteria'' | ||
:* Staphylococci (including MRSA; S.epidermidis accounts for 50% of all Gram-positive febrile neutropenia) | :* Staphylococci (including MRSA; S.epidermidis accounts for 50% of all Gram-positive febrile neutropenia) | ||
:* Streptococci | :* Streptococci | ||
:* Enterococci (including VRE) | :* Enterococci (including VRE) | ||
:* Listeria | :* Listeria | ||
''Gram-negative bacteria'' | ''Gram-negative bacteria'' | ||
:* Enterobacteriaceae (E.coli, Klebsiella, Enterobacter, including ESBL-producers) | :* Enterobacteriaceae (E.coli, Klebsiella, Enterobacter, including ESBL-producers) | ||
:* Pseudomonas | :* Pseudomonas | ||
:* Citrobacter | :* Citrobacter | ||
:* Acinetobacter | :* Acinetobacter | ||
:* Neisseria | :* Neisseria | ||
:* Haemophilus | :* Haemophilus | ||
:* Salmonella | :* Salmonella | ||
''Fungi'' (rare in low-risk patients) | ''Fungi'' (rare in low-risk patients) | ||
:* Candida | :* Candida | ||
:* Aspergillus | :* Aspergillus | ||
:* Cryptococcus | :* Cryptococcus | ||
:* Reactivation of endemic fungi (Histoplasma, Blastomyces, Coccidioides) | :* Reactivation of endemic fungi (Histoplasma, Blastomyces, Coccidioides) | ||
Anaerobes are less commonly identified, yet can cause intra-abdominal, pelvic, or periodontal infections. | Anaerobes are less commonly identified, yet can cause intra-abdominal, pelvic, or periodontal infections. | ||
'''Diagnostic Evaluation''' | |||
:* Targeted history | :* Targeted history | ||
:* Detailed physical exam focusing on: mental status, skin, eyes, mucus membranes and oropharynx, lungs, abdomen, and perineum (digital rectal exam should be avoided in neutropenic patients) | :* Detailed physical exam focusing on: mental status, skin, eyes, mucus membranes and oropharynx, lungs, abdomen, and perineum (digital rectal exam should be avoided in neutropenic patients) | ||
:* CBC with differential | :* CBC with differential | ||
:* Serum electrolytes, creatinine, liver function tests | :* Serum electrolytes, creatinine, liver function tests | ||
:* Urinalysis with culture | :* Urinalysis with culture | ||
:* Blood cultures including separate cultures from each indwelling catheter | :* Blood cultures including separate cultures from each indwelling catheter | ||
:* Cultures from any suspected sites of infection including serum or BAL galactomannan if at increased risk for aspergillosis | :* Cultures from any suspected sites of infection including serum or BAL galactomannan if at increased risk for aspergillosis | ||
:* Consider chest radiographs or CT scan of the chest and/or abdomen to detect infiltrates and bowel wall thickening in the appropriate clinical context | :* Consider chest radiographs or CT scan of the chest and/or abdomen to detect infiltrates and bowel wall thickening in the appropriate clinical context | ||
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 <ref name="PMID21258094">{{cite journal |author=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. |title=Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america|journal=Clin Infect Dis. |volume=52 |issue=4 |pages=e56-95 |year=2011 |pmid=21258094 |doi=|url=http://www.ncbi.nlm.nih.gov/pubmed/21258094}}</ref>. As such, rapid risk stratification and appropriate empiric treatment is necessary. | |||
==Prognosis== | ==Prognosis== | ||
'''Low risk''': typically patients with solid tumors on chemotherapy plus the following: | '''Low risk''': typically patients with solid tumors on chemotherapy plus the following: | ||
:* Anticipated neutropenia (ANC<500 cells/microliter) <7 days | :* Anticipated neutropenia (ANC<500 cells/microliter) <7 days | ||
:* No significant hepatic or renal dysfunction | :* No significant hepatic or renal dysfunction | ||
:* No significant comorbidities** | :* No significant comorbidities** | ||
:* [http://www.uptodate.com/contents/calculator-multinational-association-for-supportive-care-in-cancer-mascc-risk-index-for-patients-with-neutropenic-fever?source=see_link MASCC Risk Score] >21 (PPV 91%, specificity 68%, sensitivity 71%) | :* [http://www.uptodate.com/contents/calculator-multinational-association-for-supportive-care-in-cancer-mascc-risk-index-for-patients-with-neutropenic-fever?source=see_link MASCC Risk Score] >21 (PPV 91%, specificity 68%, sensitivity 71%) | ||
'''High risk''' | '''High risk''' | ||
:* Anticipated neutropenia (ANC<500 cells/microliter) >7 days | :* Anticipated neutropenia (ANC<500 cells/microliter) >7 days | ||
:* Significant hepatic or renal dysfunction | :* Significant hepatic or renal dysfunction | ||
:* Significant comorbidities** | :* Significant comorbidities** | ||
:* Disease progression | :* Disease progression | ||
:* [http://www.uptodate.com/contents/calculator-multinational-association-for-supportive-care-in-cancer-mascc-risk-index-for-patients-with-neutropenic-fever?source=see_link MASCC Risk Score] <21 (PPV 91%, specificity 68%, sensitivity 71%) | :* [http://www.uptodate.com/contents/calculator-multinational-association-for-supportive-care-in-cancer-mascc-risk-index-for-patients-with-neutropenic-fever?source=see_link MASCC Risk Score] <21 (PPV 91%, specificity 68%, sensitivity 71%) | ||
''**Significant comorbidities: | ''**Significant comorbidities:'' | ||
:* Hemodynamic instability | :* Hemodynamic instability | ||
:* Mucositis | :* Mucositis | ||
:* GI symptoms | :* GI symptoms | ||
:* Acute neurological changes | :* Acute neurological changes | ||
:* Intravascular catheters | :* Intravascular catheters | ||
:* Pulmonary infiltrates or underlying chronic lung disease'' | :* Pulmonary infiltrates or underlying chronic lung disease'' | ||
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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]
Overview
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.
Complications
Febrile Neutropenia
Diagnosis 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:
- Fever: single oral temperature >38.3 C/101 F or sustained temperature >38 C/100.4 F for 1 hour
- Severe neutropenia: ANC< 500 cells/microliter
Pathogenesis
- Damage to the immune system and/or mucosal barriers by an underlying malignancy.
- Damage to the immune system and/or mucosal barriers by chemotherapy.
The majority of cases of neutropenic fever are attributed to chemotherapy-induced mucositis, which permits endogenous bacterial and fungi to seed the bloodstream. Defects in neutrophilic phagocytosis, as well as antibody production, immune complex clearance, and T-cell mediated cytotoxic killing by hematologic malignancies or immunosuppressive chemotherapies predispose to infection by encapsulated and intracellular organisms.
Common pathogens
Gram-positive bacteria
- Staphylococci (including MRSA; S.epidermidis accounts for 50% of all Gram-positive febrile neutropenia)
- Streptococci
- Enterococci (including VRE)
- Listeria
Gram-negative bacteria
- Enterobacteriaceae (E.coli, Klebsiella, Enterobacter, including ESBL-producers)
- Pseudomonas
- Citrobacter
- Acinetobacter
- Neisseria
- Haemophilus
- Salmonella
Fungi (rare in low-risk patients)
- Candida
- Aspergillus
- Cryptococcus
- Reactivation of endemic fungi (Histoplasma, Blastomyces, Coccidioides)
Anaerobes are less commonly identified, yet can cause intra-abdominal, pelvic, or periodontal infections.
Diagnostic Evaluation
- Targeted history
- Detailed physical exam focusing on: mental status, skin, eyes, mucus membranes and oropharynx, lungs, abdomen, and perineum (digital rectal exam should be avoided in neutropenic patients)
- CBC with differential
- Serum electrolytes, creatinine, liver function tests
- Urinalysis with culture
- Blood cultures including separate cultures from each indwelling catheter
- Cultures from any suspected sites of infection including serum or BAL galactomannan if at increased risk for aspergillosis
- Consider chest radiographs or CT scan of the chest and/or abdomen to detect infiltrates and bowel wall thickening in the appropriate clinical context
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
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
References
- ↑ 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.
- ↑ 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.
- ↑ 3.0 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.
- ↑ 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.