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Febrile neutropenia
: Febrile neutropenia 1 38.3oC 38.0oC 1 neutrophil < 500/ L
< 1,000/ L neutrophil < 500/ L neutropenia 1. (aplastic
anemia) (leukemia), multiple myeloma, myelodysplastic syndrome
(MDS), (lymphoma involved bone marrow), infection lymphoma
associated hemophagocytic syndrome neutropenia autoimmune disease
autoimmune neutropenia 2. neutropenia (leukemia) (non hodgkins
lymphoma hodgkins lymphoma) multiple myeloma neutropenia
(pancreatic cancer), (gastric cancer), (bladder cancer), germ cell
tumor platinum based regimen high dose ifosfamide neutropenia ,
NSAIDS, isoniazid, rifampicin pyrazinamide azathiopine 3.
neutropenia neutropenia 1. acute myeloid leukemia anthracycline
cytarabine high dose cytarabine Gerson SL. acute myeloid leukemia
absolute neutrophil count < 500/L 10-14 absolute neutrophil
count > 500 /L 1 hyper CVAD alternating with methotrexate plus
cytarabine relapsed and refractory non hodgkins lymphoma regimen
severe neutropenia prolong neutropenia
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non hodgkins lymphoma chronic lymphocytic leukemia
myelosuppression immunosuppression immunosuppression
myelosuppression fludarabine alemtuzumab T cell suppression
pneumocystis carinii (PCP) prophylactic PCP cotrimoxazole
prophylactic viral infection acyclovir prophylactic CMV oral
ganciclovir alemtuzumab 2. neutrophil neutropenia Dale DC.
neutrophil < 500-1,000/L 14% neutrophil < 100 /L2 neutropenia
< 500/L 10 neutropenia 5 100% 3,4 3. mucositis oral mucositis
gastrointestinal mucositis mucosa barrier mucosa bacterial
colonization localized infection systemic infection sepsis 5,6 4.
catheters other devices neutropenia catheters other devices 5. , ,
SLE (hypoalbuminemia) 6. corticosteroids neutropenia
corticosteroids neutropenia corticosteroids corticosteroids 5,6
febrile neutropenia febrile neutropenia neutropenia , , , ,
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, , , , , per rectal examination anus perianal abcess lower GI
bleeding sterile febrile neutropenia febrile neutropenia complete
blood count, (peripheral blood blood catheters double lumen
hickmans catheter hickmans port) (UA), urine culture, stool exam
culture gram stain, cultureAFB culture TB wet smear culture for
fungus , (NG tube), cell count cell differentiation , (liver
function test) neutropenia (BUN/ Cr) invasive aspergillus infection
febrile neutropenia 1. Non invasive investigation 1.1 Chest x- ray
(CXR) invasive pulmonary aspergillosis (IPA) febrile neutropenia
lesion CXR pulmonary nodule pulmonary consolidation crescent form
crescent form pathognomonic sign invasive pulmonary aspergillosis
CXR IPA early detection aspergillus CXR ANC recovery out of
neutropenia 1.2 CT chest abdomen early invasive pulmonary
aspergillosis (IPA) febrile neutropenia lesion CT chest early
infection halo sign macronodular progression consolidation, patchy
infiltration, nodules, nodular lesion with ground glass opacity
cavity
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1.3 Galactomannan antigen test serum galactomannan (GM)
aspergillus infection non invasive early aspergillus infection
febrile neutropenia galactomannan fungal cell wall exoantigen
aspergillus serum GM serum GM 3 1. ELISA 2. -D-glucan testing 3.
Latex agglutination enzyme-linked immunosorbent assay (ELISA)
approve US Food and Drug Administration (FDA) invasive
aspergillosis FDA cut off GM index(GMI) =5 GMI > 0.5 positive
positive 2 aspergillus 100 FDA sensitivity specificity ELISA test
80.7% 89.2% false positive ELISA test 1-18 1. cross reactivity
other fungi Penicillium chrysogenum, Penicillium digitatum
Paecilomyces variotii 2. intestinal mucosa 3. children neonate 4.
Piperacillin/ Tazobactam GM Almudena adult hematological patients
78 90 episodes sensitivity specificity GM- ELISA test 100% 88 %
positive negative predictive value 47% 100% false positive GM 10.2
97.5 Piperacillin/ Tazobactam GM 2.5 graft versus host disease
mucositis grade IV7 body fluid GM BAL fluid sensitivity 76%
specificity 94% GM- ELISA test aspergillus infection body fluid
serum GM 1.4 Molecular testing : Polymerase chain reaction (PCR)
early aspergillus infection standardization commercial systems7 PCR
2. Invasive investigation tissue biopsy tissue culture for fungus
definite diagnosis aspergillus infection bronchoscopy hematologic
malignancies acute leukemia bronchoscopy thrombocytopenia
pneumothorax bronchoscopy tissue
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biopsy invasive aspergillosis clinical, image (CXR CT)
galactomannan ELISA test tissue pathology culture febrile
neutropenia 1. (Bacterial infection) neutropenia gram positive,
gram negative anaerobic organisms bacteremia (hemoculture) febrile
neutropenia 20-30 bacteremia febrile neutropenia empirical
treatment antibiotic febrile neutropenia 30-40 gram negative
bacilli 60-70bacteremia E. coli, K. pneumoniae P. aeruginosa8,9
Donowitz gram positive organisms gram positive organisms febrile
neutropenia catheters line infections fluoroquinolone prophylactic
bacterial infections intensive chemotherapy acute leukemia aerobic
bacterial infections gastrointestinal tract microaerophilic gram
positive high-dose cytarabine arabinoside mucositis gram positive
organisms H2 antagonists gastric PH microflora Staphylococcus
species (S. aureus coagulase-negative staphylococci), Streptococcus
species (S. viridans, S. mitis, S. oralis ) Enterococcus spicies (
E. faecium E. faecealis ) multiple myeloma immunoglobulin function
hypogammaglobulinemia chronic lymphocytic leukemia Staphylococcus
Streptococci species 10,11 anaerobic pathogens neutropenia gram
negative gram positive organisms perianal area intraabdominal
abcess
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Clostridia species (C. perfringens, C. septicum) Bacillus
species catheters 2. (fungal infections) Bodey GP. systemic fungal
infections hematologic malignancies 2012 40 autopsy13 Candida
species C. albicans C. tropicalis, C. glabrata, C. parapsilosis, C.
krusei C. lusitaniae C. krusei, C. glabrata, C. lusitaniae candida
fluconazole C. krusei center fluconazole prophylaxis 14 invasive
candida infections 15-35% candida infections neutropenia mucositis
, broad-spectum antibiotics, immune dysfunction corticosteroids,
catheters other devices15,16,17
total parenteral nutrition lipid candida oropharyngeal area
localized mucosal infection esophagitis disseminated candida
infections septic shock 14 chronic disseminated candida infections
2 organs liver, spleen kidneys neutropenic patients Aspergillus
species A. fumigatus A. flavus, A.niger A. terreus aspergillus
prolong neutropenia18 acute leukemia aplastic anemia,
corticosteroids, , graft versus host disease environment
aspergillus localized infection aspergillus pulmonary hemorrhage
disseminated infection brain brain abcess invasive aspergillus
infection 75-92
neutropenic patients Fusarium, Trichosporon, Rhizopus
Scedosporium species fusarium scedosporium rhizopus sinopulmonary
disease trichosporon disseminated disease
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3. (viral infections) malignancy neutropenia herpes viruses
herpes simplex, varicella-zoster, cytomegalovirus, epstein-barr
virus) respiratory syncytial virus, adenovirus, parainfluenza
virus, influenza A B viruses rhinovirus febrile neutropenia
febrile neutropenia 3 febrile neutropenia high, intermediate low
risk 2 febrile neutropenia high intermediate risk ANC < 100/ L,
prolong neutropenia 14 , hematologic malignancies allogeneic stem
cell transplantation, comorbidity , (vital sign) high risk solid
malignancies moderate low risk
febrile neutropenia antibiotics 6 . (mortality rate) antibiotics
3 monotherapy without vancomycin, duotherapy without vancomycin
monotherapy or duotherapy with vancomycin 1. monotherapy anti
pseudomonal penicillin+ -lactamase inhibitor (piperacillin/
tazobactam), carbapenem (imipenem meropenem), fluoroquinolone
(levofloxacin trovafloxacin), cephalosporin (maxipime) 19
2. duotherapy antipseudomonal cephalosporin aminoglycoside
fluoroquinolone (levofloxacin trovafloxacin) aminoglycoside
(amikacin, gentamycin tobramycin) piperacillin/ tazobactam
carbapenem aminoglycoside severe infection vital sign stable 19
antibiotics organism perianal abcess piperacillin/ tazobactam
gram negative anaerobic pathogens gram positive pathogens
vancomycin antibiotics catheters methicillin resistant
Staphylococcus aureus (MRSA) enterococcus
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species Elting et al antibiotics FN 5-7 20 catheter S. aureus
coagulase-negative staphylococci catheter catheter Bacillus
species, C. jeikeium, P. aeruginosa, Stenotrophomonas maltophilia,
Acinetobacter species., Candida species. atypical mycobacterium19
antibiotic antifungal drugs febrile neutropenia algorithm chart
serum GM 2 / febrile neutropenia early detection of aspergillus
infection serial determination of serum GM aspergillus infection
amphotericin B dose 1-1.5 mg/kg/d liposomal amphotericin B dose 3-5
mg/kg/d voriconazole amphotericin B caspofungin intravenous
itraconazole refractory intolerant of initial therapy New
antifungal drugs: 1. voriconazole potent second generation triazole
derivative of fluconazole Aspergillosis, Candida species, C.
neoformans,P. marneffii, Scedosporium prolificans, B. dermatitidis,
H. capsulatum, many dematiaceous fungi voriconazole brain lesion
intravenous dose 6 mg/kg q12 h x 2 doses then 4 mg/kg q 12 h oral
dose 40 kg :400 mg q12 h x 2 doses then 200 mg q12 h < 40 kg
:200 mg q12 h x 2 doses then 100 mg q12 h21,22 2. Posaconazole
derivative of itraconazole aspergillosis, Candida species,
Scedosporium prolificans, Bipolaris zygomycetes some activity
against Fusarium species. voriconazole22,23.
antibiotics antigungal drug febrile neutropenia bacteremia
source of infection antibiotics 24-48 . out of neutropenia CBC, out
of neutropenia ANC 1,000-1,500/L3 3 bacteremia antibiotics 14 ATB
intravenous route oral route sensitivity out of neutropenia
antifungal drug out of neutropenia site of fungal infection site of
fungal infection candida 2 amphotericin B fluconazole
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fluconazole resistance aspergillus infection amphotericin B
1,000 mg itraconazole solution (dose: 200 . 2 ) voriconazole
continue voriconaole oral form lesion itraconazole solution febrile
nutropenia febrile neutropenia low risk 2 quinolone
amoxicillin/clavulanate, clindanycin macrolide monotherapy
gatifloxacin moxifloxacin septic work up antibiotic 24 (supportive
treatment) febrile neutropenia 1. (G-CSF) hematological non
hematological malignancies febrile neutropenia (FN) G-CSF febrile
neutropenia G-CSF first diagnosis of acute myeloid leukemia(AML) 2
recovery G-CSF AML complete remission FN G-CSF FN 2. (blood
chemistry) electrolyte imbalance, BUN/Cr amphotericin B sepsis,
hypokalemia hypomagnesemia amphotericin B metabolic acidosis sepsis
liver function test 3. adequate hydration hydration FN acute renal
failure 4. blood components FN Hb 8.5 g/dl platelet count 10,000-
20,000/L primary prophylaxis malignancies G-CSF primary prophylaxis
hemetologic malignancies non hodgkins lymphoma, hodgkins lymphoma
acute lymphoblastic leukemia (ALL) NHL HD G-CSF chemotherapy
regimen 20% ESHAP, ICE Hyper CVAD regimen 60 , hypoalbuminemia,
renal failure,
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extensive marrow involvement , high LDH cardiac dysfunction
G-CSFALL
febrile neutropenia
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antibiotics 3
- CBC - H/C (peripheral line) 2 specimens - central line (H/C
central line) 2 specimens - UA, U/C, CXR
- abcess pus gram stain & culture - white patch KOH - zanck
smear
* * pattern
* pattern
antibiotics
antibiotics
antibiotics
* pattern
- antibiotics - evidence aspergillosis amphotericin-B
(dose:0.5-0.7 mg/kg/d)
- antibiotics - evidence aspergillosis amphotericin-B
(dose:0.5-0.7 mg/kg/d)
- antibiotics
- evidence aspergillosis amphotericin-B (dose:0.5-0.7
mg/kg/d)
- evidence aspergillosis amphotericin-B (dose: 1-1.5
mg/kg/d)
antibiotics 5
- CBC - H/C (peripheral line) 2 specimens - central line (H/C
central line) 2 specimens - UA, U/C, CXR
-
- abcess pus gram stain & culture - white patch KOH - zanck
smear
* * pattern
antibiotics 10 : 3-5 antibiotics amphotericin-B (dose: 1-1.5
mg/kg/d)
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1 Altered host defenses and associated pathogens in
immunocompromised patients with cancer Granulocytopenia
Gram-negative bacilli: P. aeruginosa, K. pneumoniae, E. coli,
Entero-bacter Gram-positive cocci: S. aureus, S. epidermidis, group
D streptococci, -hemolytic streptococci Gram-positive bacilli:
Bacillus species, Clostridium species Fungi: Aspergillus species,
Zygomycetes, Fusarium species, Trichosporon beigelii, Candida
Cellular (T-lymphocyte) immune defects Bacteria : Mycobacterium ,
Nocardia asteroides, legionella , listeria monocytogenes,
Salmonella Viruses : Cytomegalovirus, varicella-zoster virus,
herpes simplex virus, Epstein-Barr virus Protozoa : Pneumocystis
carinii, Toxoplasma gondii Fungi : Cryptococcus neoformans,
histoplasma copsulatum, Coccidioides immitis Helminths :
Strongyloides stercoralis Humoral (B-lymphocyte) immune deficiency
: Bacteria : S. pneumoniae, H. influenzae Impaired tracheobronchial
clearance: Bacteria and fungi colonizing the lower respiratory
tract Invasive procedures : Mechanical disruption of epithelial
barriers: Bacteria and fungi colonizing the respiratory tract and
skin Altered neurologic function ; Bacteria and fungi colonizing
the oropharynx and upper respiratory tract
2 Risk groups in febrile neutropenic patients. Risk Group
Patient Characteristic
High-risk Severe (ANC < 100) and prolonged (> 14d)
neutropenia. Hematological malignancy; allogeneic bone marrow/stem
cell transplantation; significant medical co-morbidity or poor
performance status; presentation with shock, complex infection
(e.g. pneumonia, meningitis)
Intermediate (moderate) risk
Solid tumors intensive chemotherapy autologous hematopoetic stem
cell transplantation. Moderate duration of neutropenia (7-14 days).
Minimal medical comorbidity. Clinical/hemodynamic stability.
Low-risk Solid tumors conventional chemotherapy. No comorbidity.
Short duration of neutropenia ( 7 days). Clinical and hemodynamic
stability. Unexplained fever (FUO) or simple infection (eg. UTI,
simple cellulitis).
References 1. Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk
EJ, et.al. Prolonged granulocytopenia: the major risk factor for
invasive pulmonary aspergillosis in patients with acute leukemia.
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et al. Chronic neutropenia.Medicine. 1979;58:128-44 . 3. Bodey GP,
Buckley M, Sathe YS, Freireich EJ. Quantitative relationships
between circulating leukocytes and infection in patients with acute
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Bodey GP, et al. 1997 guidelines for the use of antimicrobial
agents in neutropenic patients with unexplained fever: guidelines
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7. Almudena Alhambra, M Soledad Cutara, M Cruz Oritz,
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piperacillin-tazobactam. Rev Iberoam Micol, 2007;24: 106-112. 8.
Zinner SH. Changing Epidemiology of infections in patients
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species in patients with cancer who are receiving chemotherapy.
Clin Infect Dis., 1994;19(Suppl):49-53. 15. James Ito, Infectious
complications.Cancer management: A multidisciplinary approach,
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Bowden RA.Epidemiology of Aspergillus infections in a large cohort
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Patterson TF, Kirkpatrick WR, White M, et al. Invasive
aspergillosis disease spectrum, treatment practices, and outcomes.
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Elting LS, Rubenstein EB, Rolston K, et al. Time to clinical
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activity of voriconazole, itraconazole and amphotericin B against
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