[
Original Research Critical Care
]
Sepsis Severe or Septic Shock Outcome According to Immune Status and Immunodeficiency Profile Violaine Tolsma, MD; Carole Schwebel, MD, PhD; Elie Azoulay, MD, PhD; Michael Darmon, MD, PhD; Bertrand Souweine, MD, PhD; Aurélien Vesin, MSc; Dany Goldgran-Toledano, MD; Maxime Lugosi, MD; Samir Jamali, MD; Christine Cheval, MD; Christophe Adrie, MD, PhD; Hatem Kallel, MD; Adrien Descorps-Declere, MD; Maïté Garrouste-Orgeas, MD, PhD; Lila Bouadma, MD, PhD; and Jean-François Timsit, MD, PhD
This study evaluated the influence of the immune profile on the outcome at day 28 (D28) of patients admitted to the ICU for septic shock or severe sepsis.
OBJECTIVES:
We conducted an observational study using a prospective multicenter database and included all patients admitted to 11 ICUs for severe sepsis or septic shock from January 1997 to August 2011. Seven profiles of immunodeficiency were defined. The prognostic analysis used a competitive risk model (Fine and Gray), in which being alive at ICU or hospital discharge before D28 competed with death.
METHODS:
Among the 1,981 included patients, 607 (31%) were immunocompromised (including nonneutropenic solid tumor [19.6%], nonneutropenic hematologic malignancies [26.3%], and all-cause neutropenia [28%]). Compared with immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often with septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8% in immunocompetent patients (P 5 .26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (subdistribution hazard ratio [sHR], 1.37; 95% CI, 1.12-1.67). The immunodeficiency profiles independently associated with death were AIDS (sHR 5 1.9), nonneutropenic solid tumor (sHR 5 1.8), nonneutropenic hematologic malignancies (sHR 5 1.4), and all-cause neutropenia (sHR 5 1.7).
RESULTS:
Immunodeficiency is common in patients with severe sepsis or septic shock. Despite a similar crude mortality, immunodeficiency was associated with an increased risk of short-term mortality after multivariate analysis. Neutropenia and specific, but not all, profiles of immunodeficiency were independently associated with an increased risk of death. CONCLUSIONS:
CHEST 2014; 146(5):1205-1213
Manuscript received November 5, 2013; revision accepted June 2, 2014; originally published Online First July 17, 2014. ABBREVIATIONS: D0 5 day 0; D28 5 day 28; sHR 5 subdistribution hazard ratio; SOFA 5 Sequential Organ Failure Assessment AFFILIATIONS: From the A. Michallon University Hospital (Drs Tolsma, Schwebel, Lugosi, and Timsit and Ms Vesin), INSERM U823 and Joseph Fourier University, Grenoble; Saint-Louis University Hospital (Dr Azoulay), Paris; Saint-Etienne University Hospital (Dr Darmon), SaintEtienne; Gabriel Montpied University Hospital (Dr Souweine), ClermontFerrand; Gonesse Hospital (Dr Goldgran-Toledano), Gonesse; Dourdan Hospital (Dr Jamali), Dourdan; Hyeres Hospital (Dr Cheval), Hyeres; Delafontaine Hospital (Dr Adrie), Saint-Denis; Cayenne Hospital (Dr Kallel), French Guyana; A. Beclere Hospital (Dr Descorps-Declere), Clamart; Saint-Joseph Hospital Network (Dr Garrouste-Orgeas), Paris;
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AP-HP, Bichat Hospital (Drs Bouadma and Timsit), Medical and Infectious Diseases ICU, F-75018, Paris; IAME (Drs Garrouste-Orgeas, Bouadma, and Timsit), UMR 1137, University Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Jean-François Timsit, MD, PhD, Medical and Infectious Diseases ICU, Bichat Hospital, Paris, France 75018; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2618
1205
In ICUs, infection is an increasing issue at patient admission or during the ICU stay,1-4 and is an independent survival-prognosis risk factor.5 Except in cardiac intensive care, sepsis is the leading cause of ICU mortality. It is also a main cause of morbidity, associated with increased hospital-related costs.6 The mortality associated with severe sepsis and septic shock in the ICU remains high (around 30%).7 The rate of immunocompromised patients has increased steadily for 20 years,8 and immunodeficiency is a prognostic factor that is more and more often identified as associated with the increased mortality attributed to severe sepsis and septic shock.9 However, in most published studies, the evaluation of the immunodeficiency role in ICU infection faces several limitations. In some studies, immunodeficiency causes were not detailed or
Materials and Methods For this observational study, we used data from 11 French ICUs that were prospectively entered from January 1997 to August 2011 into a multicenter, high-quality database called OUTCOMEREA.16 All eligible patients were those coded as severe sepsis or septic shock for their “symptoms at ICU admission” or “main diagnosis at ICU admission.” The immunocompromised patients were defined according to seven immunodeficiency profiles: AIDS, organ transplant, solid organ tumor without neutropenia, hematologic malignancy without neutropenia, all-cause neutropenia, inflammatory and/or immune disorder, and primary or congenital immunodeficiency. Of note, patients with neutropenia with solid tumor or with hematologic malignancy were classified in the neutropenia group. In addition, we complemented the study database with all patient data collected from charts or records that could contribute to better characterizing the underlying disease or specific treatment.
were mixed; other studies focused only on one profile of immunodeficiency, such as AIDS10 or malignancies,11,12 or only on one type of infection, such as bloodstream infection13 or pneumonia.14 In addition, in many studies, the influence of the immunodeficiency profile on the prognosis is likely underestimated, as the patients’ immune status is not characterized.15 This study aims to describe immunocompromised patients admitted to ICU for severe sepsis or septic shock according to the type of immunosuppressive disease or treatment and to prognostic characteristics, to compare them to immunocompetent patients, and eventually to measure the impact of each immunodeficiency profile on patient short-term prognosis.
immunodeficiency being used as reference class. Two-way, clinically relevant, potential interactions were tested in the final model. Proportionality of hazard for risk factors was tested for all variables. The threshold of 5% was deemed statistically significant in all analyses. Statistical analyses were performed using the SAS 9.3 (SAS Institute Inc) and R 2.1 software.
Characteristics of patients, of their immunodeficiency, and of their outcome were described using frequency and percentages for qualitative variables, and median and quartiles for the quantitative variables. The comparison between patients with and without immunodeficiency was performed using the x2 test for qualitative variables and the Mann-Whitney test for the quantitative ones. The judgment criterion for the survival analysis was the vital status at day 28 [D28] (with day 0 [D0] as the ICU admission day). Patients were censored after 28 days of follow-up. Any death occurring before D28 (in the ICU or in the hospital) was considered, regardless of its cause. Risk factors for death at D28 were identified using the Fine and Gray subdistribution model, which allows the simultaneous evaluation of two competing events: being discharged alive from ICU or hospital, and death. A multivariate model was built by including all risk factors for death that met the 25% significance threshold in univariate analysis. A stepwise process was then applied until all remaining factors met the 5% threshold in multivariate context. The analysis was stratified by center. The results were given as subdistribution hazard ratio (sHR) and 95% CI. At this stage, the immunodeficiency (regardless of its cause) as binary variable was entered into the multivariate model; then the immunodeficiency category was entered as class variable, the lack of
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Figure 1 – Study flowchart with patients’ immunodeficiency characteristics and outcome. *Neutropenia from all causes, mostly related to solid tumor or hematologic malignancies and their treatment. D28 5 day 28.
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TABLE 1
] Patients’ Characteristics at ICU Admission and Comparison According to the Immune Status
Variables
Full Population (N 5 1,981)
Nonimmunocompromised Patients (n 5 1,374)
Immunocompromised Patients (n 5 607)
, .01
Admission Medical Unscheduled surgery Scheduled surgery Transfer from another ward Length of stay before transfer, d Age, y Male sex
P Valuea
1,436 (72.5)
896 (65.2)
464 (23.4)
405 (29.5)
81 (4.1) 1,040 (52.5) 2 [1; 6] 65 [53; 76]
2 [1; 6]
59 (9.7) 8 (1.3) 316 (52.1) 2 [1; 8]
68 [56; 78]
60 [49; 70]
.79 .44 , .01
802 (58.4)
367 (60.5)
302 (15.2)
249 (18.1)
53 (8.7)
, .01
Liver
132 (6.7)
106 (7.7)
26 (4.3)
, .01
Cardiovascular
258 (13)
199 (14.5)
59 (9.7)
, .01
Respiratory
208 (10.5)
152 (11.1)
56 (9.2)
.22
Renal
132 (6.7)
87 (6.3)
45 (7.4)
.37
At least one comorbidity
588 (29.7)
Diabetes
1,169 (59)
73 (5.3) 724 (52.7)
540 (89)
.38
Comorbidities according to Knaus et al17 (except immune deficiency)
Therapeutic limitation at day 1
440 (32)
48 (2.4)
34 (2.5)
Therapeutic limitation during ICU stay
260 (13.1)
Time interval from day 1 to therapeutic limitation
9 [3; 19.5]
Noninvasive ventilation ⱕ 48 h
135 (6.8)
Mechanical ventilation ⱕ 48 h
1,193 (60.2)
No. of antimicrobials at day 1 Effective empirical antimicrobial therapy at day 1b
… 1,097 (55.4)
148 (24.4)
, .01
14 (2.3)
.82
173 (12.6)
87 (14.3)
.29
9 [4; 21]
9 [3; 18]
.44
82 (6)
53 (8.7)
.02
910 (66.2) 3 [2; 3]
283 (46.6)
, .01
3 [2; 4]
, .01
756 (55)
341 (56.2)
.63
Associated bacteremia
705 (35.6)
421 (30.6)
284 (46.8)
, .01
Hospital-acquired infection
755 (38.1)
529 (38.5)
226 (37.2)
.59
Multiresistant bacteriac
280 (14.1)
196 (14.3)
84 (13.8)
.80
1,094 (55.2)
788 (57.4)
306 (50.4)
, .01
8 [5; 11]
8 [6; 11]
8 [5; 11]
.74
Coagulation
1 [0; 2]
0 [0; 1]
2 [0; 3]
, .01
Pulmonary
2 [1; 3]
2 [1; 3]
2 [1; 2]
, .01
Hepatic
0 [0; 1]
0 [0; 1]
0 [0; 1]
.03
Hemodynamic
3 [1; 4]
3 [2; 4]
3 [1; 4]
, .01
Neurologic
0 [0; 2]
0 [0; 2]
0 [0; 1]
, .01
Renal
2 [0; 3]
2 [0; 3]
1 [0; 2]
, .01
7 [3; 14]
7 [4; 15]
5 [3; 12]
, .01
22 [10; 42]
22 [10; 45]
22 [9; 39]
.19
396 (28.8)
190 (31.3)
.26
Septic shock SOFA score SOFA score items
Length of ICU stay, d Length of hospital stay, d Death at 28 d or before
586 (29.6)
Data for qualitative variables given as No. (%), and as median [first; third quartile] for quantitative variables. SOFA 5 Sequential Organ Failure Assessment. P values were obtained by x2 test for qualitative variables and by Mann-Whitney test for quantitative variables. bAn effective empirical antimicrobial therapy at d 1 is a therapy effective on all causative agents by at least one of the empirically selected antimicrobials on the day of the diagnosis of an episode of severe sepsis. cMultiresistant bacteria refer to vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, extended-spectrum b-lactamaseproducing Enterobacteriaceae, AmpC-producing Enterobacteriaceae, Pseudomonas aeruginosa resistant to more than two antimicrobial families, or Stenotrophomonas maltophilia. a
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Results Among 14,419 patients admitted to the ICU, 1,981 (13.7%) were admitted for severe sepsis or septic shock (Fig 1), including 607 immunocompromised patients (30.6%). The cause of the immunodeficiency was multiple in almost 10% of patients. Most immunocompromised patients had at least one of the following immunodeficiency causes: all-cause neutropenia (28%), nonneutropenic hematologic malignancy (26.3%), nonneutropenic solid tumor (19.6%), or AIDS (11.2%). Death at D28 or before occurred in 31.3% of immunocompromised patients vs 28.8% of immunocompetent patients (P 5 .26). The median interval between the malignant disease diagnosis and the ICU admission was 9 months for the patients with a solid tumor, and 7 months for patients with hematologic malignancy. Most of them were treated with chemotherapy and admitted in ICU during
their first line of chemotherapy. They were admitted to the ICU a median of 17 days after their last chemotherapy course. Conversely, the median interval between disease diagnosis and ICU admission was much longer for patients with HIV, solid organ transplant, or inflammatory or immune disease (70, 26, and 122 months, respectively). Sixty-five percent of patients with solid organ transplant and 75% of patients with inflammatory or immune disease received corticosteroids. A subgroup analysis showed treatment with corticosteroids had no significant impact on D28 mortality among these patients (76 of 104 [73%] among survivors vs 20 of 31 [64.5%] among nonsurvivors, P 5 .31). Patients’ characteristics at ICU admission according to immune status are described in Table 1. Some sites of infection were significantly more often involved in immunocompromised patients (Fig 2). In addition,
Figure 2 – A, Infection sites according to immune status. B, Causative microorganisms according to immune status. *P , .05. **Others: CNS, heart and mediastinum, bone and joints, upper respiratory tract, and genital tract. E. coli 5 Escherichia coli.
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immunocompromised patients more frequently had infection involving several sites (50% vs 29.9%). Some causative bacterial pathogens were also different in immunocompromised patients, such as Pseudomonas species (13.5% vs 6.6%, P , .01), gram-positive cocci other than pneumococci (11.6% vs 8.8%, P 5 .06), anaerobes, mycobacteria, viruses, parasites, or fungi (Fig 2). Infections were more frequently microbiologically documented. Rates of hospital-acquired infections or of infections due to multiresistant pathogens were similar among both groups. Initial septic shock was less frequent (50.4% vs 57.4%, P , .01). The overall Sequential Organ Failure Assessment (SOFA) score was not different; however, immunocompromised patients more often had liver and hematologic failures. The length of ICU stay was significantly shorter for immunocompromised patients (median 5 days vs 7 days, P , .01), whereas length of hospital stay was similar. The curves of the cumulative incidence of death risk between D0 and D28 were not different according to the immune status (Fig 3). The risk factors for death at D28 identified through the univariate analysis are described in Table 2. The multivariate analysis showed that age, cardiovascular, and hepatic comorbidities (according to the Knaus et al17 definition), therapeutic limitation, do-not-resuscitate order the day of ICU admission, the infection site, the occurrence of septic shock, and a high SOFA score were associated with D28 mortality. The infection site was an independent poor-prognosis factor, with an increased risk of death in case of pulmonary infection (sHR, 1.682; 95% CI, 1.171-2.417) or intraabdominal infection (sHR, 1.498; 95% CI, 1.017-2.207). After adjustment of prognosis factors, the immunodeficiency,
regardless of its cause, was identified as an independent risk factor (sHR, 1.368; 95% CI, 1.120-1.672). Some profiles of immunodeficiency were associated to a higher risk of death at D28 (Table 3): AIDS (sHR, 1.921; 95% CI, 1.077-3.408), solid tumor without neutropenia (sHR, 1.808; 95% CI, 1.249-2.616), hematologic malignancies without neutropenia (sHR, 1.414; 95% CI, 1.002-1.994), and neutropenia regardless of its cause (sHR, 1.653; 95% CI, 1.229-2.224). Immunodeficiency combining several causes was not an independent poor-prognosis factor. Among the specific subgroup of patients with malignant disease, solid tumor, or hematologic malignancy, neutropenia was not a risk factor for D28 mortality (sHR, 1.196; 95% CI, 0.83-1.72; P 5 .33).
Discussion In this cohort of patients admitted to the ICU for severe sepsis or septic shock, we found a high percentage of patients with prior immunodeficiency. Sepsis risks were higher among immunocompromised patients, and sepsis causes were different from those observed in immunocompetent patients. Immunodeficiency was an independent poor-prognosis factor for survival, and some immunodeficiency causes were associated with a greater risk of death at D28, such as AIDS, any malignant disease without neutropenia, or a neutropenia regardless of its cause. This study specifically evaluated the overall impact of immunodeficiency on the prognosis of patients admitted to the ICU for severe sepsis or septic shock. The specific impact of each immunodeficiency profile was evaluated, which has never been done. This prognostic
Figure 3 – Kaplan-Meier survival curve between d 1 and d 28 according to the immune status. Immun 5 immunodeficiency.
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TABLE 2
] Risk Factors of Death at Day 28 or Before: Univariate Analysis
Variables
Alive at Day 28 (n 5 1,395)
Dead at Day 28 (n 5 586)
Admission
.18
Medical
997 (69.4)
439 (30.7)
Emergency surgery
336 (72.4)
1218 (27.6)
62 (76.5)
19 (23.5)
Scheduled surgery
P Valuea
, .0001
Age, y 0-54
425 (79.9)
107 (20.1)
55-64
302 (72.6)
114 (27.4)
65-74
301 (64.7)
164 (35.3)
ⱖ 75
367 (64.6)
201 (35.4)
Male sex
807 (69)
362 (31)
Diabetes
214 (70.9)
.12
88 (29.1)
.93
Comorbidities according to Knaus et al17 definitions 60 (45.5)
72 (54.5)
, .0001
Cardiovascular
151 (58.5)
107 (41.5)
, .0001
Respiratory
133 (63.9)
75 (36.1)
.05
88 (66.7)
44 (33.3)
.29
351 (59.7)
237 (40.3)
, .0001
704 (67.7)
336 (32.3)
.01 .44
Liver
Renal At least one other comorbidity Transfer from another ward Length of stay prior to transfer into ICU, d
2 [1; 6]
2 [1; 8]
ⱕ2
691 (73.4)
250 (26.6)
3-7
377 (69.3)
167 (30.7)
.7
326 (65.9)
169 (34.1)
12 (25)
36 (75)
Therapeutic limitation at ICU admission Infection site
.01
Lung
246 (64.9)
133 (35.1)
Intraabdominal
215 (71.4)
86 (26.8)
Urinary tract Other
91 (78.4)
25 (21.6)
146 (79.3)
38 (20.7)
Unknown
241 (69.7)
105 (30.3)
Multiple
456 (69.6)
199 (30.4)
Bacteremia
486 (68.9)
219 (31.1)
Microorganism
.8
Staphylococcus aureus
51 (67.1)
25 (32.9)
Streptococcus pneumoniae
45 (70.3)
19 (29.7)
Other gram-positive pathogens
88 (72.7)
33 (27.3)
101 (75.9)
32 (24.1)
Pseudomonas species
34 (70.8)
14 (29.2)
Other gram-negative pathogens
74 (66.1)
38 (33.9)
Escherichia coli
Other pathogens
80 (70.8)
33 (29.2)
Not documented
419 (69.1)
187 (30.9)
Multiple
503 (71.0)
205 (29.0)
192 (68.6)
88 (31.4)
Multiresistant bacteria
.28
.52 (Continued)
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TABLE 2
] (continued) Alive at Day 28 (n 5 1,395)
Dead at Day 28 (n 5 586)
P Valuea
Hospital-acquired infection
508 (67.3)
247 (32.7)
.03
Appropriate antimicrobials at day 1
802 (73.1)
295 (26.9)
.002
Septic shock
682 (62.3)
412 (37.7)
, .0001
,3
303 (88.3)
40 (11.7)
3-5
386 (81.1)
90 (18.9)
5-8
487 (73.2)
178 (26.8)
.8
219 (44.1)
278 (55.9)
Variables
, .0001
SOFA score (without immunodeficiency)
Data for qualitative variables given as No. (%), and as median [first; third quartile] for quantitative variables. See Table 1 legend for expansion of abbreviation. aP value obtained by Gray test.
study took into account as many confounding factors as possible and used a statistical model adapted to survival studies in the ICU (ie, paying attention to the event acquisition rate and to informative censoring).18 The D28 mortality was chosen, as it is mainly associated with the severity of severe sepsis itself, whereas the mortality at longer term may be associated with sepsis and also with chronic underlying illnesses.3,19 In our study, we gathered data on all kinds of immunodeficiency and this could explain an incidence of immunodeficiency higher than that observed in other studies.1,2 In addition, all ICUs belonged to a university hospital, with a likely higher rate of patients at risk for severe immunodeficiency. The crude mortality was around 30%, consistent with published data.20 Risk factors identified through the multivariate analysis are those usually identified in studies on severe sepsis and septic shock; however, the infection site was an independent risk factor, in contrast to results of another study.21 The survival analysis confirmed the impact of the immunodeficiency on the prognosis, regardless of its cause, as has been reported.15 Remarkably, this study enabled the identification of immunodeficiency profiles associated with a poorer survival prognosis. Our study underlines the poor prognosis associated with AIDS, solid tumor, or hematologic malignancy without neutropenia, in accordance with previous studies.22 In contrast, the lack of prognostic impact of solid organ transplant and inflammatory or immune disorder or primary immunodeficiency need to be confirmed by further studies. Interestingly, although neutropenia was initially reported as a risk factor in cancer patients,23 recent studies failed to associate neutropenia with outcome in cancer patient populations.20,24,25
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In our study, prognostic burden of neutropenia was similar to that of other relevant types of immunodeficiency. More specifically, among patients with solid tumor or hematologic malignancy, neutropenia was not a risk factor for D28 mortality. The study has some limitations. First, the selection of patients with severe sepsis or septic shock was based on diagnosis coded by investigators. We limited the analysis to severe sepsis diagnosed at ICU admission and did not evaluate the impact of ICU-acquired severe sepsis on prognosis. Second, characteristics of immunodeficiency may have been omitted in the patients’ charts. However, these complementary data were used only for descriptive statistics. Third, the D0 point for the survival analysis was the time of ICU admission and not exactly the starting time of the sepsis, which is more difficult to pinpoint.
Conclusions This study showed the differences of sepsis characteristics in immunocompromised vs immunocompetent patients among patients admitted to the ICU for severe sepsis or septic shock. Although the crude mortality of immunocompetent and immunocompromised patients was similar, immunodeficiency was an independent factor for poor prognosis after adjustment of confounding factors. The impact on sepsis survival was evaluated according to the immunodeficiency profile. AIDS, solid tumor or hematologic malignancies without neutropenia, and neutropenia regardless of its cause were independent factors for short-term mortality. Further studies are required to more precisely evaluate the characteristics of sepsis according to each immunodeficiency profile.
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TABLE 3
] Risk Factors for Death at Day 28: Multivariate Analysis
Variables
sHR
95% CI
ref
…
55-64
1.155
0.884-1.509
65-74
1.655
1.294-2.117
1.679
1.318-2.139
P Valuea , .0001
Age, y 0-54
ⱖ 751 Liver comorbidity
1.772
1.360-2.309
, .0001
Cardiovascular comorbidity17
1.622
1.308-2.012
, .0001
Therapeutic limitation at day 1
2.806
1.983-3.970
, .0001
17
Infection site
.04
Other
ref
…
Lung
1.682
1.171-2.417
Intraabdominal
1.498
1.017-2.207
Urinary tract
1.118
0.672-1.859
Unknown
1.395
0.961-2.027
Multiple
1.293
0.908-1.840
Adequate antimicrobials at day 1
0.660
0.557-0.782
, .0001
Septic shock
1.649
1.370-1.983
, .0001
,3
ref
…
3-4
1.549
1.066-2.250
5-8
2.239
1.584-3.164
.8
5.455
3.868-7.692
1.368
1.120-1.672
ref
…
AIDSd
1.921
1.077-3.408
Solid organ transplant
0.587
0.287-1.200
b
, .0001
SOFA score (without hemodynamics)
Immunodeficiency (all causes)
.002
Same model as above, but replacing immunodeficiency by the specific profile of immunodeficiency: .0003
Immunodeficiency profilec Not immunocompromised
Nonneutropenic solid tumor
1.808
1.249-2.616
Nonneutropenic hematologic malignancyc
1.414
1.002-1.994
Neutropeniad
1.653
1.229-2.224
Immune deficiency or primary immunodeficiency
0.800
0.473-1.352
Combined profiles (n 5 60)
1.289
0.771-2.157
c
ref 5 reference; sHR 5 subdistribution hazard ratio. See Table 1 legend for expansion of other abbreviation. P value of Gray test. bIncludes skin and soft tissues, central venous access, liver and biliary tract, CNS, heart and mediastinum, upper respiratory tract, bone and joints, and genitals. cAfter adjustment on the risk factors for death at d 28 from the multivariate analysis. dAll causes; mostly associated with solid tumor or hematologic malignancies. a
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Acknowledgments Author contributions: J.-F. T. had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. V. T., E. A., M. D., A. V., and J.-F. T. contributed to the original design of the study; V. T., A. V., and J.-F. T. contributed to drafting of the manuscript; A. V. and J.-F. T. contributed to statistical analysis; and V. T., C. S., E. A., M. D., B. S., A. V., D. G.-T., M. L., S. J., C. C., C. A., H. K., A. D.-D., M. G.-O., L. B., and J.-F. T. contributed to critical review of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Darmon has received pharmaceutical grant monies from Merck & Co Inc. Dr Souweine has participated in speaking activities for Pfizer Inc. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: The authors thank Celine Feger, MD, of EMIBiotech for her editorial support.
References 1. Brun-Buisson C, Meshaka P, Pinton P, Vallet B; EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30(4):580-588. 2. Annane D, Aegerter P, Jars-Guincestre MC, Guidet B; CUB-Réa Network. Current epidemiology of septic shock: the CUBRéa Network. Am J Respir Crit Care Med. 2003;168(2):165-172. 3. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med. 2002;28(2):108-121. 4. Vincent JL, Sakr Y, Sprung CL, et al; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344-353. 5. Vincent JL, Rello J, Marshall J, et al; EPIC II Group of Investigators. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323-2329.
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6. Adrie C, Alberti C, Chaix-Couturier C, et al. Epidemiology and economic evaluation of severe sepsis in France: age, severity, infection site, and place of acquisition (community, hospital, or intensive care unit) as determinants of workload and cost. J Crit Care. 2005;20(1):46-58. 7. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34(1):17-60. 8. Linden PK. Approach to the immunocompromised host with infection in the intensive care unit. Infect Dis Clin North Am. 2009;23(3):535-556. 9. Brun-Buisson C, Doyon F, Carlet J, et al; French ICU Group for Severe Sepsis. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. JAMA. 1995;274(12):968-974. 10. Japiassú AM, Amâncio RT, Mesquita EC, et al. Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients. Crit Care. 2010;14(4):R152. 11. Soares M, Caruso P, Silva E, et al; Brazilian Research in Intensive Care Network (BRICNet). Characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study. Crit Care Med. 2010;38(1):9-15. 12. Kroschinsky F, Weise M, Illmer T, et al. Outcome and prognostic features of intensive care unit treatment in patients with hematological malignancies. Intensive Care Med. 2002;28(9):1294-1300. 13. Pittet D, Thiévent B, Wenzel RP, Li N, Gurman G, Suter PM. Importance of pre-existing co-morbidities for prognosis of septicemia in critically ill patients. Intensive Care Med. 1993;19(5):265-272. 14. Naccache JM. Pneumonia in the immunocompromised patient [in French]. Rev Prat. 2011;61(8):1095-1101. 15. Alberti C, Brun-Buisson C, Goodman SV, et al; European Sepsis Group. Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients. Am J Respir Crit Care Med. 2003;168(1):77-84. 16. Laupland KB, Zahar JR, Adrie C, et al. Severe hypothermia increases the risk for intensive care unit-acquired infection. Clin Infect Dis. 2012;54(8):1064-1070.
17. Knaus W, Draper E, Wagner D. APACHE III study design: analytic plan for evaluation of severity and outcome in intensive care unit patients. Introduction. Crit Care Med. 1989;17(12 pt 2): S176-S180. 18. Resche-Rigon M, Azoulay E, Chevret S. Evaluating mortality in intensive care units: contribution of competing risks analyses. Crit Care. 2006;10(1):R5. 19. Angus DC, Barnato AE, Linde-Zwirble WT, et al; Robert Wood Johnson Foundation ICU End-Of-Life Peer Group. Use of intensive care at the end of life in the United States: an epidemiologic study. Crit Care Med. 2004;32(3):638-643. 20. Azoulay E, Mokart D, Pène F, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium—a groupe de recherche respiratoire en réanimation oncohématologique study. J Clin Oncol. 2013;31(22):2810-2818. 21. Zahar JR, Timsit JF, Garrouste-Orgeas M, et al. Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med. 2011;39(8):1886-1895. 22. Moreno RP, Metnitz PG, Almeida E, et al; SAPS 3 Investigators. SAPS 3—From evaluation of the patient to evaluation of the intensive care unit. Part 2: Development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31(10):1345-1355. 23. Hampshire PA, Welch CA, McCrossan LA, Francis K, Harrison DA. Admission factors associated with hospital mortality in patients with haematological malignancy admitted to UK adult, general critical care units: a secondary analysis of the ICNARC Case Mix Programme Database. Crit Care. 2009;13(4):R137. 24. Darmon M, Azoulay E, Alberti C, et al. Impact of neutropenia duration on shortterm mortality in neutropenic critically ill cancer patients. Intensive Care Med. 2002;28(12):1775-1780. 25. Vandijck DM, Benoit DD, Depuydt PO, et al. Impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies. Intensive Care Med. 2008;34(5):847-855.
1213
Original Research Critical Care
]
Sepsis Severe or Septic Shock Outcome According to Immune Status and Immunodeficiency Profile Violaine Tolsma, MD; Carole Schwebel, MD, PhD; Elie Azoulay, MD, PhD; Michael Darmon, MD, PhD; Bertrand Souweine, MD, PhD; Aurélien Vesin, MSc; Dany Goldgran-Toledano, MD; Maxime Lugosi, MD; Samir Jamali, MD; Christine Cheval, MD; Christophe Adrie, MD, PhD; Hatem Kallel, MD; Adrien Descorps-Declere, MD; Maïté Garrouste-Orgeas, MD, PhD; Lila Bouadma, MD, PhD; and Jean-François Timsit, MD, PhD
This study evaluated the influence of the immune profile on the outcome at day 28 (D28) of patients admitted to the ICU for septic shock or severe sepsis.
OBJECTIVES:
We conducted an observational study using a prospective multicenter database and included all patients admitted to 11 ICUs for severe sepsis or septic shock from January 1997 to August 2011. Seven profiles of immunodeficiency were defined. The prognostic analysis used a competitive risk model (Fine and Gray), in which being alive at ICU or hospital discharge before D28 competed with death.
METHODS:
Among the 1,981 included patients, 607 (31%) were immunocompromised (including nonneutropenic solid tumor [19.6%], nonneutropenic hematologic malignancies [26.3%], and all-cause neutropenia [28%]). Compared with immunocompetent patients, immunocompromised patients were younger, with less comorbidity, were more often admitted for medical reasons, and presented less often with septic shock. The D28 crude mortality was 31.3% in immunocompromised patients and 28.8% in immunocompetent patients (P 5 .26). However, after adjustment for other prognostic factors, immunodeficiency was an independent risk factor for death at D28 (subdistribution hazard ratio [sHR], 1.37; 95% CI, 1.12-1.67). The immunodeficiency profiles independently associated with death were AIDS (sHR 5 1.9), nonneutropenic solid tumor (sHR 5 1.8), nonneutropenic hematologic malignancies (sHR 5 1.4), and all-cause neutropenia (sHR 5 1.7).
RESULTS:
Immunodeficiency is common in patients with severe sepsis or septic shock. Despite a similar crude mortality, immunodeficiency was associated with an increased risk of short-term mortality after multivariate analysis. Neutropenia and specific, but not all, profiles of immunodeficiency were independently associated with an increased risk of death. CONCLUSIONS:
CHEST 2014; 146(5):1205-1213
Manuscript received November 5, 2013; revision accepted June 2, 2014; originally published Online First July 17, 2014. ABBREVIATIONS: D0 5 day 0; D28 5 day 28; sHR 5 subdistribution hazard ratio; SOFA 5 Sequential Organ Failure Assessment AFFILIATIONS: From the A. Michallon University Hospital (Drs Tolsma, Schwebel, Lugosi, and Timsit and Ms Vesin), INSERM U823 and Joseph Fourier University, Grenoble; Saint-Louis University Hospital (Dr Azoulay), Paris; Saint-Etienne University Hospital (Dr Darmon), SaintEtienne; Gabriel Montpied University Hospital (Dr Souweine), ClermontFerrand; Gonesse Hospital (Dr Goldgran-Toledano), Gonesse; Dourdan Hospital (Dr Jamali), Dourdan; Hyeres Hospital (Dr Cheval), Hyeres; Delafontaine Hospital (Dr Adrie), Saint-Denis; Cayenne Hospital (Dr Kallel), French Guyana; A. Beclere Hospital (Dr Descorps-Declere), Clamart; Saint-Joseph Hospital Network (Dr Garrouste-Orgeas), Paris;
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AP-HP, Bichat Hospital (Drs Bouadma and Timsit), Medical and Infectious Diseases ICU, F-75018, Paris; IAME (Drs Garrouste-Orgeas, Bouadma, and Timsit), UMR 1137, University Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Jean-François Timsit, MD, PhD, Medical and Infectious Diseases ICU, Bichat Hospital, Paris, France 75018; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2618
1205
In ICUs, infection is an increasing issue at patient admission or during the ICU stay,1-4 and is an independent survival-prognosis risk factor.5 Except in cardiac intensive care, sepsis is the leading cause of ICU mortality. It is also a main cause of morbidity, associated with increased hospital-related costs.6 The mortality associated with severe sepsis and septic shock in the ICU remains high (around 30%).7 The rate of immunocompromised patients has increased steadily for 20 years,8 and immunodeficiency is a prognostic factor that is more and more often identified as associated with the increased mortality attributed to severe sepsis and septic shock.9 However, in most published studies, the evaluation of the immunodeficiency role in ICU infection faces several limitations. In some studies, immunodeficiency causes were not detailed or
Materials and Methods For this observational study, we used data from 11 French ICUs that were prospectively entered from January 1997 to August 2011 into a multicenter, high-quality database called OUTCOMEREA.16 All eligible patients were those coded as severe sepsis or septic shock for their “symptoms at ICU admission” or “main diagnosis at ICU admission.” The immunocompromised patients were defined according to seven immunodeficiency profiles: AIDS, organ transplant, solid organ tumor without neutropenia, hematologic malignancy without neutropenia, all-cause neutropenia, inflammatory and/or immune disorder, and primary or congenital immunodeficiency. Of note, patients with neutropenia with solid tumor or with hematologic malignancy were classified in the neutropenia group. In addition, we complemented the study database with all patient data collected from charts or records that could contribute to better characterizing the underlying disease or specific treatment.
were mixed; other studies focused only on one profile of immunodeficiency, such as AIDS10 or malignancies,11,12 or only on one type of infection, such as bloodstream infection13 or pneumonia.14 In addition, in many studies, the influence of the immunodeficiency profile on the prognosis is likely underestimated, as the patients’ immune status is not characterized.15 This study aims to describe immunocompromised patients admitted to ICU for severe sepsis or septic shock according to the type of immunosuppressive disease or treatment and to prognostic characteristics, to compare them to immunocompetent patients, and eventually to measure the impact of each immunodeficiency profile on patient short-term prognosis.
immunodeficiency being used as reference class. Two-way, clinically relevant, potential interactions were tested in the final model. Proportionality of hazard for risk factors was tested for all variables. The threshold of 5% was deemed statistically significant in all analyses. Statistical analyses were performed using the SAS 9.3 (SAS Institute Inc) and R 2.1 software.
Characteristics of patients, of their immunodeficiency, and of their outcome were described using frequency and percentages for qualitative variables, and median and quartiles for the quantitative variables. The comparison between patients with and without immunodeficiency was performed using the x2 test for qualitative variables and the Mann-Whitney test for the quantitative ones. The judgment criterion for the survival analysis was the vital status at day 28 [D28] (with day 0 [D0] as the ICU admission day). Patients were censored after 28 days of follow-up. Any death occurring before D28 (in the ICU or in the hospital) was considered, regardless of its cause. Risk factors for death at D28 were identified using the Fine and Gray subdistribution model, which allows the simultaneous evaluation of two competing events: being discharged alive from ICU or hospital, and death. A multivariate model was built by including all risk factors for death that met the 25% significance threshold in univariate analysis. A stepwise process was then applied until all remaining factors met the 5% threshold in multivariate context. The analysis was stratified by center. The results were given as subdistribution hazard ratio (sHR) and 95% CI. At this stage, the immunodeficiency (regardless of its cause) as binary variable was entered into the multivariate model; then the immunodeficiency category was entered as class variable, the lack of
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Figure 1 – Study flowchart with patients’ immunodeficiency characteristics and outcome. *Neutropenia from all causes, mostly related to solid tumor or hematologic malignancies and their treatment. D28 5 day 28.
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TABLE 1
] Patients’ Characteristics at ICU Admission and Comparison According to the Immune Status
Variables
Full Population (N 5 1,981)
Nonimmunocompromised Patients (n 5 1,374)
Immunocompromised Patients (n 5 607)
, .01
Admission Medical Unscheduled surgery Scheduled surgery Transfer from another ward Length of stay before transfer, d Age, y Male sex
P Valuea
1,436 (72.5)
896 (65.2)
464 (23.4)
405 (29.5)
81 (4.1) 1,040 (52.5) 2 [1; 6] 65 [53; 76]
2 [1; 6]
59 (9.7) 8 (1.3) 316 (52.1) 2 [1; 8]
68 [56; 78]
60 [49; 70]
.79 .44 , .01
802 (58.4)
367 (60.5)
302 (15.2)
249 (18.1)
53 (8.7)
, .01
Liver
132 (6.7)
106 (7.7)
26 (4.3)
, .01
Cardiovascular
258 (13)
199 (14.5)
59 (9.7)
, .01
Respiratory
208 (10.5)
152 (11.1)
56 (9.2)
.22
Renal
132 (6.7)
87 (6.3)
45 (7.4)
.37
At least one comorbidity
588 (29.7)
Diabetes
1,169 (59)
73 (5.3) 724 (52.7)
540 (89)
.38
Comorbidities according to Knaus et al17 (except immune deficiency)
Therapeutic limitation at day 1
440 (32)
48 (2.4)
34 (2.5)
Therapeutic limitation during ICU stay
260 (13.1)
Time interval from day 1 to therapeutic limitation
9 [3; 19.5]
Noninvasive ventilation ⱕ 48 h
135 (6.8)
Mechanical ventilation ⱕ 48 h
1,193 (60.2)
No. of antimicrobials at day 1 Effective empirical antimicrobial therapy at day 1b
… 1,097 (55.4)
148 (24.4)
, .01
14 (2.3)
.82
173 (12.6)
87 (14.3)
.29
9 [4; 21]
9 [3; 18]
.44
82 (6)
53 (8.7)
.02
910 (66.2) 3 [2; 3]
283 (46.6)
, .01
3 [2; 4]
, .01
756 (55)
341 (56.2)
.63
Associated bacteremia
705 (35.6)
421 (30.6)
284 (46.8)
, .01
Hospital-acquired infection
755 (38.1)
529 (38.5)
226 (37.2)
.59
Multiresistant bacteriac
280 (14.1)
196 (14.3)
84 (13.8)
.80
1,094 (55.2)
788 (57.4)
306 (50.4)
, .01
8 [5; 11]
8 [6; 11]
8 [5; 11]
.74
Coagulation
1 [0; 2]
0 [0; 1]
2 [0; 3]
, .01
Pulmonary
2 [1; 3]
2 [1; 3]
2 [1; 2]
, .01
Hepatic
0 [0; 1]
0 [0; 1]
0 [0; 1]
.03
Hemodynamic
3 [1; 4]
3 [2; 4]
3 [1; 4]
, .01
Neurologic
0 [0; 2]
0 [0; 2]
0 [0; 1]
, .01
Renal
2 [0; 3]
2 [0; 3]
1 [0; 2]
, .01
7 [3; 14]
7 [4; 15]
5 [3; 12]
, .01
22 [10; 42]
22 [10; 45]
22 [9; 39]
.19
396 (28.8)
190 (31.3)
.26
Septic shock SOFA score SOFA score items
Length of ICU stay, d Length of hospital stay, d Death at 28 d or before
586 (29.6)
Data for qualitative variables given as No. (%), and as median [first; third quartile] for quantitative variables. SOFA 5 Sequential Organ Failure Assessment. P values were obtained by x2 test for qualitative variables and by Mann-Whitney test for quantitative variables. bAn effective empirical antimicrobial therapy at d 1 is a therapy effective on all causative agents by at least one of the empirically selected antimicrobials on the day of the diagnosis of an episode of severe sepsis. cMultiresistant bacteria refer to vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, extended-spectrum b-lactamaseproducing Enterobacteriaceae, AmpC-producing Enterobacteriaceae, Pseudomonas aeruginosa resistant to more than two antimicrobial families, or Stenotrophomonas maltophilia. a
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1207
Results Among 14,419 patients admitted to the ICU, 1,981 (13.7%) were admitted for severe sepsis or septic shock (Fig 1), including 607 immunocompromised patients (30.6%). The cause of the immunodeficiency was multiple in almost 10% of patients. Most immunocompromised patients had at least one of the following immunodeficiency causes: all-cause neutropenia (28%), nonneutropenic hematologic malignancy (26.3%), nonneutropenic solid tumor (19.6%), or AIDS (11.2%). Death at D28 or before occurred in 31.3% of immunocompromised patients vs 28.8% of immunocompetent patients (P 5 .26). The median interval between the malignant disease diagnosis and the ICU admission was 9 months for the patients with a solid tumor, and 7 months for patients with hematologic malignancy. Most of them were treated with chemotherapy and admitted in ICU during
their first line of chemotherapy. They were admitted to the ICU a median of 17 days after their last chemotherapy course. Conversely, the median interval between disease diagnosis and ICU admission was much longer for patients with HIV, solid organ transplant, or inflammatory or immune disease (70, 26, and 122 months, respectively). Sixty-five percent of patients with solid organ transplant and 75% of patients with inflammatory or immune disease received corticosteroids. A subgroup analysis showed treatment with corticosteroids had no significant impact on D28 mortality among these patients (76 of 104 [73%] among survivors vs 20 of 31 [64.5%] among nonsurvivors, P 5 .31). Patients’ characteristics at ICU admission according to immune status are described in Table 1. Some sites of infection were significantly more often involved in immunocompromised patients (Fig 2). In addition,
Figure 2 – A, Infection sites according to immune status. B, Causative microorganisms according to immune status. *P , .05. **Others: CNS, heart and mediastinum, bone and joints, upper respiratory tract, and genital tract. E. coli 5 Escherichia coli.
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immunocompromised patients more frequently had infection involving several sites (50% vs 29.9%). Some causative bacterial pathogens were also different in immunocompromised patients, such as Pseudomonas species (13.5% vs 6.6%, P , .01), gram-positive cocci other than pneumococci (11.6% vs 8.8%, P 5 .06), anaerobes, mycobacteria, viruses, parasites, or fungi (Fig 2). Infections were more frequently microbiologically documented. Rates of hospital-acquired infections or of infections due to multiresistant pathogens were similar among both groups. Initial septic shock was less frequent (50.4% vs 57.4%, P , .01). The overall Sequential Organ Failure Assessment (SOFA) score was not different; however, immunocompromised patients more often had liver and hematologic failures. The length of ICU stay was significantly shorter for immunocompromised patients (median 5 days vs 7 days, P , .01), whereas length of hospital stay was similar. The curves of the cumulative incidence of death risk between D0 and D28 were not different according to the immune status (Fig 3). The risk factors for death at D28 identified through the univariate analysis are described in Table 2. The multivariate analysis showed that age, cardiovascular, and hepatic comorbidities (according to the Knaus et al17 definition), therapeutic limitation, do-not-resuscitate order the day of ICU admission, the infection site, the occurrence of septic shock, and a high SOFA score were associated with D28 mortality. The infection site was an independent poor-prognosis factor, with an increased risk of death in case of pulmonary infection (sHR, 1.682; 95% CI, 1.171-2.417) or intraabdominal infection (sHR, 1.498; 95% CI, 1.017-2.207). After adjustment of prognosis factors, the immunodeficiency,
regardless of its cause, was identified as an independent risk factor (sHR, 1.368; 95% CI, 1.120-1.672). Some profiles of immunodeficiency were associated to a higher risk of death at D28 (Table 3): AIDS (sHR, 1.921; 95% CI, 1.077-3.408), solid tumor without neutropenia (sHR, 1.808; 95% CI, 1.249-2.616), hematologic malignancies without neutropenia (sHR, 1.414; 95% CI, 1.002-1.994), and neutropenia regardless of its cause (sHR, 1.653; 95% CI, 1.229-2.224). Immunodeficiency combining several causes was not an independent poor-prognosis factor. Among the specific subgroup of patients with malignant disease, solid tumor, or hematologic malignancy, neutropenia was not a risk factor for D28 mortality (sHR, 1.196; 95% CI, 0.83-1.72; P 5 .33).
Discussion In this cohort of patients admitted to the ICU for severe sepsis or septic shock, we found a high percentage of patients with prior immunodeficiency. Sepsis risks were higher among immunocompromised patients, and sepsis causes were different from those observed in immunocompetent patients. Immunodeficiency was an independent poor-prognosis factor for survival, and some immunodeficiency causes were associated with a greater risk of death at D28, such as AIDS, any malignant disease without neutropenia, or a neutropenia regardless of its cause. This study specifically evaluated the overall impact of immunodeficiency on the prognosis of patients admitted to the ICU for severe sepsis or septic shock. The specific impact of each immunodeficiency profile was evaluated, which has never been done. This prognostic
Figure 3 – Kaplan-Meier survival curve between d 1 and d 28 according to the immune status. Immun 5 immunodeficiency.
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1209
TABLE 2
] Risk Factors of Death at Day 28 or Before: Univariate Analysis
Variables
Alive at Day 28 (n 5 1,395)
Dead at Day 28 (n 5 586)
Admission
.18
Medical
997 (69.4)
439 (30.7)
Emergency surgery
336 (72.4)
1218 (27.6)
62 (76.5)
19 (23.5)
Scheduled surgery
P Valuea
, .0001
Age, y 0-54
425 (79.9)
107 (20.1)
55-64
302 (72.6)
114 (27.4)
65-74
301 (64.7)
164 (35.3)
ⱖ 75
367 (64.6)
201 (35.4)
Male sex
807 (69)
362 (31)
Diabetes
214 (70.9)
.12
88 (29.1)
.93
Comorbidities according to Knaus et al17 definitions 60 (45.5)
72 (54.5)
, .0001
Cardiovascular
151 (58.5)
107 (41.5)
, .0001
Respiratory
133 (63.9)
75 (36.1)
.05
88 (66.7)
44 (33.3)
.29
351 (59.7)
237 (40.3)
, .0001
704 (67.7)
336 (32.3)
.01 .44
Liver
Renal At least one other comorbidity Transfer from another ward Length of stay prior to transfer into ICU, d
2 [1; 6]
2 [1; 8]
ⱕ2
691 (73.4)
250 (26.6)
3-7
377 (69.3)
167 (30.7)
.7
326 (65.9)
169 (34.1)
12 (25)
36 (75)
Therapeutic limitation at ICU admission Infection site
.01
Lung
246 (64.9)
133 (35.1)
Intraabdominal
215 (71.4)
86 (26.8)
Urinary tract Other
91 (78.4)
25 (21.6)
146 (79.3)
38 (20.7)
Unknown
241 (69.7)
105 (30.3)
Multiple
456 (69.6)
199 (30.4)
Bacteremia
486 (68.9)
219 (31.1)
Microorganism
.8
Staphylococcus aureus
51 (67.1)
25 (32.9)
Streptococcus pneumoniae
45 (70.3)
19 (29.7)
Other gram-positive pathogens
88 (72.7)
33 (27.3)
101 (75.9)
32 (24.1)
Pseudomonas species
34 (70.8)
14 (29.2)
Other gram-negative pathogens
74 (66.1)
38 (33.9)
Escherichia coli
Other pathogens
80 (70.8)
33 (29.2)
Not documented
419 (69.1)
187 (30.9)
Multiple
503 (71.0)
205 (29.0)
192 (68.6)
88 (31.4)
Multiresistant bacteria
.28
.52 (Continued)
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TABLE 2
] (continued) Alive at Day 28 (n 5 1,395)
Dead at Day 28 (n 5 586)
P Valuea
Hospital-acquired infection
508 (67.3)
247 (32.7)
.03
Appropriate antimicrobials at day 1
802 (73.1)
295 (26.9)
.002
Septic shock
682 (62.3)
412 (37.7)
, .0001
,3
303 (88.3)
40 (11.7)
3-5
386 (81.1)
90 (18.9)
5-8
487 (73.2)
178 (26.8)
.8
219 (44.1)
278 (55.9)
Variables
, .0001
SOFA score (without immunodeficiency)
Data for qualitative variables given as No. (%), and as median [first; third quartile] for quantitative variables. See Table 1 legend for expansion of abbreviation. aP value obtained by Gray test.
study took into account as many confounding factors as possible and used a statistical model adapted to survival studies in the ICU (ie, paying attention to the event acquisition rate and to informative censoring).18 The D28 mortality was chosen, as it is mainly associated with the severity of severe sepsis itself, whereas the mortality at longer term may be associated with sepsis and also with chronic underlying illnesses.3,19 In our study, we gathered data on all kinds of immunodeficiency and this could explain an incidence of immunodeficiency higher than that observed in other studies.1,2 In addition, all ICUs belonged to a university hospital, with a likely higher rate of patients at risk for severe immunodeficiency. The crude mortality was around 30%, consistent with published data.20 Risk factors identified through the multivariate analysis are those usually identified in studies on severe sepsis and septic shock; however, the infection site was an independent risk factor, in contrast to results of another study.21 The survival analysis confirmed the impact of the immunodeficiency on the prognosis, regardless of its cause, as has been reported.15 Remarkably, this study enabled the identification of immunodeficiency profiles associated with a poorer survival prognosis. Our study underlines the poor prognosis associated with AIDS, solid tumor, or hematologic malignancy without neutropenia, in accordance with previous studies.22 In contrast, the lack of prognostic impact of solid organ transplant and inflammatory or immune disorder or primary immunodeficiency need to be confirmed by further studies. Interestingly, although neutropenia was initially reported as a risk factor in cancer patients,23 recent studies failed to associate neutropenia with outcome in cancer patient populations.20,24,25
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In our study, prognostic burden of neutropenia was similar to that of other relevant types of immunodeficiency. More specifically, among patients with solid tumor or hematologic malignancy, neutropenia was not a risk factor for D28 mortality. The study has some limitations. First, the selection of patients with severe sepsis or septic shock was based on diagnosis coded by investigators. We limited the analysis to severe sepsis diagnosed at ICU admission and did not evaluate the impact of ICU-acquired severe sepsis on prognosis. Second, characteristics of immunodeficiency may have been omitted in the patients’ charts. However, these complementary data were used only for descriptive statistics. Third, the D0 point for the survival analysis was the time of ICU admission and not exactly the starting time of the sepsis, which is more difficult to pinpoint.
Conclusions This study showed the differences of sepsis characteristics in immunocompromised vs immunocompetent patients among patients admitted to the ICU for severe sepsis or septic shock. Although the crude mortality of immunocompetent and immunocompromised patients was similar, immunodeficiency was an independent factor for poor prognosis after adjustment of confounding factors. The impact on sepsis survival was evaluated according to the immunodeficiency profile. AIDS, solid tumor or hematologic malignancies without neutropenia, and neutropenia regardless of its cause were independent factors for short-term mortality. Further studies are required to more precisely evaluate the characteristics of sepsis according to each immunodeficiency profile.
1211
TABLE 3
] Risk Factors for Death at Day 28: Multivariate Analysis
Variables
sHR
95% CI
ref
…
55-64
1.155
0.884-1.509
65-74
1.655
1.294-2.117
1.679
1.318-2.139
P Valuea , .0001
Age, y 0-54
ⱖ 751 Liver comorbidity
1.772
1.360-2.309
, .0001
Cardiovascular comorbidity17
1.622
1.308-2.012
, .0001
Therapeutic limitation at day 1
2.806
1.983-3.970
, .0001
17
Infection site
.04
Other
ref
…
Lung
1.682
1.171-2.417
Intraabdominal
1.498
1.017-2.207
Urinary tract
1.118
0.672-1.859
Unknown
1.395
0.961-2.027
Multiple
1.293
0.908-1.840
Adequate antimicrobials at day 1
0.660
0.557-0.782
, .0001
Septic shock
1.649
1.370-1.983
, .0001
,3
ref
…
3-4
1.549
1.066-2.250
5-8
2.239
1.584-3.164
.8
5.455
3.868-7.692
1.368
1.120-1.672
ref
…
AIDSd
1.921
1.077-3.408
Solid organ transplant
0.587
0.287-1.200
b
, .0001
SOFA score (without hemodynamics)
Immunodeficiency (all causes)
.002
Same model as above, but replacing immunodeficiency by the specific profile of immunodeficiency: .0003
Immunodeficiency profilec Not immunocompromised
Nonneutropenic solid tumor
1.808
1.249-2.616
Nonneutropenic hematologic malignancyc
1.414
1.002-1.994
Neutropeniad
1.653
1.229-2.224
Immune deficiency or primary immunodeficiency
0.800
0.473-1.352
Combined profiles (n 5 60)
1.289
0.771-2.157
c
ref 5 reference; sHR 5 subdistribution hazard ratio. See Table 1 legend for expansion of other abbreviation. P value of Gray test. bIncludes skin and soft tissues, central venous access, liver and biliary tract, CNS, heart and mediastinum, upper respiratory tract, bone and joints, and genitals. cAfter adjustment on the risk factors for death at d 28 from the multivariate analysis. dAll causes; mostly associated with solid tumor or hematologic malignancies. a
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Acknowledgments Author contributions: J.-F. T. had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. V. T., E. A., M. D., A. V., and J.-F. T. contributed to the original design of the study; V. T., A. V., and J.-F. T. contributed to drafting of the manuscript; A. V. and J.-F. T. contributed to statistical analysis; and V. T., C. S., E. A., M. D., B. S., A. V., D. G.-T., M. L., S. J., C. C., C. A., H. K., A. D.-D., M. G.-O., L. B., and J.-F. T. contributed to critical review of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Darmon has received pharmaceutical grant monies from Merck & Co Inc. Dr Souweine has participated in speaking activities for Pfizer Inc. The remaining authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: The authors thank Celine Feger, MD, of EMIBiotech for her editorial support.
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