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ORIGINAL ARTICLE

Differentiating sepsis from non-infective

systemic inflammatory response syndrome:

Comparison between C-reactive protein and Leptin

N.A. Farag

a

, K.M. Taema

b,*

, E. Abdel-Latiff

b

, G. Hamed

b

a Critical Care Medicine, Elsahel Teaching Hospital, Cairo, Egyptb Critical Care Medicine, Cairo University, Cairo, Egypt

Received 15 May 2013; revised 15 November 2013; accepted 16 November 2013

Available online 5 December 2013

KEYWORDS

Sepsis;

SIRS;Leptin;

CRP

Abstract Background: Differentiation of sepsis from non-infectious SIRS is important in improv-

ing sepsis outcome. We intended in this study to evaluate the role of serum Leptin and to compare it

with CRP in differentiating sepsis from non-infectious SIRS.Methods: We included 30 patients with SIRS. According to the presence or absence of infection,

our patients were classified into SIRS group and sepsis group. Leptin and CRP were evaluated in all

patients on admission, day 2 and day 4.

Results: Our patients had a mean age of 52.3 18.6 year old, 10 males (33.3%). There were no

significant differences regarding baseline demographic and clinical data apart from blood pressures

which were lower in the sepsis group. Serum Leptin on Day 2 only was higher in the sepsis group

(44.2 17.7lg/L vs. 31.1 2.1 lg/L,P = 0.008) with no difference in days 0 and 4 of admission.

We detected a serum Leptin level of 38.05 lg/L on day 2 to be 93% sensitive and 100% specific to

diagnose sepsis. The three serum CRP levels were higher in sepsis compared to SIRS group

(61.2 9 mg/L vs. 48.9 7.1 mg/L, P< 0.001 in day 0, 71.5 9.6 mg/L and 196.8 39.8 mg/

L in sepsis group vs. 56.9 8 mg/L and 73.7 32.5 mg/L in SIRS group for days 2 and 4 respec-

tively, P< 0.001 for both). We found a CRP of 67.5 mg/L on day 2 having 87% sensitivity and

* Corresponding author. Tel.: +20 1000412603.

E-mail addresses: [email protected], Khaledtoai-

[email protected] (K.M. Taema).

Peer review under responsibility of The Egyptian College of Critical

Care Physicians.

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93% specificity for the diagnosis of sepsis.

Conclusion: We concluded that despite serum Leptin may not be beneficial in early differentia-

tion between sepsis and non infectious SIRS on admission; it may be highly specific on second day.

2013 Production and hosting by Elsevier B.V. on behalf of The Egyptian College of Critical Care

Physicians.

Introduction

Despite the use of modern management strategies, sepsis is a

leading cause of death in critically ill patients[1]. The septic re-

sponse is an extremely complex chain of events involving

inflammatory and anti-inflammatory processes, humoral and

cellular reactions and circulatory abnormalities[2,3].

The diagnosis of sepsis and evaluation of its severity are

complicated by the highly variable and non-specific nature of

the signs and symptoms of sepsis [4]. However, the early diag-

nosis and stratification of the severity of sepsis are very impor-

tant, increasing the possibility of starting timely and the

specific treatment[5,6].

Leptin is an adipokine that reveals pleiotropic neurohumo-

ral function, which regulates appetite and energy expenditurevia the hypothalamicpituitaryadrenal axis, vascular func-

tion, bone and cartilage growth, and pregnancy. It is also an

important immunoregulatory hormone that enhances a num-

ber of immune responses, including macrophage effector func-

tions and cytokine synthesis [7]. Leptin level was found to

increase in response to infection and inflammatory stimuli [8].

We sought to evaluate the value of Leptin in critically ill pa-

tients and to compare it with the C-reactive protein for early

diagnosis and differentiation between sepsis and non-infec-

tious systemic inflammatory response syndrome (SIRS).

Patients and methods

This is a prospective study that was conducted on 30 adult crit-

ically ill patients staying for more than 24 h in the ICU (surgi-

cal/medical) department, El Sahel Teaching Hospital, Cairo,

Egypt. We included in the study patients diagnosed with SIRS

based on the 1991 ACCP/SCCM Sepsis Directory[9] and the

diagnostic criteria advanced by the 2001 International Sepsis

Definition Conference[10], exhibiting two or more of the fol-

lowing signs: (1) temperature of >38 or 90 beats/min, (3) respiratory rate of >20 breaths/min or

hyperventilation with a partial pressure of arterial carbon diox-

ide (PaCO2) of 12,000 or 10% immature cells.

We excluded from the study, patients who received anti-

inflammatory drugs or corticosteroids before admission, pa-

tients who had immunosuppressive illness, and patients who

had received massive blood transfusion.

The presence of infection was defined according to the clin-

ical and microbiological criteria of the CDC definitions [11]

and was held as a gold standard and determined by three inde-

pendent experts who were blinded to the serum Leptin and

CRP results and examined the patients daily for the 1st 48 h

of admission. According to the presence or absence of infec-

tion, our patients were divided into two groups; group A in-

cluded patients with non-infectious SIRS (SIRS group) and

group B included patients with infection (sepsis group).

The study protocol was approved by the institutional re-

view board at Cairo University together with representatives

of study conduction site, and a written informed consent to

participate was obtained from all participating patients or first

degree relatives.

For all cases the following were performed

Full history taking and meticulous physical examination, with

sequential organ failure assessment (SOFA) score to be as-

sessed on admission, and days 2 and 4.

Routine laboratory investigations (e.g. complete blood

count, blood urea nitrogen, blood sugar, serum sodium, potas-

sium, calcium, aspartate aminotransferase, alanine amino-

transferase, INR, albumin) were done in the patients. Serumbiomarkers (Leptin and CRP levels) were done on admission,

and days 2 and 4. Routine cultures of blood, sputum, urine,

and suspected sites of infection were obtained.

All patients were managed by conventional supportive mea-

sures for critically ill patients including fluids, oxygen therapy,

and ventilatory support whenever required. However, when-

ever criteria of infection appeared or suspected (according to

CDC and guided by Surviving sepsis campaign guidelines),

antibiotics were immediately instituted even in SIRS patients.

Leptin assay

Blood samples were collected aseptically by venipuncture 3

times (on admission and on days 2 and 4 of admission). The

blood was then left to clot then centrifuged for 15 min at

5000 rpm. The sera were separated and stored at 20 C until

the time of the assay.

Serum Leptin was determined by quantitative sandwich en-

zyme immunoassay (USA) according to the manufacturers

instructions. The assay is an ELISA format, performed in

microwells coated with anti-Leptin antibody (monoclonal).

Leptin present in a measured volume of sample or calibrator

will bind to the anti-Leptin antibody on the microtitre plate.

Non-bound material was removed by washing. Subse-

quently, a horseradish peroxidase (HRP) conjugated antibody

to Leptin is added. After removal of non-bound conjugate by

washing, substrate solution is added to the wells. The colorthat develops is proportional to the amount of Leptin present

in sample or calibrator.

The enzymatic reaction is stopped chemically and the color

intensity is read at 450 nm in an ELISA reader. From the

absorbance of the samples and those of a calibration curve,

the concentration of Leptin is determined by interpolation.

Statistical analysis

Data were prospectively collected and coded prior to analysis

using the professional statistical Package for Social Science

112 N.A. Farag et al.


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(SPSS version 16). Continuous variables were expressed as

mean and standard deviation (SD). Categorical variables were

expressed as frequency and proportion. Student-t Test (t) was

used for comparison between two groups as regards normally

distributed (parametric) quantitative data. Chi-Square Test

(v2) was used for comparison between two groups as regards

qualitative data. Results were considered statistically signifi-

cant if P 6 0.05. A receiver operating characteristic (ROC)

analysis was performed to define a cutoff value of differentmarkers.

Results

During the period between August 2011 and February 2012,

thirty critically ill patients with expected length of stay more

than 24 h in the surgical/medical ICU in El Sahel Teaching

Hospital were enrolled in the study. Our patients had a mean

age of 52.3 18.6 year old, including 10 males (33.3%) and 20

females (66.6%). After enrollment, our patients were classified

into two groups according to the diagnosis that included non-

infective SIRS group and sepsis group.

Each group comprised 15 patients; patients demographicsand baseline clinical data are shown in Table 1. The presence

or absence of co-morbid conditions as well as cause of ICU

admission being medical or surgical was similar in both groups

(Table 1). The causes of ICU admission are illustrated in

Table 2.

As shown inTable 3, there was no significant difference be-

tween both groups regarding clinical and laboratory data, ex-

cept higher systolic blood pressure (SBP), diastolic blood

pressure (DBP), mean blood pressure (MBP), and P/F ratio

and lower heart rate (HR), respiratory rate, serum creatinine,

and INR in SIRS group compared to sepsis group.

We found that the serum Leptin levels on days 2 and 4 in

the SIRS group were positively correlated with the SOFA

score (r= 0.76, P= 0.002 and r= 0.67, P= 0.006 respec-tively). Meanwhile, all three samples of serum CRP levels

(on admission and on days 2 and 4) were correlated positively

with the SOFA score (r= 0.75, P= 0.002; r= 0.67,P= 0.009; and r = 0.64,P = 0.01 respectively). On the other

hand, in the sepsis group, neither the Leptin nor the CRP re-

vealed a correlation with the SOFA score (r= 0.39, P = 0.2;

r= 0.36, P= 0.2; and r= 0.15, P= 0.6 for admission and

days 2 and 4 of Leptin respectively and r= 0.38, P= 0.2;

r= 0.4, P= 0.13; and r= 0.22, P= 0.43 for CRP

respectively).

Table 4shows a higher incidence for the need of mechanical

ventilation and use of inotropic and/or vasoactive support in

the sepsis group than in the SIRS group. There was also signif-

icantly higher SOFA score in the sepsis group.

Serum Leptin and serum CRP were compared in both

groups on days 0, 2, and 4. Serum Leptin level on admission

revealed a modest non significant higher level in the sepsisgroup (3.5 0.9lg/L vs. 3 0.7lg/L, P = 0.1) while on

Table 1 Baseline demographic and clinical data.

SIRS Sepsis P-value

Age 51.3 16 53.3 21.3 0.77

Gender [N (%)]

Male 6 (40%) 4 (26.7%) 0.35

Female 9 (60%) 11 (73.3%)

BMI 23.9 2.4 24.3 3.7 0.7

HTN [N(%)] 8 (53.3%) 7 (46%) 0.8

DM [N (%)] 10 (66.7%) 7 (46%) 0.47

CVS [N (%)] 2 (13.3%) 1 (6.66%) 0.56CRF [N (%)] 1 (6.66%) 2 (13.3%) 0.56

CHF [N (%)] 0 (0%) 1 (6.66%) 0.32

Co-morbidity

1 co-morbidity 3 3 0.68

2 co-morbidities 3 5

More than two co-morbidities 9 7

Cause of admission

Medical 12 12 0.67

Surgical 3 3

BMI: body mass index, HTN: hypertension, DM: diabetes mellitus, CVS: cerebrovascular stroke, CRF: chronic renal failure, CLD: chronic

lung disease, CHF: congestive heart failure.

Table 2 Causes of admission in both groups.

SIRS N (%) Sepsis N(%) Total

Respiratory distress

Pneumonia 0 (0 %) 7 (46.7 %) 7 (23.3 %)

Acute lung injury 4 (26.7 %) 0 (0 %) 4 (13.3 %)

Bronchogenic carcinoma 1 (6.7 %) 0 (0 %) 1 (3.3 %)

Abdominal sepsis 0 (0 %) 1 (6.7 %) 1 (3.3 %)

Suspected central line

infection

1 (6.7 % ) 1 (6 .7 % ) 2 (6. 7 %)

Soft tissue infection 0 (0 %) 1 (6.7 %) 1 (3.3 %)

Uri nary tr act in fect ion 0 (0 %) 2 (1 3.3% ) 2 (6. 7 %)

DKA 3 (20 %) 0 (0 %) 3 (10 %)

Post-operative 3 (20 %) 3 (20 %) 6 (20 %)

I ntes tinal o bstr ucti on 1 (6.7 % ) 0 (0 % ) 1 (3. 3 %)

Hematologic malignancy 1 (6.7 %) 0 (0 %) 1 (3.3 %)

CRF with volume overload 1 (6.7 %) 0 (0 %) 1 (3.3 %)

Total 15 (100 %) 15 (100 %) 30 (100 %)

DKA: diabetic ketoacidosis, CRF: chronic renal failure.

Differentiating sepsis from non-infective systemic inflammatory response syndrome 113


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Day 2 the serum Leptin level was significantly higher in the

sepsis group compared to the SIRS group (44.2 17.7 lg/L

vs. 31.1 2.1 lg/L,P= 0.008). This significant difference dis-

appeared again on day 4 where there was no significant differ-

ence between the two groups (18.2 3.9 lg/L in sepsis group

compared to 17 1.4lg/L in SIRS group,P = 0.23) (Fig. 1).

Serum Leptin level of 38.05 lg/L on second day of admission

was found to have a sensitivity of 93% and a specificity of

100% for the diagnosis of sepsis with a positive predictive va-

lue (PPV) of 100% and a negative predictive value (NPV) of

94% (Fig. 2).

Serum CRP level on admission was 61.2 9 mg/L in the

sepsis group compared to 48.9 7.1 mg/L in the SIRS group

which is a statistically significant difference (P< 0.001)

(Fig. 3). Day 2 and day 4 serum levels of serum CRP were also

significantly higher in the sepsis group than in the SIRS group

(71.5 9.6 mg/L and 196.8 39.8 mg/L vs. 56.9 8 mg/L

and 73.7 32.5 mg/L respectively, P< 0.001 for both)

(Fig. 3). We found a serum CRP level of 51 mg/L on the day

of admission to have 93% sensitivity, 80% specificity, 82%

PPV, and 92% NPV for the diagnosis of sepsis (Fig. 4) and

a level of 67.5 mg/L on day 2 to have 87% sensitivity, 93%

specificity, 93% PPV, and 88% NPV for the diagnosis of sepsis

(Fig. 5). The serum CRP on day 4 of 95.5 mg/L has a sensitiv-ity and specificity of 93% and PPV and NPV of 93% for the

diagnosis of sepsis (Fig. 6).

Only 2 patients (in the sepsis group) died in our study and

had a Leptin of 3.1 and 38.5 lg/L and a CRP of 65 and 73 mg/

L on admission and day 2.

Discussion

Severe sepsis is the most common cause of death for patients

admitted to the critical care units [1]. The early diagnosis of

sepsis, the identification of its origin, and an adequate thera-peutic management are crucial to overcome sepsis-associated

mortality. So, the matter at heart in the early differentiation

Table 3 Baseline clinical and laboratory data.

SIRS Sepsis P-value

HR 111.6 14.4 124.8 18.8 0.04

SBP 112.33 23.7 90.67 20.5 0.012

DBP 69.33 14.7 54 11.8 0.004

MBP 83.7 16.8 66.2 14.2 0.005

RR 25.7 3.7 34.5 8.7 0.001

Temperature 38 1 38.9 1.7 0.078

CVP 6.3 3.2 4 4.5 0.17

ScvO2 72.3 6.3 67.4 14.8 0.25

Serum urea 67.3 52.8 91.2 79.9 0.34

Serum Creatinine 1.7 0.98 3.4 2.2 0.01

Na+ 133.2 5.2 135.9 7.3 0.25

K+ 3.9 0.8 3.5 0.5 0.095

Ca++ 8.3 0.8 7.8 1.6 0.32

RBG 199.7 64.6 284.3 163.6 0.07

AST 78.9 110.4 95.9 106.9 0.67

ALT 38.2 22.4 88 118.1 0.12

Serum albumin 3.1 0.8 3.2 0.5 0.9

INR 1.4 0.32 1.97 0.86 0.04

Hemoglobin 11 2.8 10.9 2.3 0.85

Platelet count 199.3 107.9 226 137 0.55

TLC 14.8 5.9 19.3 8.5 0.09

P/Fratio 373.93 61.7 263.27 95.7 0.001

Table 4 Need of mechanical ventilation, use of inotropic and/or vasoactive support, and SOFA score in both groups.

SIRS Sepsis P-value

Mechanical ventilation [N(%)] Yes 0 (0 %) 9 (60 %) 0.002

No 15 (100%) 6 (40 %)

Use of inotropic and/or vasoactive support [N (%)] Yes 2 (13.3 %) 7 (47 %) 0.05

No 13 (86.6 %) 8 (53 %)

SOFA score Mean SD 5 3 8 3 0. 02

Figure 1 Serum Leptin during days 0, 2, and 4 in both groups.

Figure 2 ROC curve for cut-off value of serum Leptin of day 2.



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between Sepsis and non-infectious SIRS is the impact on

outcome.

The adipokine Leptin regulates energy expenditure, vascu-

lar function, bone and cartilage growth as well as the immune

system and systemic inflammatory response. Several activating

effects toward T cells, monocytes, endothelium cells and cyto-

kine production have been reported suggesting a protective

role of Leptin in the setting of an acute systemic inflammation

[7,12]. Some studies found that serum Leptin is a powerful bio-

marker that helps to differentiate sepsis from the non-infec-tious SIRS in critically ill patients with higher levels in sepsis

[8,1315].

We intended in this study to evaluate the value of monitor-

ing serum Leptin in critically ill patients and to compare it with

serum CRP for early diagnosis of sepsis and its differentiation

from non-infectious SIRS.

Both groups of the study had comparable demographic

data and comorbidities, however data of disease severity were

significantly worse in the sepsis group e.g. HR, MAP, RR,

and need of mechanical ventilation and vasoactive support

that was reflected on higher SOFA score. Higher heart

rate and lower blood pressures were also reported by many

investigators in patients with definite bacterial infection

[1618]. This was attributed by many authors to the well

known systemic vasodilation and myocardial depression that

occurs in sepsis. Endothelium dysfunction, inflammatory

cytokines release, and inducible NO synthase mediated NO

release are involved in sepsis associated profound vasodilation

and biventricular failure[1921].

Respiratory rate was significantly higher in sepsis than

SIRS groups and this is in agreement with other studies in

which patients with sepsis had higher RR and rapid shallow

breathing index[18,22]. They explained this by reduced respi-

ratory muscle capacity and increased load. The negative im-pact of sepsis on respiratory muscle function was attributed

to circulating mediators [23], changes in intracellular calcium

[24], oxygen metabolism[25], or changes in respiratory muscle

ultrastructure [26]. These effects, however, could happen in

critical illness irrespective of sepsis.

According to these differences in blood pressures, heart

rate, and respiratory rate, it is not surprising that the use of

inotropic and vasoactive supports and the need for mechanical

ventilation and subsequently SOFA score were significantly

higher in the sepsis group. Higher SOFA score in sepsis was

reported in some other studies [8,27,28]. Despite these signifi-

cant differences of clinical and laboratory data that were ob-

served in our study and in others, Shapiro et al, [29] showed

that these data are not pathognomonic for infection andmay also be observed in a wide variety of noninfectious inflam-

matory conditions. In addition, they may be absent in patients

with serious infections, especially in elderly individuals [29].

Our results showed that serum Leptin level on 2nd day and

not on admission can differentiate between sepsis and non-

infectious SIRS. We found a serum Leptin level of 38.05 lg/

L on second day of admission to diagnose sepsis in patients

admitted with SIRS with a sensitivity of 93% and a specificity

of 100%.

Torpy et al., [13] reported a higher Leptin level in septic

patients on the day of admission. Arnalich et al., [14] even

found that the admission serum Leptin was higher in patients

Figure 3 Serum CRP during days 0, 2, and 4 in both groups.

Figure 5 ROC curve for cut-off value of serum CRP of day 2.




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with septic shock than patients with severe sepsis without

shock[14].

Similar to our results, Yousef et al, [8] showed that the

admission serum Leptin was nearly equal among patients in

the sepsis, SIRS, and non-SIRS groups and that the second

day levels significantly increased in septic and SIRS patients

compared to non-SIRS patients. They detected a cut-off serum

Leptin level of 38 lg/L with a sensitivity of 91.2% and a spec-

ificity of 85% to identify sepsis from SIRS [8]. Cesur et al,[15]

also stated that there was no statistically significant difference

between the patient group with sepsis and the control group in

terms of serum Leptin levels on admission but Leptin washigher in patient group with sepsis on days 3 and 5.

This reported rise in serum Leptin concentration following

acute infection suggests that it may actively participate in the

immune response and host defense. Leptin and its receptors

have structural similarities with cytokine family that includes

IL-6 and IL-12 [30,31], so it should not be surprising that it

acts as a pro-inflammatory cytokine. Leptin itself was shown

by some authors to increase the production of TNF a and

IL-6 from macrophages[12].

Contrary to these results, Carlson et al showed that sepsis

was not associated with significant change in serum Leptin

concentration[32]. The population of this study was however

not comparable with ours as patients were enrolled in thestudy after about 14 days of sepsis diagnosis. This delay in

time of enrollment relative to sepsis onset could explain these

differences as other authors had identified an increase in serum

Leptin concentration for only the first 5 days following pro-

longed administration of IL-1a[33]. On the other hand, many

of the studies that concluded an elevated serum Leptin in re-

sponse to sepsis including ours did not report on body compo-

sition or feeding regimens that might conceivably have

influenced the results.

On the extreme, Langouche et al in [34] even showed low

serum Leptin levels in critically ill patients that were postulated

by the authors to be due to an acute stress response. This study

was planned to evaluate the effect of conventional and intense

insulin therapy on serum Leptin. So, like Carlson and cowork-

ers [32], they screened prolonged critically ill patients and an

early effect may have been missed. Another explanation of this

discrepancy could be attributed to differences in illness severity

between their population and ours. Langouche and his col-

leagues [34]reported high death rates that were 51.5% in pa-

tients with sepsis while only two of our sepsis group

population died (13.3%). Many authors showed an associationbetween low serum Leptin level and mortality [14] as Leptin

was found to stimulate proliferation of lympho-hematopoetic

cells and phagocytic activity of macrophages [35].

We detected in this study that the serum CRP levels on

admission, 2nd day, and 4th day following admission were sig-

nificantly higher in sepsis compared to non-infectious SIRS.

Many other studies [17,27,36] showed that a high serum

CRP concentration in patients within 24 h of admission to hos-

pital is indicative of sepsis and can differentiate septic patients

from non-infectious SIRS. Yousef et al, [8] however showed

that despite the mean values of CRP on admission cannot dif-

ferentiate between the two groups, the CRP level on the 4th

day of admission was significantly higher in sepsis compared

to non-infectious SIRS groups[8].C reactive protein production is a part of a larger picture of

the acute phase response. This is principally regulated by the

cytokines IL-6 [37], Tumor necrosis factor a, and IL-1b are

also regulatory mediators of CRP synthesis [38]. C-reactive

protein is directly involved in clearance of microorganisms

[39]. It causes activation of neutrophils and enhances NK cell

activity[40,41].

We detected a CRP level of 51 mg/L on the day of admis-

sion to have 93% sensitivity and 80% specificity for the

diagnosis of sepsis. Many other investigators described CRP

cut-off values for detection of sepsis. Povoa et al detected also

a level of 50 mg/L with sensitivity of 98.5% and specificity of

75%[42]. Liu et al, [17]found a value of 60 mg/L with a sen-sitivity of 80.7% and specificity of 96.0% for diagnosing bac-

terial infection. Higher cut-off values were reported by other

authors. Sierra et al, [43] showed the cut-off value of 80 mg/

L is 94.3% sensitive and 87.3% specific for sepsis[43]however

Miller and his colleagues reported a higher value of 170 mg/L

for CRP with 100% specificity[44].

In a study on postoperative patients, the investigators

found that the CRP started to be elevated 12 h and peaked

36 h after the operation [45]. Other authors reported that the

CRP starts to elevate within 46 h of stimulus and doubles

every 8 h to reach a peak at 3650 h[39]. On the other hand,

Leptin was found to start being elevated and peaked 24 h after

stimulus[45]. This could explain the lack of significance of ser-

um Leptin between both groups in our study on admission andon day 4 but the only significance was on day 2.

Despite the detection of an early serum CRP on admission

of 51 mg/L to have 80% specificity for the diagnosis of sepsis,

the later serum Leptin on day 2 of 38.05 lg/L was found to

have 100% specificity. The late yet more specific elevation of

serum Leptin level in sepsis needs to be further evaluated.

Conclusion

Serum CRP level can differentiate early between sepsis and

non infectious SIRS on admission, however on the second




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day of admission the use of elevated serum Leptin level may be

more specific than elevated CRP level either on admission or

on second day in identifying sepsis patients.

Study limitations

Limitations of this study included the limited number of sam-

ples of the biomarkers (only three samples) that may have

missed higher levels. Some other studies screened Leptin in6 h intervals; however we aimed at evaluating the patients on

admission. Another limitation was the limited number of pa-

tients included in the study; further studies are needed to con-

firm our results. Finally, Antibiotics had to be given early in

some patients with SIRS with no obvious infection, for the

possibility of hidden infection, which may have had an impact

on the markers. In other patients in which infection appeared

later could have had an occult infection that aggravated rather

than a superadded infection, and may not have been appropri-

ately assigned.

Conflict of interest

None declared.

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