Beruflich Dokumente
Kultur Dokumente
a r t i c l e
i n f o
a b s t r a c t
Article history:
Received 24 March 2016
Received in revised form 16 August 2016
Accepted 22 August 2016
Available online xxxx
Keywords:
Afebrile
Bacteremia
Risk factors
Objective: There is limited research on afebrile bacteremia. We aimed to compare the risk factors and outcomes of
patients with afebrile and febrile infections.
Methods: This was a retrospective cohort study of bloodstream isolates from 994 adults admitted to the
emergency department of a university hospital. Afebrile infections, dened as the absence of fever history or
measured fever through the emergency department course, was compared with febrile infection. Frequencies
and proportions of sources of infection, comorbidities, along with organ failure and mortality were presented.
The major outcome measure was 30-day survival. chi-Square or Student's t test was used for univariate analysis,
and Cox proportional hazard model was used for multivariate analysis.
Results: We found that the risk factors and outcomes of febrile and afebrile bacteremia patients were very
different. The afebrile patients were older, have higher Charlson comorbidity index, and had poorer outcomes
than the febrile patients. We also found that oldest old age, nonhematologic malignancy, necrotizing fasciitis,
spontaneous bacterial peritonitis, and pneumonia were each positive independent predictors of afebrile
bacteremia, whereas Escherichia coli infection and liver abscess were independent negative predictors of afebrile
bacteremia. Finally, the 30-day all-cause mortality was higher in the afebrile group than in the febrile group
(45% versus 12%, log-rank P b 0.001).
Conclusions: This series of patients with afebrile bacteremia conrmed the previously reported associations with old
age and immunocompromised conditions. Clinicians should explore the possibility of occult severe infection, and initiate early hemodynamic support and empirical antimicrobial therapy for patients with the aforementioned risk factors.
2016 Elsevier Inc. All rights reserved.
1. Introduction
The establishment of systemic inammatory reaction syndrome
(SIRS) criteria has greatly aided clinicians to detect systemic infection
(Dellinger et al., 2013; Jones and Lowes, 1996; Levy et al., 2003).
However, fever is still the most commonly used criterion for initiating
infection workup. Fever is a complex and often nonspecic host defense
Following guideline: STROBE.
This study is supported by the Taiwan National Science Foundation Grant NSC 1022314-B-002-131-MY3; Taiwan National Ministry of Science and Technology Grants MOST
104-2314-B-002-039-MY3, and MOST 105-2811-B-002-031; Far Eastern Memorial
Hospital Grants FEMH-2015-C-016 and FEMH-2016-C-028; and Far Eastern Memorial
Hospital and National Taiwan University Hospital Cooperation Grant 105-FTN14.
No funding bodies had any role in the study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
The authors have no conicts of interest to disclose.
Corresponding author. Tel.: +886-2-23565926; fax: +886-2-23223150.
E-mail address: cclee100@gmail.com (C.-C. Lee).
2. Methods
2.1. Population and setting
A retrospective observational study was conducted in the ED at
National Taiwan University Hospital (NTUH) from June 1, 2010, to
http://dx.doi.org/10.1016/j.diagmicrobio.2016.08.020
0732-8893/ 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Yo C-H, et al, Risk factors and outcomes of afebrile bacteremia patients in an emergency department, Diagn Microbiol
Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.08.020
Downloaded from ClinicalKey.com at UNIVERSIDAD AUTONAMA DE NUEVA LEON September 19, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C-H. Yo et al. / Diagnostic Microbiology and Infectious Disease xxx (2016) xxxxxx
June 1, 2011. NTUH is a primary and tertiary care hospital with 2400
beds and annual ED census more than 100,000 visits. This study is approved
by the institutional review board of National Taiwan University Hospital.
During the study period, ED patients who were presented with a
clinical manifestation of SIRS or clinical indication of severe infection
such as pneumonia, cellulitis, abscess formation, cholecystitis, or pyelonephritis in the absence of SIRS were enrolled. Patients under 15 years
of age and a negative blood culture were excluded in this study. True
bacteremia was dened as positive blood cultures for at least 2 sets at
separate sites, or alternatively 1 set for gram-positive pathogen/gramnegative pathogen in a patient with an intravascular device and clinical
compatibility.
The following data were collected retrospectively for all eligible
patients from admission to discharge: demographic characteristics,
preexisting comorbid medical conditions, exposure to indwelling
catheters, initial vital signs, and laboratory tests, admission and nal discharge diagnoses, and microorganisms isolated from the blood cultures.
Vital sign data were taken from both the physician and nursing records.
Information included initial values and maximum temperature over a
patient's ED course, oxygen saturation, blood pressure, respiratory rate,
and heart rate. Patient outcomes were dened as 30-day all-cause mortality acquired either by hospital records or telephone interviews.
2.2. Denitions
3. Results
Please cite this article as: Yo C-H, et al, Risk factors and outcomes of afebrile bacteremia patients in an emergency department, Diagn Microbiol
Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.08.020
Downloaded from ClinicalKey.com at UNIVERSIDAD AUTONAMA DE NUEVA LEON September 19, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C-H. Yo et al. / Diagnostic Microbiology and Infectious Disease xxx (2016) xxxxxx
Table 1
A comparison of demographic characteristics and underlying comorbidities between
patients with afebrile and febrile bacteremia.
Total
Age (y)
Elderly patients
Oldest old (age 85 years)
Gender (Male)
Nosocomial infection
Prior use of steroids
Indwelling catheter
Underlying comorbidity
Diabetes mellitus
End-stage renal disease
Liver cirrhosis
Hemiparetic stroke
HIV infection
Hematologic malignancy
Nonhematologic malignancy
Charlson Score
01
25
69
Afebrile bacteremia
(n = 140)
Febrile bacteremia
(n = 797)
140/937 (14.94%)
66.67 17.46
80 (57.1%)
19 (13.6%)
70 (50.0%)
11 (7.9%)
5 (3.6%)
15 (10.7%)
797/937 (85.05%)
62.35 17.37
416 (52.2%)
54 (6.8%)
418 (52.4%)
36 (4.5%)
30 (3.8%)
88 (11.0%)
0.007
0.279
0.006
0.593
0.095
0.912
0.909
35 (25.0%)
7 (5.0%)
23 (16.4%)
24 (17.1%)
1 (0.7%)
3 (2.1%)
45 (32.1%)
249 (31.2%)
43 (5.4%)
86 (10.8%)
140 (17.6%)
7 (0.9%)
38 (4.8%)
162 (20.3%)
0.138
0.848
0.055
0.901
0.846
0.161
0.002
41 (29.3%)
69 (49.3%)
30 (21.4%)
324 (40.7%)
377 (47.3%)
96 (12.0%)
0.011
0.665
0.003
Table 3
A comparison of microbiological ndings between patients with afebrile and febrile
bacteremia.
Independent factors associated with afebrile bacteremia
Positive predictors
Necrotizing fasciitits
Spontaneous bacterial peritonitis
Age 85
Pneumonia
Nonhematologic malignancy
Negative predictors
E. coli infection
Liver abscess
Results on the multivariate analysis of risk factors for afebrile bloodstream infection in the study cohort were shown in Table 3. Necrotizing
fasciitis, spontaneous bacterial peritonitis, age greater than 85,
pneumonia, and nonhematologic malignancy were independent risk
factors associated with the development of afebrile bacteremia,
whereas E. coli infection and liver abscess were independently associated
with febrile bacteremia.
The overall mortality rate of bacteremia in this study was 17.0%. The
30-day all-cause mortality was higher in the afebrile group than in the
febrile group (45% versus 12%, log-rank P b 0.001). Kaplan-Meier survival curves for 30-day survival comparing afebrile and febrile patients
were shown in Fig. 1. The mean length of hospitalization was longer
for surviving afebrile patients than for surviving febrile patients (29.25
versus 21.46 days, P = 0.049). Controlling for age, sex, underlying comorbidities (Charlson index), and clinical severity (sepsis classication)
in the Cox-regression model, afebrile episodes was independently associated with an increased probability of 30-day mortality (adjusted hazard ratio, 95% condence interval, 2.76, 1.9833.836).
4. Discussion
In this study of 994 bacteremia patients, we found that the epidemiology and outcome of febrile and afebrile patients are very different.
The afebrile patients were older, have higher Charlson comorbidity
index, and have a poorer outcome than the febrile patients. We also
found that oldest old age, nonhematologic malignancy, necrotizing
fasciitis, spontaneous bacterial peritonitis, and pneumonia were each
positive independent predictors of afebrile bacteremia, whereas E. coli
infection and liver abscess were independent negative predictors of
afebrile bacteremia.
Previous studies described that afebrile bacteremia is a unique manifestation of geriatric or immunocompromised patients (Drewry et al.,
2013; Girard et al., 2005; Gleckman and Hibert, 1982; Hernandez-Bou
et al., 2014; Kameda et al., 2015; Norman, 2000; Richardson, 1993).
Table 2
A comparison of the source of bacteremia between patients with afebrile and febrile
bacteremia.
Source of bacteremia
Afebrile
bacteremia
(n = 147)
Febrile
bacteremia
(n = 847)
Gram-negative pathogen
Gram-positive pathogen
Anaerobe
Polymicrobial infection
E. coli
Primary bacteremia
Urinary tract infection
Biliary tract infection
Pneumonia
Liver abscess
Spontaneous bacterial peritonitis
Skin and musculoskeletal infection
Intraabdomen infection
Infective endocarditis
Necrotizing fasciitis
Central nervous system infection
Catheter related infection
94 (67.1%)
35 (23.8%)
7 (5.0%)
15 (10.7%)
32 (22.9%)
31 (22.1%)
22 (15.7%)
19 (13.6%)
20 (14.3%)
1 (0.7%)
12 (8.6%)
9 (6.4%)
6 (4.1%)
6 (4.3%)
4 (2.9%)
2 (1.4%)
5 (3.6%)
569 (71.4%)
195 (23.0%)
44 (5.5%)
69 (8.7%)
292 (36.6%)
136 (17.1%)
221 (27.7%)
127 (15.9%)
54 (6.8%)
42 (5.3%)
28 (3.5%)
78 (9.8%)
28 (3.4%)
36 (4.5%)
3 (0.4%)
8 (1.0%)
34 (4.3%)
0.308
0.301
0.802
0.432
0.002
0.148
0.003
0.477
0.002
0.018
0.006
0.207
0.652
0.903
0.012
0.652
0.704
Table 4
A comparison of the severity of clinical and laboratory manifestations between patients
with afebrile and febrile bacteremia.
Clinical and laboratory manifestations
Afebrile
bacteremia
(n = 147)
Febrile
bacteremia
(n = 847)
44 (31.4%)
37 (26.4%)
30 (21.4%)
32 (22.9%)
41 (29.3%)
36 (25.7%)
19 (13.6%)
16 (11.4%)
96 (66.7%)
7 (5.0%)
37 (20.0%)
48 (36.4%)
54 (38.6%)
100 (12.5%)
56 (7.0%)
73 (9.2%)
66 (8.3%)
193 (24.2%)
97 (12.2%)
87 (10.9%)
96 (12.0%)
679 (80.6%)
39 (4.9%)
452 (56.7%)
169 (21.2%)
137 (17.2%)
b0.001
b0.001
b0.001
b0.001
0.301
b0.001
0.360
0.797
b0.001
0.957
b0.001
b0.001
b0.001
Please cite this article as: Yo C-H, et al, Risk factors and outcomes of afebrile bacteremia patients in an emergency department, Diagn Microbiol
Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.08.020
Downloaded from ClinicalKey.com at UNIVERSIDAD AUTONAMA DE NUEVA LEON September 19, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C-H. Yo et al. / Diagnostic Microbiology and Infectious Disease xxx (2016) xxxxxx
Acknowledgement
We thank Medical Wisdom Consulting Group for technical
assistance in statistical analysis, and the staff of the Core Labs, Department
of Medical Research at the National Taiwan University Hospital for
technical support.
References
Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013;369:84051.
Armen SB, Freer CV, Showalter JW, Crook T, Whitener CJ, West C, et al. Improving outcomes
in patients with sepsis. Am J Med Qual 2014.
Barie PS, Hydo LJ, Shou J, Larone DH, Eachempati SR. Inuence of antibiotic therapy on
mortality of critical surgical illness caused or complicated by infection. Surg Infect
(Larchmt) 2005;6:4154.
Castellanos-Ortega A, Suberviola B, Garcia-Astudillo LA, Holanda MS, Ortiz F, Llorca J, et al.
Impact of the surviving sepsis campaign protocols on hospital length of stay and
mortality in septic shock patients: results of a three-year follow-up quasiexperimental study. Crit Care Med 2010;38:103643.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic
comorbidity in longitudinal studies: development and validation. J Chronic Dis
1987;40:37383.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis
campaign: international guidelines for management of severe sepsis and septic
shock: 2012. Crit Care Med 2013;41:580637.
Drewry AM, Fuller BM, Bailey TC, Hotchkiss RS. Body temperature patterns as a predictor
of hospital-acquired sepsis in afebrile adult intensive care unit patients: a casecontrol study. Crit Care 2013;17:R200.
Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, et al. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir
Crit Care Med 2009;180:8616.
Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, et al. Empiric
antibiotic treatment reduces mortality in severe sepsis and septic shock from the rst
hour: results from a guideline-based performance improvement program. Crit Care
Med 2014;42:174955.
Girard TD, Opal SM, Ely EW. Insights into severe sepsis in older patients: from epidemiology to evidence-based management. Clin Infect Dis 2005;40:71927.
Gleckman R, Hibert D. Afebrile bacteremia. A phenomenon in geriatric patients. JAMA
1982;248:147881.
Hernandez-Bou S, Trenchs V, Alarcon M, Luaces C. Afebrile very young infants with urinary tract infection and the risk for bacteremia. Pediatr Infect Dis J 2014;33:2447.
Jones GR, Lowes JA. The systemic inammatory response syndrome as a predictor of
bacteraemia and outcome from sepsis. QJM 1996;89:51522.
Kameda K, Kimura SI, Akahoshi Y, Nakano H, Harada N, Ugai T, et al. High incidence of
afebrile bloodstream infection detected by surveillance blood culture in patients on
corticosteroid therapy following allogeneic hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant 2015.
Kramer RD, Cooke CR, Liu V, Miller 3rd RR, Iwashyna TJ. Variation in the contents of sepsis
bundles and quality measures: a systematic review. Ann Am Thorac Soc 2015.
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension
before initiation of effective antimicrobial therapy is the critical determinant of
survival in human septic shock. Crit Care Med 2006;34:158996.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/
ACCP/ATS/SIS international sepsis denitions conference. Crit Care Med 2003;31:
12506.
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of
early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:130111.
Please cite this article as: Yo C-H, et al, Risk factors and outcomes of afebrile bacteremia patients in an emergency department, Diagn Microbiol
Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.08.020
Downloaded from ClinicalKey.com at UNIVERSIDAD AUTONAMA DE NUEVA LEON September 19, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C-H. Yo et al. / Diagnostic Microbiology and Infectious Disease xxx (2016) xxxxxx
Norman DC. Fever in the elderly. Clin Infect Dis 2000;31:14851.
Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and
meta-analysis of the efcacy of appropriate empiric antibiotic therapy for sepsis.
Antimicrob Agents Chemother 2010;54:485163.
Richardson JP. Bacteremia in the elderly. J Gen Intern Med 1993;8:8992.
van Zanten AR. The golden hour of antibiotic administration in severe sepsis: avoid a false
start striving for gold*. Crit Care Med 2014;42:19312.
Yokota PK, Marra AR, Martino MD, Victor ES, Durao MS, Edmond MB, et al. Impact of
appropriate antimicrobial therapy for patients with severe sepsis and septic shocka
quality improvement study. PLoS One 2014;9:e104475.
Please cite this article as: Yo C-H, et al, Risk factors and outcomes of afebrile bacteremia patients in an emergency department, Diagn Microbiol
Infect Dis (2016), http://dx.doi.org/10.1016/j.diagmicrobio.2016.08.020
Downloaded from ClinicalKey.com at UNIVERSIDAD AUTONAMA DE NUEVA LEON September 19, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.