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| __NOTOC__ | | __NOTOC__ |
| {{ Neutropenia }} | | {{ Neutropenia }} |
| {{CMG}}; Aric Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA[mailto:achall@bidmc.harvard.edu] {{AE}}{{Faizan}}; {{DG}} | | {{CMG}}; Aric Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA[mailto:achall@bidmc.harvard.edu] {{AE}}{{DG}}, {{Faizan}} |
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| {{SK}} Agranulocytosis, agranulosis, benign familial neutropenia, chronic benign neutropenia, cyclic neutropenia, CN, cyclic hematopoiesis, granulocytopenia, granulopenia, human cyclic neutropenia, neutropaenia, neutrophilic leukopenia, neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia | | {{SK}} Agranulocytosis, agranulosis, benign familial neutropenia, chronic benign neutropenia, cyclic neutropenia, CN, cyclic hematopoiesis, granulocytopenia, granulopenia, human cyclic neutropenia, neutropaenia, neutrophilic leukopenia, neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia |
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| Although agranulocytosis and granulocytopenia should include reduced numbers of all granulocytes (either neutrophils, eosinophils, or basophils), the majority of cases of granulocytopenia are actually neutropenia since neutrophils constitute the majority of leukocytes; the term granulocytopenia almost always refers to deficient neutrophils. To read about eosinophilic leukopenia and basophilic leukopenia, click [[leukopenia|here]]. | | Although agranulocytosis and granulocytopenia should include reduced numbers of all granulocytes (either neutrophils, eosinophils, or basophils), the majority of cases of granulocytopenia are actually neutropenia since neutrophils constitute the majority of leukocytes; the term granulocytopenia almost always refers to deficient neutrophils. To read about eosinophilic leukopenia and basophilic leukopenia, click [[leukopenia|here]]. |
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| =[[Neutropenia overview|Overview]]= | | ==[[Neutropenia overview|Overview]]== |
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| =[[Neutropenia classification|Classification]]= | | ==[[Neutropenia historical perspective|Historical Perspective]]== |
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| =[[Neutropenia pathophysiology|Pathophysiology]]= | | ==[[Neutropenia classification|Classification]]== |
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| =[[Neutropenia causes|Causes]]= | | ==[[Neutropenia pathophysiology|Pathophysiology]]== |
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| =[[Neutropenia epidemiology and demographics|Epidemiology and Demographics]]= | | ==[[Neutropenia causes|Causes]]== |
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| =[[Neutropenia diagnosis|Diagnosis]]= | | ==[[Neutropenia differential diagnosis|Differentiating Neutropenia from other Diseases]]== |
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| =[[Neutropenia treatment|Treatment]]= | | ==[[Neutropenia epidemiology and demographics|Epidemiology and Demographics]]== |
| ==Medical Therapy==
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| There is no specific therapy for neutropenia itself aside from removing the offending agents in drug-induced cases and treating the underlying disease in other, however recombinant [[Granulocyte-colony stimulating factor|G-CSF]] (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.
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| Asymptomatic, mild to moderate neutropenia can often be monitored closely on an outpatient basis with serial CBCs and evaluation for medications, infections, or alternative sources of neutropenia as described in detail above. Offending medications are often held and the patient is monitored for response to discontinuation while evaluating for alternative, more concerning etiologies. With mild neutropenia, medications can often be reintroduced after neutrophil counts recover as the neutropenia is typically dose-dependent.
| | ==[[Neutropenia risk factors|Risk Factors]]== |
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| Patients who are febrile, acutely ill, or with severe neutropenia often warrant urgent hospitalization for close monitoring and treatment. Offending medications must be discontinued as drug-induced agranulocytosis presents up to a 10% mortality and is very likely to recur if the offending agent is restarted.
| | ==[[Neutropenia screening|Screening]]== |
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| Resuscitate all patients screening positive for sepsis syndromes per goal-directed therapy and the [[surviving sepsis campaign]]. Initiate empiric antibiotics as early as possible after cultures are drawn and within 60 minutes of presentation as there is significantly higher mortality when antibiotic administration is delayed <ref name="PMID4994878">{{cite journal |author=Schimpff S, Satterlee W, Young VM, Serpick A |title=Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia |journal=N Engl J Med. |volume=284 |issue=19 |pages=1061-5 |year=1971 |pmid=4994878 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/4994878}}</ref>
| | ==[[Neutropenia natural history, complications and prognosis|Natural History, Complications, and Prognosis]]== |
| <ref name="PMID16625125">{{cite journal |author=Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M |title=Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock |journal=Crit Care Med. |volume=34 |issue=6 |pages=1589-96 |year=2006 |pmid=16625125 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/16625125}}</ref>
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| <ref name="PMID24752269">{{cite journal |author=Rosa RG, Goldani LZ. |title=Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia |journal=Antimicrob Agents Chemother. |volume=58 |issue=7|pages=3799-803 |year=2014 |pmid=24752269 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/24752269}}</ref>. Initial antibiotic selection should provide broad coverage of the most common, most virulent, and most likely pathogens and should be bactericidal so as not to rely on assistance from the host's impaired immune system. Remove central venous catheters when possible if there is suspicion for infection or with positive blood cultures.
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| '''Low risk patients'''
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| ANC>100 cells/microliter, normal liver and renal function, normal chest x-ray, no evidence of central line infection, MASCC >21, and duration of neutropenia expected <7 days in a patient with close monitoring and access to medical care.
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| '''- Ciprofloxacin 500mg PO BID + amoxicillin/clavulanate 500mg PO TID
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| '''High risk patients'''
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| Hospitalize and initiate empiric parenteral antimicrobial therapy. IDSA guidelines recommend initial monotherapy with:
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| - '''Cefepime 2 g IV Q8H'''
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| - '''Meropenem 1 g IV Q8H'''
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| - '''Imipenem/cilastatin 500 mg IV Q6H'''
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| - '''Piperacillin/tazobactam 4.5 g IV Q6H'''
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| - '''Ceftazidime 2 g IV Q8H''' (recent data shows increasing resistance to ceftazidime and inferior Gram-positive coverage to alternative regimens)
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| '''Indications for resistant Gram-positive coverage'''
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| Vancomycin or linezolid is NOT recommended as part of initial treatment unless one of the following is present and, if started, should be discontinued after 2-3 days if there is no evidence of Gram-positive infection:
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| - Hemodynamic instability
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| - Suspected catheter-associated infection
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| - [[Mucositis]] or cellulitis
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| - [[Pneumonia]]
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| - History of [[MRSA]] infection or colonization
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| - Gram-positive bacteremia prior to final culture results
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| - Recent fluoroquinolone prophylaxis
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| '''Alternative regimens'''
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| - ''Pneumonia'': Broaden coverage to include Vancomycin or Linezolid and a macrolide or fluoroquinolone. Consider PJP.
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| - ''Diarrhea'': Evaluate for C.difficile, treat if positive.
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| - ''Sinusitis'': Urgent ENT evaluation. Broaden coverage to include invasive fungi.
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| - ''Oral ulceration'': Consider broadening coverage to include Acyclovir for HSV and/or Fluconazole for Candida.
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| - ''BMT'': Evaluate for CMV. Consider broadening coverage to include Ganciclovir.
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| - ''Hemodynamic instability'': Broaden coverage to include resistant Gram-positive, Gram-negative, and anaerobic bacteria and fungi, typically with Vancomycin or Linezolid, a Carbapenem, and Amphotericin, Voriconazole, or Caspofungin.
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| ===Persistent Fever===
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| ----
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| Continue empiric therapy until either culture data is available to direct management or after 3-5 days if the patient fails to improve. The median time to defercescence in adequately treated patients is 5 days with hematologic malignancies and 2-3 days with solid tumors. If the patient is still febrile or develops recurrent fevers after this time period further work up is suggested.
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| Re-evaluate sources of infection. Re-evaluate indications for resistant Gram-positive coverage and consider adding vancomycin or linezolid. Re-evaluate indications for resistant Gram-negative organisms and anaerobes and consider broadening to carbapenem antibiotics. Consider fungal coverage in high risk patients if fevers persist after 4-7 days of appropriate antibiotic coverage and duration of neutropenia is expected to last >7 days as follows:
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| - '''Caspofungin 70 mg IV x 1 dose, then 50mg IV daily'''
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| - '''Liposomal Amphotericin B 3 mg/kg/day'''
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| - '''Voriconazole 6 mg/kg IV Q12H x 2 doses, then 4 mg/kg IV Q12H'''
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| Caspofungin provides excellent coverage for Candida and is well tolerated, however nodular pulmonary infiltrates warrant coverage of Aspergillus with Voriconazole or Amphotericin B as echinocandins do not provide adequate coverage of Aspergillus or endemic fungi.
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| In cases of severe or refractory febrile neutropenia, consider granulocyte colony stimulating factor (G-CSF) to facilitate neutrophil count recovery, however routine use is NOT recommended as it does not reduce duration of fever or mortality despite shortening duration of neutropenia <ref name="PMID21095116">{{cite journal |author=Aapro MS, et al. |title=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 tumors |journal=Eur J Cancer. |volume=47 |issue=1|pages=8-32 |year=2011 |pmid=21095116 |doi=|url=https://www.ncbi.nlm.nih.gov/pubmed/21095116}}</ref>.
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| ===Duration of Antimicrobials===
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| '''Documented infection:''' Continue antimicrobials as directed by culture data. Continue treatment for the standard duration for that particular infection and until myeloid recovery (ANC>500 cells/microliter). If counts recover prior to completing the treatment course, consider transition to an oral regimen guided by culture data.
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| '''Negative Cultures:''' Continue empiric antimicrobial regimen until myeloid recovery (ANC>500 cells/microliter). If afebrile with no evidence of ongoing infection, consider transition to oral regimen (e.g. Ciprofloxacin + Amoxicillin/Clavulanate) and continue until myeloid recovery.
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| | ==Diagnosis== |
| | [[Neutropenia history and symptoms|History and Symptoms]] | [[Neutropenia physical examination|Physical Examination]] | [[Neutropenia laboratory findings|Laboratory Findings]] | [[Neutropenia chest x ray|X Ray]] | [[Neutropenia CT|CT]] | [[Neutropenia MRI|MRI]] | [[Neutropenia ultrasound|Ultrasound]] | [[Neutropenia other imaging findings|Other Imaging Findings]] | [[Neutropenia other diagnostic studies|Other Diagnostic Studies]] |
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| | ==Treatment== |
| | [[Neutropenia medical therapy|Medical Therapy]] | [[Neutropenia surgery|Surgery]] | [[Neutropenia primary prevention|Primary Prevention]] | [[Neutropenia secondary prevention|Secondary Prevention]] | [[Neutropenia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Neutropenia future or investigational therapies|Future or Investigational Therapies]] |
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| {{Hematology}} | | {{Hematology}} |