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Leukemia Research 34 (2010) 294–300

Contents lists available at ScienceDirect

Leukemia Research

journa l homepage: www.e lsev ier .com/ locate / leukres

he suggestion of a risk stratification system for febrile neutropenia in patientsith hematologic disease

ong Parka, Dae Sik Kima, Seh Jong Parka, Hee Yun Seoa, Se Ryeon Leea, Hwa Jung Sunga,yong Hwa Parka, In Keun Choia, Seok Jin Kimb, Sang Cheul Oha, Jae Hong Seoa, Chul Won Choia,yung Soo Kima,∗, Sang Won Shina, Yeul Hong Kima, Jun Suk Kima

Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of KoreaDivision of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

r t i c l e i n f o

rticle history:eceived 5 April 2009eceived in revised form 3 August 2009ccepted 17 August 2009vailable online 16 September 2009

a b s t r a c t

We analyzed the prognostic factors from 259 cases of febrile neutropenia occurring in 137 patientswith hematologic disease. Based on multivariate analysis, significant prognostic factors are recovery ofneutropenia, respiratory infection, baseline serum albumin, baseline bicarbonate, baseline CRP, and CRPon the fifth day after antibiotic treatment. From these variables, we derived a predictive model for theprognosis of febrile neutropenia using baseline serum albumin, bicarbonate, and CRP, which could be

eywords:ebrile neutropeniarognosisematologic malignancylbuminicarbonate

easily checked before chemotherapy. Further studies in prospective setting are needed for the validationof this model.

© 2009 Published by Elsevier Ltd.

-reactive protein

. Introduction

Febrile neutropenia is one of the most serious hematologicoxicities seen in cancer patients receiving chemotherapy. Febrileeutropenia is sometimes life-threatening, and immediate admin-

stration of empiric, broad-spectrum antibiotics is required. Therere many guidelines for antibiotic therapy, including those issuedy the Infectious Diseases Society of America (IDSA) in the USA.hese guidelines are designed to optimize the management ofebrile neutropenia [1]. However, the mortality rate associated withebrile neutropenia is still high.

Not all patients with febrile neutropenia have the same risk andhould be classified according to risk level [2–4]. Over the pastecade, subsets of patients with febrile neutropenia have been

dentified who were at low-risk for the development of compli-ations, including mortality [4,5]. In the interest of reducing costnd hospitalization, the feasibility of new treatment approachesas been addressed in low-risk patients, such as outpatient ther-

∗ Corresponding author at: Division of Hematology and Oncology, Departmentf Internal Medicine, Korea University Medical Center, 126-1, Anamdong 5-ga,eongbuk-ku, Seoul, 136-705, Korea. Tel.: +82 2 920 5488; fax: +82 2 920 6520.

E-mail address: kbs0309@korea.ac.kr (B.S. Kim).

145-2126/$ – see front matter © 2009 Published by Elsevier Ltd.oi:10.1016/j.leukres.2009.08.024

apy for the entire febrile episode after early discharge from thehospital. Outpatient therapy consists of a parenteral, sequen-tial (intravenous followed by oral), or oral antibiotic regimen[6–8].

The Multinational Association for Supportive Care in Cancer(MASCC) risk index has been widely used as a risk stratifica-tion model for febrile neutropenia in cancer patients. This systemaccounts for age, burden of illness, absence of hypotension, absenceof dehydration, absence of underlying pulmonary disease, historyof fungal infection, outpatient status, and type of tumor [4]. TheMASCC model was developed mainly from patients with solid organtumors, and its primary purpose was to identify low-risk patientswith febrile neutropenia. However, the progression of infection isusually more rapid and critical in patients receiving treatment forhematologic disease than it is in patients with solid tumors. There-fore, it may be more valuable to identify the high-risk group amongthe febrile neutropenic patients, rather than to identify the low-riskgroup. Because of this special feature of patients with hematologicdisease, a risk stratification model based only on patients with

hematologic disease should be developed. However, there havebeen few attempts to derive a predictive model in this way.

For such a predictive model to be useful in clinical practice, clin-icians must be able to check its components easily before febrileneutropenia develops. If a model is developed successfully, it will

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Y. Park and D.S. Kim et al. / Leu

ecrease the morbidity and mortality associated with chemother-py and it will improve outcomes in high-risk patients througharlier, more intensive treatment. This study was designed to iden-ify the prognostic factors of febrile neutropenia in patients withematologic disease and to derive a risk stratification model fromatients with hematologic disease only.

. Materials and methods

We retrospectively analyzed 259 episodes of febrile neutropenia that occurredn 137 patients treated with chemotherapy and stem cell transplantation for theirematologic disease between January 2006 and July 2008 at the Korea Univer-ity Medical Center, Anam Hospital. Patients who were eligible for this studyncluded those who were diagnosed with acute or chronic leukemia, Hodgkin oron-Hodgkin lymphoma, myelodysplastic syndrome, multiple myeloma, or aplas-

ic anemia. Table 1 shows the baseline characteristics of enrolled patients. Thoseho had not received chemotherapy were excluded from this study. Subsequent

pisodes of febrile neutropenia in the same patient were included as separate febrileeutropenia episodes.

Chest radiography, complete blood count, blood urea nitrogen (BUN), creatinine,ST, ALT, bilirubin, albumin, bicarbonate, erythrocyte sedimentation rate (ESR),

able 1aseline patient characteristics.

Patient characteristics No. (N = 259) Rate (%)

Age≥60 78 30.1%<60 181 69.9%

SexMale 139 53.7%Female 120 46.3%

Underlying diseaseLeukemia 141 54.4%Lymphoma 81 31.3%Othersa 37 14.3%

ComorbidityDiabetes 43 16.6%Hypertension 38 14.7%Renal disease 13 5%Liver disease 18 6.9%

Location of fever onsetOutpatient 61 23.6%General ward 83 32%Aseptic room 91 35.1%Isolation room 18 6.9%Intensive care unit 6 2.3%

Pattern of feverHospitalized patients

Early onset (≤3daysb) 92 35.5%Late onset (>3daysb) 114 44%

Outpatient 53 20.5%

Duration of fever≤3 days 88 34%>3 days, ≤7 days 65 25.1%>7 days 106 40.9%

ANCc at fever onset>100 cells/mm3 95 36.7%≤100 cells/mm3 164 63.3%

Duration of neutropenia≤7 days 71 27.4%>7 days, ≤14 days 70 27%>14 days 118 45.6%

Recovery of neutropeniaYes 206 79.5%No 53 20.5%

History of neutropeniaYes 187 72.2%No 72 27.8%

a Others included multiple myeloma, myelodysplastic syndrome, and aplastic anemia.b From onset of neutropeniac ANC: Absolute neutrophil count

Research 34 (2010) 294–300 295

C-reactive protein (CRP), PT, and complete urinalysis were assessed prior to theimplementation of chemotherapy and on the fifth day of chemotherapy. If a feverdeveloped after chemotherapy, all patients were evaluated by physical examination,at least two blood cultures, urine culture and, if appropriate, cultures from othersuspected body sites. Additional blood cultures were done if the patient’s fever wassustained.

Patients with febrile neutropenia were immediately treated with broad-spectrum antibiotics following Infectious Diseases Society of America (IDSA)guidelines. If the fever persisted after 3 days of antibiotic therapy, glycopeptides(vancomycin or teicoplanin) against MRSA were added. The use of anti-fungal agentsdepended on the clinical course. All patients were given granulocyte colony stimu-lating factor according to indications. This study was approved by the InstitutionalReview Board of the Korea University, Anam Hospital.

2.1. Definitions

Fever was defined as a single oral temperature of 38.3 ◦C (101 ◦C) or a temper-ature of 38.0 ◦C (100.4 ◦C) for 1 h. Neutropenia was defined as a neutrophil count of<500 cells/mm3 or a neutrophil count of <1000 cells/mm3 with a predicted decreaseto <500 cells/mm3.

Febrile neutropenia episodes were classified into one of three groups: (1)microbiologically documented infection (MDI); (2) clinically documented infection

OR 95% C.I. p

0.0012.67 1.507–4.731

0.077

0.606 0.348–1.058

0.0100.452 0.259–0.786 0.0051.478 0.834–2.619 0.1822.259 1.102–4.628 0.029

1.006 0.485–2.088 0.9862.443 1.203–4.962 0.0122.338 0.758–7.210 0.1302.825 1.074–7.435 0.029

<0.00012.970 1.622–5.437 <0.00010.626 0.339–1.154 0.1400.521 0.283–0.957 0.0420.499 0.140–1.776 0.41413.881 1.593–120.98 0.007

<0.0001

1.440 0.940–1.313 0.2460.316 0.172–0.579 <0.00012.742 1.451–5.115 0.003

<0.00010.195 0.092–0.416 <0.00011.473 0.804–2.702 0.2632.482 1.425–4.325 0.002

0.301

0.746 0.427–1.302

0.9700.931 0.504–1.720 0.8771.054 0.573–1.937 0.8771.015 0.588–1.752 1.000

<0.0001

26.245 11.884–57.958

0.0640.577 0.322–1.036

2 kemia Research 34 (2010) 294–300

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Table 2Univariate analysis of infection type, site, and culture results.

No.(N = 259)

Rate (%) OR 95% C.I. p

Infection typeMDIa 95 36.7% 2.765 1.580–4.837 <0.0001CDIb 57 22% 1.911 1.026–3.558 0.045FUOc 107 41.3% 0.171 0.085–0.345 <0.0001

Infection siteOral cavity 12 4.6% 0.506 0.108–2.367 0.378Respiratory tract 69 26.6% 7.510 4.058–13.90 <0.0001Catheter related 22 8.5% 0.972 0.365–2.590 0.954GI tract 20 7.7% 1.823 0.713–4.663 0.205Urinary tract 15 5.8% 0.382 0.084–1.739 0.198Skin & soft tissue 12 4.6% 0.225 0.029–1.778 0.123

Culture resultGram-positive 29 30.2% 0.808 0.329–1.982 0.826Gram-negative 50 52% 1.804 0.941–3.458 0.081Fungus 5 5.2% 10.941 1.202–99.621 0.022Virus 5 5.2% 1.752 0.287–10.710 0.62

a MDI: microbiologically documented infection.b CDI: clinically documented infection without microbiological evidence, defined

as the presence of physical or radiological findings compatible with an underlying

glycopeptide was similar between the complicated group and thenon-complicated group (4.46 days and 4.20 days, respectively,p = 0.497), and there was no significant difference between thetwo groups with respect to the median time to the addition of

Table 3Univariate analysis of time of additional antibiotic administration in patients withfebrile neutropenia, who were initially treated with broad-spectrum antibiotics.

96 Y. Park and D.S. Kim et al. / Leu

ithout microbiological evidence (CDI) (defined as the presence of physical or radi-logical findings compatible with an underlying infection, including pneumonia,kin and soft tissue infections, and sepsis syndrome, but without any microbiologi-al evidence); and (3) fever of unknown origin (FUO) (without a clinically suspectedite of infection or a microbiologically documented cause of infection).

‘Serious complications’ was defined as hypotension (systolic blood pressure90 mmHg), respiratory failure (arterial oxygen pressure <60 mmHg in room airr the need for mechanical ventilation), altered mental status, congestive heart fail-re, uncontrolled arrhythmia, hepatic or renal failure requiring treatment, severeleeding requiring transfusion, intensive care unit admission, and death. Patientsere classified into either the “complicated group” or the “non-complicated group”

ccording whether serious complications developed.

.2. Evaluation of prognostic risk factors

The risk factors for serious complications of febrile neutropenia were investi-ated by comparing the non-complicated group with the complicated group. Theollowing factors were assessed for their prognostic value in febrile neutropenia:ge, sex, underlying disease, co-morbidities, location of fever onset (i.e., outpatient,eneral ward, etc.), time between neutropenia onset and fever onset, duration ofever, duration of neutropenia, severity of neutropenia, previous history of febrileeutropenic episode, recovery of neutropenia, and blood tests before chemother-py and on the fifth day of chemotherapy. These blood tests included hemoglobin,BC count, platelet count, BUN, creatinine, electrolytes, AST, ALT, bilirubin, albu-in, bicarbonate, PT, ESR, and CRP. To estimate the response to antibiotic therapy,follow-up CRP level was checked after five days of antibiotic therapy. We also

etermined the relationship between prognosis and the microbiological state, typef infection, culture result, and antibiotic and antifungal administration times.

.3. Statistical analysis

Data analysis was performed using the Statistical Package for Social SciencesSPSS) version 13.0. For univariate analysis, the chi square test or the Fisher exactest was used, and the odds ratio and level of significance were calculated. To deter-

ine the cutoff level of each variable, we used the receiver operating characteristicROC) curve of each variable versus the absence or presence of serious complica-ions. The best point on the ROC curve, satisfying both the highest sensitivity andpecificity for the presence of serious complications, was determined as the cut-ff value of each variable. The variables significantly associated with prognosis ofebrile neutropenia based on univariate analysis were further analyzed using multi-ariate logistic regression analysis. Statistical significance was assigned to two-sidedvalues less than 0.05.

. Results

.1. Patient characteristics

We evaluated 259 cases of febrile neutropenia occurring in37 patients with hematologic disorders. Baseline characteristicsre summarized in Table 1. The median patient age was 48 yearsrange 14–85 years), and the male to female ratio was 1.16:1139 male patients, 120 female patients). There were 141 cases54.4%) of leukemia and 81 cases (31.3%) of lymphoma; otherases included multiple myeloma, myelodysplastic syndrome, andplastic anemia. All patients were treated with chemotherapy,nd some patients received stem cell transplantation. In the uni-ariate analysis, age and underlying hematologic disease wereignificantly associated with serious complications (p = 0.001 and= 0.010, respectively), but sex was not associated with seriousomplications (p = 0.077). Co-morbidities, such as hypertension andiver disease were significantly associated with serious complica-ions of febrile neutropenia (OR = 2.443, p = 0.012, and OR = 2.825,= 0.029, respectively). There was mortality in 61 cases (24%). The

eading causes of death were septic shock with multiorgan failure21 cases) and respiratory failure (9 cases). Only two patients diedue to disease progression.

The median neutropenia duration was 17 days, and the medianever duration was 10 days. The median time lag with the onset

f fever and neutropenia was 4.3 days. The fever onset time waslassified as “early” or “late” in hospitalized patients based on autoff of 3 days after the onset of neutropenia. The development ofever outside the hospital was significantly associated with seriousomplications (OR = 2.742, p = 0.003). In hospitalized patients, the

infection, but without any microbiological proof; including pneumonia, skin andsoft tissue infections, and sepsis syndrome.

c FUO: fever of unknown origin without a clinically suspected site of infection ora microbiologically documented cause of infection.

late onset of fever showed a significant relationship with favorableoutcome (OR 0.316, p < 0.0001). Fever duration and recovery fromneutropenia were significantly associated with mortality. However,characteristics such as the neutrophil count at the onset of febrileneutropenia, duration of neutropenia, and history of neutropeniafailed to show a significant relationship with serious complications.

3.2. Microbiological state

Of the 259 episodes, 95 (36.7%) were MDI, 57 (22%) were CDI,and 107 (41.3%) were FUO. The most common focus of infectionwas the respiratory tract (69 episodes, 26.6%), and second mostcommon focus was a catheter (22 episodes, 8.5%) (Table 2).

Gram-negative bacteria were isolated in 50 episodes, withEscherichia coli being the most common. Gram-positive bacteriawere isolated in 29 episodes, with Staphylococcus aureus beingthe most common. On univariate analysis, MDI cases were moreassociated with serious complications than cases with no iso-lated pathogen were. Respiratory tract infections, Gram-negativeinfections, fungal infections, and polymicrobial infections were sig-nificantly associated with mortality.

The most common initial antibiotic choice was cefepime, whichwas administered in 142 episodes (55%). If fever was sustained3 days after the initial antibiotic treatment, a glycopeptide wasadded. If a fungal infection was suspected, an antifungal treat-ment was considered. The median time to the addition of a

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Glycopeptide 4.46a 4.20a 0.497Antifungal agent 6.37a 6.38a 0.878

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ntifungal agents (6.38 days and 6.37 days, respectively, p = 0.087)Table 3).

.3. Laboratory results

We evaluated blood tests just prior to chemotherapy as aredictive marker of serious complications and on the fifth dayfter the initiation of chemotherapy. Univariate analysis showedhat the risk of serious complications was significantly associatedith some blood test variables before chemotherapy. These vari-

bles included hemoglobin (< 8 g/dL), platelet count (<50,000/�L),UN (≥20 mg/dL), creatinine (≥1.0 mg/dL), AST (≥40 IU/L), albumin<3.3 g/dL), sodium (<135 mmol/L), ESR (≥20 mm/h), bicarbonate<21 mmol/L), PT (≥14.4 s), and CRP (≥20 mg/L) (Table 4). High CRPn the fifth day after the commencement after antibiotic treatmentcutoff: ≥100 mg/L) was also significantly associated with seri-us complications. However, the neutrophil count and lymphocyteount before chemotherapy and on the fifth day of chemotherapyad no association with serious complications.

.4. Multivariate analysis

Multivariate analysis was performed with the variables thathowed statistical significance in the univariate analysis. Theseariables included age, underlying hematologic disease, co-orbidities, location of fever onset (i.e., outpatient, general ward,

tc.), time of fever onset, recovery from neutropenia, infection type,espiratory infection status, and culture results. Significant pre-hemotherapy blood test results (e.g., hemoglobin, platelet count,UN, creatinine, AST, albumin, ESR, bicarbonate, sodium, PT, CRP)ere also included, as were CRP measurements obtained on thefth day after antibiotic treatment. Multivariate analysis showedhat independent prognostic factors included recovery from neu-ropenia, respiratory infection, baseline serum albumin, baselineicarbonate, baseline CRP, and CRP on the fifth day after antibioticreatment. Table 5 shows the results of multivariate analysis withhe odds ratios (ORs) and their confidence intervals (95% C.I.s).

.5. Derivation of risk stratification system

To predict the outcome of patients with febrile neutropenia asarly as possible, we developed a predictive scoring model with fac-ors selected through multivariate analysis. Among the prognosticactors determined through multivariate analysis, baseline serumlbumin, serum bicarbonate, and CRP were easily detectable at thearliest time point and were measurable objectively. Therefore, wesed these variables to construct a predictive model for prognosis.ur scoring model gave one point to each of the following fac-

ors: low pretreatment albumin level (<3.3 g/dL), low pretreatmenticarbonate (<21 mmol/L), and high pretreatment CRP (≥20 mg/L).he final score was obtained by summing the points (maximumotal score of 3). This model was applied to the complicated groupnd the rate of serious complications was 100% in patients with acore of 3, while it was 6% in patients with a score of 0. The rate oferious complications increased according to the increase in scoreTable 6).

. Discussion

In this study, serious complications, including death, occurredn 72 cases (28%) and the mortality rate was 24%. Sepsis and

espiratory failure were the most common causes of death. Res-iratory tract infection was the most common site of infection26.6%) and was a good predictor of poor outcome based on

ultivariate analysis (OR = 3.52, p = 0.024). These findings wereonsistent with previous studies [9–11]. We also observed that

Research 34 (2010) 294–300 297

the incidence of Gram-positive bacteremia was lower than thatof Gram-negative bacteremia (30.2% and 52%, respectively). Overthe last decade, a shift has occurred from Gram-negative organ-isms to Gram-positive organisms as the causative pathogens offebrile neutropenia [9,12,13]. This shift can be explained by thedevelopment of potent antibiotics for Gram-negative organisms[12]. However, some recent studies have reported the reemergenceof Gram-negative organisms as the predominant pathogen, whichmay be due to the increased use of more intensive chemotherapyregimens and the decreased use of quinolone prophylaxis [14,15].Our results also reflect this phenomenon. In this study, MDI, Gram-negative infections, and polymicrobial infections were significantlyassociated with serious complications based on univariate analy-sis. This was consistent with previous studies [16–18]. However,these variables were not statistically significant based on multivari-ate analysis. This difference is explained partially by the fact thatthe number of patients infected with polymicrobial organisms wasrelatively small and fluoroquinolone prophylaxis was not routinelyused.

Neutrophil count and the duration of neutropenia are gener-ally thought to be related to infection susceptibility and prognosis.The resolution and duration of neutropenia have been suggestedas prognostic factors in febrile neutropenia [9]. In this study,although the duration of neutropenia and neutrophil count didnot differ significantly between complicated patients and non-complicated patients, recovery from neutropenia was shown tobe the most significant factor for survival (OR = 17.31, p < 0.0001).Though neutrophil count and duration of neutropenia carry clinicalsignificance, these variables are considered not to be universal pre-dictive markers for predicting the prognosis of febrile neutropenia,based on our results.

In this study, a low level of pretreatment serum albu-min (<3.3 g/dL) was a significant prognostic marker for seriouscomplications in febrile neutropenia (OR = 4.027, p = 0.022). Thepretreatment albumin level is the net result of numerous path-ways involved in albumin synthesis and catabolism. It not onlyreflects the status of patients but also influences the status ofpatients. Because the serum albumin level reflects general nutri-tional status, low serum albumin was reported to be associatedwith mortality in patients with septicemia [19,20]. Pretreatmentserum albumin in chemotherapy patients may reflect previous tox-icity of chemotherapy. Chemotherapy itself can cause capillaryendothelial damage [21] which may increase the transcapillaryescape rate of albumin and contribute to low pretreatment hypoal-buminemia. Chemotherapy-induced mucositis and nephrotoxicitycan also cause loss of serum albumin and pretreatment hypoal-buminemia might reflect these toxicities [22,23]. The significanceof the serum albumin level has also been emphasized in develop-ment of febrile neutropenia during chemotherapy [11,24]. Someinvestigators have suggested that decreased serum albumin canincrease the toxicity of anticancer agents which are characterizedby high plasma protein binding [25]. Moreover, the administrationof antineoplastic agents results high oxidative stress [26]. Becausealbumin is a significant antioxidant in blood and extracellular flu-ids [27], low pretreatment serum albumin level can increase thechemotherapy toxicities. Therefore, hypoalbuminemia can influ-ence the function of normal tissues, including the immune system,during cytotoxic chemotherapy and increase susceptibility to seri-ous complications of febrile neutropenia.

Metabolic acidosis in patients with severe infection correlatedwith poor prognosis in several studies [10,28]. Lactic acidosis occur-

ring with severe infection may reflect circulatory collapse andtissue hypoxia and is, therefore, correlated with poor prognosis[28]. In patients with hematologic malignancies, lactic acidosiscan occasionally develop as a paraneoplastic syndrome, which alsoreflected the poor prognosis [29]. The current study showed that

298 Y. Park and D.S. Kim et al. / Leukemia Research 34 (2010) 294–300

Table 4Univariate analysis of pretreatment blood tests and CRP on 5th day from onset of fevera.

Patient characteristics No. (N = 259) Rate (%) OR 95% C.I. p

Hemoglobin<8 g/dL 58 22.9% 2.525 1.362–4.682 0.003≥8 g/dL 195 77.1%

Platelet count<50,000/�L 94 37.2% 3.779 2.124–6.723 <0.0001≥50,000/�L 159 62.8%

Neutrophil count<1000 cells/mm3 66 26.9% 1.702 0.930–3.115 0.083≥1000 cells/mm3 179 73.1%

Lymphocyte count<1000 cells/mm3 117 48.1% 1.359 0.777–2.377 0.282≥1000 cells/mm3 126 51.9%

Blast on PBb smearYes 72 29.8% 1.389 0.765–2.523 0.280No 170 70.2%

Serum BUNc

≥20 mg/dL 26 10.3% 5.096 2.184–11.890 <0.0001<20 mg/dL 226 89.7%

Serum creatinine≥1.0 mg/dL 69 27.4% 1.910 1.055–3.457 0.031<1.0 mg/dL 183 72.6%

ASTd

≥40 IU/L 47 18.7% 3.222 1.668–6.222 <0.0001<40 IU/L 205 81.3%

ALTe

≥40 IU/L 66 26.2% 1.438 0.783–2.641 0.241<40 IU/L 186 73.8%

Serum bilirubin≥1.0 mg/dL 39 15.5% 4.449 2.187–9.047 <0.0001<1.0 mg/dL 213 84.5%

Serum albumin<3.3 g/dL 52 20.7% 19.54 9.177–41.607 <0.0001≥3.3 g/dL 199 79.3%

Serum sodium<135 mmol/L 44 17.5% 3.333 1.700–6.535 <0.0001≥135 mmol/L 208 82.5%

Serum potassium<3.5 mmol/L 37 14.7% 1.728 0.832–3.589 0.139≥3.5 mmol/L 215 85.3%

Serum bicarbonate<21 mmol/L 56 22.5% 4.896 2.599–9.224 <0.0001≥21 mmol/L 193 77.5%

PTf

<12.3 s 94 37.8% 0.568 0.312–1.032 0.081≥12.3 s, <14.4 s 120 48.2% 1.021 0.588–1.775 1.000≥14.4 s 35 14.1% 2.495 1.199–5.194 0.016

ESRg

≥20 mm/h 132 52.6% 1.788 1.016–3.149 0.043<20 mm/h 119 47.4%

CRPh

≥20 mg/L 103 41.4% 7.251 3.875–13.567 <0.0001<20 mg/L 146 58.6%

Fifth day CRPi

≥100 mg/L 94 37.8% 23.361 10.882–50.149 <0.0001<100 mg/L 155 62.2%

a The cutoff level of each variables was determined by using receiver operating characteristic curve of each variables versus the absence or presence of a seriouscomplications.

b PB: peripheral blood.c BUN: blood urea nitrogen.d AST: aspartate aminotransferase.e ALT: alanine aminotransferase.f PT: prothrombin time.g ESR: erythrocyte sediment rate.h CRP: C-reactive protein.i Fifth day CRP: CRP on fifth day after initiation of antibiotic treatment.

Y. Park and D.S. Kim et al. / Leukemia Research 34 (2010) 294–300 299

Table 5Prognostic factors showing significance in multivariate analysis.

Variables OR 95% C.I. p

Recovery of neutropenia 17.310 5.298–56.557 <0.001Low serum albumin level (<3.3 g/dL) 4.027 1.223–13.267 0.022Low serum bicarbonate level (<21 mmol/L) 3.344 1.148–9.744 0.027High CRP (≥20 mg/L)a 3.556 1.286–9.838 0.015High CRP on fifth day of treatment (≥100 mg/L)b 11.224 4.076–30.904 <0.001

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he low pretreatment serum bicarbonate level (<21 mmol/L) hadignificant prognostic value in patients with febrile neutropeniaOR = 3.344, p = 0.027). We could not accurately analyze the rolef acidosis in this setting because we could determine the causesf acidosis in only a few sample patients due to an incompletevaluation at that time. Because patients in this study had no res-iratory co-morbidities (Table 1), most patients are considered toave a metabolic cause for low bicarbonate level. Metabolic acido-is might be related to some clinical features in patients under thective chemotherapy. First, high anion gap metabolic acidosis (e.g.,actic acidosis and uric acidosis) may be correlated with the bur-en of illness [29,30]. Second, normal anion gap metabolic acidosisight reflect the nephrotoxic effect of previous chemotherapy.

ommonly used drugs such as cisplatin, ifosfamide, methotrex-te can induce renal tubular damage which can lead to normalnion gap metabolic acidosis [31–33]. A possible mechanism forncreased toxicity in acidic body fluid can be explained in phar-

acokinetic point of view. Because cytotoxic drugs commonlysed in hematologic disease are weak acids or become weak acidshen they are mixed with distilled water before injection, theserugs tend to exist in uncharged forms in acidic conditions, mak-

ng them more lipid-soluble. Therefore, more cytotoxic agents caniffuse into the cell in acidic body fluid, which might contribute toome serious complications of febrile neutropenia. This may occurith drugs which are commonly used in treating patients withematologic malignancies, including cyclophosphamide, doxoru-icin, methotrexate, epirubicin, etoposide, ifosfamide, cytarabine,isplatin, dacarbazine, melphalan, idarubicin, and busulfan. To ournowledge, this is the first report addressing the prognostic value ofaseline serum bicarbonate in febrile neutropenia occurring duringhemotherapy.

It should be emphasized that serum albumin and bicarbonateevels before chemotherapy are correctable. Further study will beecessary to determine whether correction of low serum albuminnd bicarbonate can modify the severity of febrile neutropenia inatients with hematologic disease.

The serum CRP level during febrile neutropenia has been associ-

ted with prognosis in several studies, even though controversy stillxists [34–36]. Specifically, the CRP level on the fifth day of antibi-tic treatment has been reported to be an independent prognosticactor for poor outcome in neutropenic patients [34]. However, it

able 6redictive scoring model using pretreatment serum albumin, bicarbonate, and CRPevel.

Scorea Patients Complication (%) Death Mortality

0 117 7 (6.0) 3 3.4%1 71 21 (30) 12 16.2%2 43 24 (55.8) 24 40.7%3 18 18 (100) 20 69.0%

a Score in this model was calculated by the number of each prognostic factor usedn this model. For example, if a patient has low serum albumin (<3.3 g/dL), low serumicarbonate (<21 mmol/L), and High CRP (≥20 mg/L) before chemotherapy, the scoref this patient is 3. Patients with score ≥2 could be considered as high-risk group.

1.120–9.072 0.030

was the serum CRP level after fever onset that was investigated inthose studies. In this study, the serum CRP level before chemother-apy, which was measured in afebrile state, was shown to haveprognostic value in febrile neutropenia. Elevated baseline CRP wasreported to have prognostic significance in various kinds of cancer[37–40]. In non-Hodgkin’s lymphoma patients, the elevated CRPreflects the burden of illness because IL-6, which enhances the syn-thesis of acute phase reactants including CRP, is secreted by tumors[41,42]. The burden of illness was also reported to have prognosticsignificance in MASCC risk index, although it was crudely evaluatedby the degree of symptoms [4]. From this point of view, baselineCRP is considered to correlate with prognosis in febrile neutrope-nia, which is compatible with the results of this study. Moreover,there is evidence that inflammatory cytokines, including CRP, caninfluence hepatic metabolism of anticancer drug and reduce drugclearance in patients with cancer [25]. Elevated pretreatment CRPwas also suggested as a predictor of worse outcome after reduced-intensity allogeneic hematopoietic cell transplantation [43]. Thus,high CRP may contribute to the toxicity of chemotherapy suchas febrile neutropenia. The baseline CRP level is more practicalthan the febrile CRP level in identifying the high-risk group andimplementing more intensive treatments at an earlier time. Weinvestigated ESR, another inflammatory marker, as a predictive fac-tor but could not find any prognostic significance. However, weconsider that other inflammatory cytokines, such as IL-6, IL-8, andTNF�, may have a role in the outcome of febrile neutropenia andfurther study is required.

In cases of severe infection, rapid and intensive management iscritical. There is a great need for efficient, early detection meth-ods to identify high-risk febrile neutropenia patients. Although theMultinational Association for Supportive Care in Cancer (MASCC)risk index is most frequently used to stratify patients, it is focusedon the detection of low-risk febrile neutropenic cancer patients.No generally accepted predictive model for high-risk febrile neu-tropenic patients, especially with hematologic malignancies, hasbeen developed. Therefore, identification of high-risk patientswith hematologic disease could be more beneficial. We made ahypothesis that differences in medical health before chemotherapycontribute to outcome differences in patients with febrile neu-tropenia. Thus we focused on baseline blood tests which wereobjectively and easily checkable as the candidates of prognosticfactors and constructed a scoring system using baseline albumin,bicarbonate, and CRP based on multivariate analysis (Table 6). Sim-ilar attempts have been made to stratify risk in patients with febrileneutropenia. Possible prognostic variables include the lymphocytecount on the fifth day of chemotherapy, the serum procalcitonin atthe time of fever onset, and the baseline serum mannose-bindinglectin level [14,24,35,44–46]. However, in these previous stud-ies, these parameters were measured after chemotherapy or fever

onset and could not be easily checked in clinical practice. Moreover,these study populations were heterogeneous group, including bothsolid and hematologic malignancies. The current study looked at arelatively homogenous group which was composed of only patientswith hematologic disease. The baseline serum albumin, bicarbon-

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te, and CRP have another advantage in that they can be measuredt relatively low cost.

A limitation of this study is that the data might not be indepen-ent because several episodes were assessed in the same patients259 episodes in 137 patients). Therefore, the possibility of con-ounding factors cannot be fully excluded in multivariate analysis.his is a difficulty that is commonly encountered in retrospectivetudies. Thus, further prospective studies will be needed to verifyhe results of this study. However, this study may be the first reporthat suggests the possibility of prognosis prediction of febrile neu-ropenia by variables before chemotherapy or hematopoietic stemell transplantation in the patients of hematologic diseases.

onflict of interest

We have no conflicts of interest regarding our study.Contributions. YP and DSK contributed equally as co-first

uthors. BSK and SJK designed this study. BSK contributed asorresponding author. The other co-authors participated in data-athering and statistical analysis.

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