SURGICAL INFECTIONS

Volume XX, Number XX, 2020 Original Article

ª Mary Ann Liebert, Inc.
DOI: 10.1089/sur.2020.348

Detection of Infection and Sepsis in Burns

Mark Jason M. Torres,1 Joshua M. Peterson,2, and Steven E. Wolf 2,3

Abstract

Background: Infection is the most frequent complication after severe burns and has a propensity to progress
into sepsis then septic shock and multiple organ dysfunction syndrome (MODS). Improving outcomes in acute
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burn care depends on early detection of infection to allow prompt interventions. Diagnosis of sepsis in severe
burns is uniquely challenging because otherwise-typical clinical signs are masked by the hypermetabolic state
and systemic inflammation induced by the burn itself. For this reason, burns have historically been excluded
from high-impact studies on the diagnosis and treatment of sepsis.
Methods: This article provides a comprehensive three-fold review of current findings and guidelines pertinent
to the early detection of infection and sepsis in severe burns.
Results: First, evidence-based detection of the most common infections encountered in the burn intensive care
unit is reviewed. Second, we analyze the evolution of the diagnostic criteria for sepsis and the evidence
regarding their utility in severe burns. Last, we examine the development of biomarkers, from procalcitonin to
molecular genomics, for the detection of sepsis.
Conclusions: Although gold standard methods of early detection of sepsis in burn patients have yet to be
identified, improved understanding and appropriate application of the available diagnostic criteria and assays
are paramount to providing effective care of patients with severe burns.

Keywords: burn; burn injury; burn wound; infection; pneumonia; procalcitonin; sepsis; sepsis biomarkers;
septic shock; wound infection

I nfection leading to sepsis, septic shock, and multiple

organ dysfunction syndrome (MODS) is well known as a
leading cause of death after severe burns, accounting for
article, we review the current modalities for the detection of
infections and sepsis in severe burns as well as explore why a
consensus regarding appropriate diagnostic methods has not
50%–60% of in-patient deaths [1,2]. With the growth of yet been achieved.
specialized burn units, implementation of fluid resuscitation,
and early excision and grafting of burn wounds, the historical Detection of Infection
trend of early shock-related death after severe burns has
Among patients admitted to the burn intensive care unit
transitioned to a trend of death from infection and sepsis after
(ICU), infection is the most frequent complication. Pneu-
prolonged hospitalization [3,4]. Burned patients are particu-
monia and wound infections are most common and often are
larly susceptible to wound infections and pneumonia (espe-
nosocomial in origin [5]. For the severely burned, unique
cially after inhalation injury), which can progress ultimately
considerations must be made during evaluation for possible
to sepsis. Establishing a timely diagnosis of sepsis has proved
pneumonia or wound infections.
uniquely challenging in the background of the intense hy-
permetabolic and inflammatory state associated with massive
Pneumonia
injury, confounding traditional clinical signs of sepsis and
greatly hindering the utility of contemporary diagnostic Respiratory infections are the most frequently reported
methods. Moreover, frequent fluctuations in the definition of infections in burned patients, who have the highest overall
sepsis as well as exclusion of burn patients from landmark rate of ventilator-associated pneumonia (VAP) (7.4%) of all
studies on sepsis have muddled investigative efforts. In this ICU sub-populations. Those with inhalation injury have four

1
School of Medicine, 2Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA.
3
Shriners Hospitals for Children, Galveston, Texas, USA.

1
 2 TORRES ET AL.
times the risk of developing VAP, a state caused by several
factors including prolonged mechanical ventilation with en-
dotracheal tubes, systemic immunosuppression, common
development of pulmonary edema, and direct pulmonary
tissue injury [6]. Specifically, direct tissue injury to the lower
respiratory tract predisposes to pneumonia through creation
of a pro-infectious microenvironment with massive cytokine
secretion and inflammation and subsequent protein-rich fluid
secretions, bronchial edema, failure of surfactant production
by injured type II pneumocytes, failure of mucous clearance
by injured ciliated cells, and formation of bronchial casts
from cellular sloughing. These pathophysiologic changes
precipitate alveolar collapse, atelectasis, and bacterial growth
leading to VAP, which occurs at a rate of 10%–60% after
inhalation injury and is the leading cause of death among
burn patients with nosocomial infections, who have a VAP
mortality rate of 40% [7]. Risk factors for contracting
pneumonia include grade 3 (severe) or grade 4 (massive)
inhalation injury on fiberoptic bronchoscopy (FOB), in-
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creasing burn size (total body surface area [TBSA] burned
>20%), PaO2/FiO2 ratio of <300 mm Hg on admission, car-
boxyhemoglobin concentrations of >10% on admission,
and a smoking history [8]. Patients are at highest risk of
developing VAP within the first 5 days of mechanical ven-
tilation (estimated at 3% per day) with a steadily declining
risk to 2% and 1% per day on days 5-10 and after day 10,
respectively [6].
Traditional clinical signs of pneumonia including pulmo-
nary infiltrates on radiographic imaging, fever, leukocytosis,
and purulent tracheobronchial secretions have notoriously
poor specificity in the diagnosis of VAP. Studies correlating
clinical diagnosis of VAP with post-mortem histologic ex-
amination and cultures demonstrate a sensitivity and speci-
ficity of clinical criteria as only 69% and 75%, respectively
[9]. Outside of autopsy, no gold standard exists for the di-
agnosis of VAP, complicating both treatment and meaningful
research.
To address this deficiency, the American Burn Association
(ABA) released guidelines for the diagnosis and treatment of
VAP in 2009, supporting a microbiologic approach to diag-
nosis via FOB with sampling of pulmonary flora by bronch-
ioalveolar lavage (BAL), mini-BAL, or protected specimen
brush sampling as the recommended diagnostic pathway in
patients who have VAP suspected on the basis of clinical
findings [10]. Then, in 2018, the International Society for
Burn Injuries (ISBI) released practice guidelines (part 2)
wherein the clinical and microbiologic diagnoses of pneu-
monia were defined as noted in Table 1. They affirmed that
BAL and subglottic sampling demonstrated equivalency to
protected specimen brush sampling in intubated burn patients
and are the preferred sampling methods [8].
Bronchoscopic microbiologic diagnosis of pneumonia in
burn patients has a sensitivity of 73% – 18% with a specificity
of 82% – 19%, and direct sampling is postulated also to have
therapeutic benefits through mechanical relief of bronchial
obstruction by suction of exudates [6]. In fact, patients with
inhalation injury who develop pneumonia and undergo FOB
have a shorter duration of mechanical ventilation (21 versus
28 days), decreased length of ICU stay (35 versus 39 days)
and hospital stay (45 versus 49 days), and a lower total cost of
care ($370,572 versus $473,654). However, no statistically
significant mortality benefit has yet been demonstrated [7]. It
is emphasized that treatment for pneumonia in patients
meeting the clinical criteria for diagnosis should not be de-
layed while awaiting microbiologic confirmation of infec-
tion. In the interim, initial antibiotic therapy may be guided
by Gram stain results as well as wound culture findings, as the
causative organism of pneumonia is found to be identical to
organisms isolated from wound cultures in approximately
50% of cases [8].
Wound infection
Immediately after a severe burn the affected skin surface
becomes sterilized and remains free of flora for approxima-
tely 2 days until flora from adjacent unaffected skin, the naso-
oropharyngeal tract, lower gastrointestinal tract, and the
environment proliferate over the wound [11]. Burn eschars
allow colonization of microorganisms through abundant co-
agulated protein, elemental co-factors, and protein-rich ex-
udates. The absence of leukocytes in eschar and loss of skin
barrier function sets the stage for proliferation of virulent
pathogens such as Staphylococcus aureus (both methicillin-
resistant and methicillin-sensitive), Pseudomonas aeruginosa,
Klebsiella spp., and Acinetobacter baumannii that outcom-
pete other organisms and develop as soon as 5–7 days after
injury [12].
Between the 1950s and early 1980s, initial therapy for burn
wounds included repetitive submersion hydrotherapy aimed
at breaking down eschars and promoting underlying wound
bed granulation prior to autografting while simultaneously
suppressing infection through application of topical anti-
septic agents such as silver sulfadiazine, mafenide acetate,
and silver nitrate. In addition to clinical signs of infection
such as rapid separation of eschar, foci of eschar discolor-
ation, suppurative secretions, and hematogenous spread of
organisms (i.e., ecthyma gangrenosum), the gold standard for
wound infection diagnosis during this era was tissue biopsy
with histopathologic analysis and quantitative culture; bac-
terial loads of >105 organisms/g signaled invasive infection
best treated with wound excision (Table 1). In 1981, a land-
mark paper by Woolfrey et al. [13] demonstrated marked
discordance of quantitative cultures (44% with a log10 dif-
ference of 2 or greater) when specimens were divided into two
separate cultures, casting doubt on their utility. Subsequently,
early excision and grafting of burn eschars was shown to
improve outcomes dramatically in part by preventing wound
infections through removal of the nutrient-rich eschar and
restoration of skin barrier function. Early excision and graft-
ing have since become widely implemented as standard of
care throughout the world.
Of late, wound cultures serve for surveillance of wounds
and to acquire qualitative and semi-quantitative data when
infection is suspected. In the ISBI 2018 guidelines, wound
surfaces should be cleansed with alcohol-based solutions
prior to sampling, and sampling should be guided by clini-
cal signs such as formation of exudates, widespread graft
loss, or systemic signs of infection. Importantly, surveillance
swabs should not guide initiation of antimicrobial therapy;
however, they provide useful information about organism
susceptibilities that guide decisions regarding antibiotic
coverage. Tissue biopsy with quantitative culture and his-
topathologic analysis retain utility in assessing fungal in-
fections and should be strongly considered when such
 DETECTING BURN INFECTION AND SEPSIS 3

Table 1. International Society for Burn Injuries (ISBI) 2018 Diagnostic Criteria
for Pneumonia and Wound Infection
Pneumonia
Clinical diagnosis
Two of the following are present:
1. Chest radiograph with a new and persistent infiltrate, consolidation, or cavitation
2. Sepsis
3. Recent change in sputum or purulence in the sputum

Microbiologic modifier: Clinical diagnosis Pathogen isolateda

Confirmed + +
Probable + -
Possibleb - +

Wound infection

Extent Bacterial load Local host response? Systemic host response? Wound healing slowed?
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Colonization W: <105 CFU/g - - -

Local infection W: >105 CFU/g + - +
Invasive infection W, T: >105 CFU/g + + +
Cellulitis Clinical diagnosisc + +/- +
a
Tracheal aspirate with ‡105 organisms, or bronchoalveolar lavage with ‡104 organisms, or protected specimen brush with ‡103
organisms.
b
Abnormal chest radiograph with uncertain cause and low or moderate clinical suspicion.
c
Adjacent unburned skin is warm, indurated, erythematous, tender.
+ = present, - = absent, CFU = colony-forming units; T = deep tissues; W = wound.

infection is suspected, as invasive fungal infections can
progress rapidly with high rates of death [8].
Detection of Sepsis
The progression of infection to sepsis, septic shock, and
MODS remains the leading cause of death in both adult
(50%–84%) and pediatric (55%) burn patients [14]. In 2016,
the Sepsis-3 criteria defined sepsis as ‘‘a life-threatening
organ dysfunction caused by a dysregulated host response to
infection’’ [15]. Unlike many other causes of sepsis, its clinical
diagnosis in severe burns is nuanced and elusive, clouded by a
storm of inflammatory cytokines known as damage-associated
molecular patterns (DAMPs) and the pathophysiologic hy-
permetabolic response they create. This confounding hyper-
metabolic response mimics systemic inflammatory response
syndrome (SIRS) patterns with tachycardia, tachypnea, ele-
vated body temperatures, and leukocytosis, which develop
reliably as a pathophysiologic response to large (>40%)
TBSA burns and persist for more than a year after injury [16].
The development of diagnostic criteria and assays for the
accurate and timely diagnosis of sepsis has been a subject of
tremendous investigative effort for more than three decades.
Evolution in sepsis definitions and diagnostic criteria
Prior to 1991, no formal or rigid diagnostic criteria for sepsis
existed. To improve the quality of epidemiologic and investi-
gative research, the Society of Critical Care Medicine and the
American College of Chest Physicians developed a definition
now known as Sepsis-1 (Table 2) [17]. Ten years later, Sepsis-
2 expanded SIRS to include a vast array of possible parameters
with infection only documented or suspected, with the openly
stated aim of improving bedside diagnosis rather than
facilitating precise parameters amenable to investigative
efforts [18,19].
Although MODS and the Sequential Organ Failure
Assessment (SOFA) score were referenced directly by
Sepsis-2, the focus of the definition rested on SIRS and
identification of infection. Importantly, the clinical studies
of sepsis on which these definitions and criteria were con-
structed excluded burned patients [1,8].
In 2007, the ABA convened 23 experts to devise consensus
definitions specific to burn sepsis, arguing that the Sepsis-2
criteria were too inclusive to be applicable to severe burns and
did not account for the hypermetabolic state. It made several
changes as defined in Table 2, notably the presence of a large
burn (>20% TBSA), establishment of higher thresholds of SIRS
parameters, abandonment of severe sepsis, and addition of
thrombocytopenia, hyperglycemia, and intolerance of enteral
feeding as triggers for concern [20]. Furthermore, emphasis was
placed on burn sepsis being defined as a change in patient status.
A subsequent retrospective study by Mann-Salinas et al.
evaluated the effectiveness of the ABA criteria in adult burn
patients and found that they were predictive of sepsis one day
prior to the drawing of blood for culture with an area under the
receiver operator curve (AUROC) of 0.619. Using a statistical
regression model, they were able to define six sepsis predic-
tors that improved the AUROC to 0.775 but which did not
prove to be accurate in prospective studies [21,22].
Again in 2016 as a product of the Surviving Sepsis Cam-
paign, Sepsis-3 guidelines revised the definitions, abolishing
SIRS and severe sepsis and incorporating host organ response
into the definition. The SOFA was formally incorporated, with
a score of 2 or greater requisite for diagnosis [15]. Despite
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Table 2. Evolution of Adult Sepsis Diagnostic Criteria and Definitions

Criteria Sepsis-3 (2016) ABA burn sepsis (2007) Sepsis-2 (2001) Sepsis-1 (1991)
Sepsis 1. Infectiona 1. Burn injury >20% TBSA 1. Infectiona 1. Infectiona
2. Acute change in SOFA 2. Documented infection 2. Someb of the following: 2. SIRS
j
score ‡2 Positive cultures, or General
j
Tissue source, or T > 38.3C or <36C; HR >90 min-1; VR
j
Clinical response to >20 min-1; AMS; significant edema or
SOFA score with 0–4-point antibiotics fluid retention; BG >120 mg_dL-1 (no SIRS defined as ‡2 of the
range: 3. ‘‘Triggers’’ ‡3 of these: diabetes) following:
j j
Respiration PaO2/FiO2: ‡400 T > 39C or <36.5C Inflammatory T > 38C or <36C
j j
to <100 HR >110 min-1 WBC >12,000 mm-3 or <4000 mm-3 or HR >90 min-1
j j
Coagulation PLT: >150,000 RR >22 min-1 or PaCO2 >10% immature forms; CRP >2 SD VR >20 min-1
to <20,000 mm-3 < 32 mm Hg above normal; PCT >2 SD above or PaCO2 < 32 mm Hg
j j
Liver Total bilirubin: <1.2 to PLT <100,000 mm-3 normal WBC >12,000 or
>12.0 mg_dL-1 (‡3 d after resuscitation) Hemodynamic <4,000 mm-3 or >10%
j
Cardiovascular MAP: ‡70 to BG >200 mg_dL-1; SBP <90 mm Hg, MAP <70, or SBP immature forms
‡70 mm Hg with >7 units_h-1 intravenous decrease >40 mm Hg; SVO2 > 70%;
vasopressors insulin, or >25% dose CI >3.5 L_min-1_m-2
CNS GCS: 15 to <6 increase in 24 h. Organ dysfunction
j
Renal Cr <1.2 to Intolerance of enteral PaO2/FiO2 < 300; UOP
>5.0 mg_dL-1; UOP >500 feeding for >24 h <0.5 mL_kg-1_hr-1; Cr elevation
to <200 mL_d-1 (abdominal distention, >0.5 mg_dL-1; INR >1.5 or aPTT

4
diarrhea >2.5 L_d-1) >60 sec; bowel sounds absent; PLT
<100,000 mm-3; total bilirubin
>4 mg_dL-1
Tissue perfusion
Lactate >1 mmol_L-1; decreased capillary
refill; mottling

Severe sepsis [abandoned] [abandoned] 1. Sepsis 1. Sepsis

2. Organ dysfunction 2. Hypotension,c
(SOFA or Marshall MOD score hypoperfusion, or organ
recommended) dysfunction

Septic shock 1. Sepsis 1. Sepsis 1. Sepsis 1. Sepsis

2. Vasopressors given for 2. Lactate >4 mmol_L-1 2. Hypotensionc 2. Hypotensionc
MAP <65 mm Hg 3. Organ dysfunction 3. Hypoperfusion or organ
3. Lactate >2 mmol_L-1 (SOFA or Marshall MOD score dysfunction
recommended)
aPTT = activated partial thromboplastin time; AMS = altered mental status; BG = blood glucose; CI = cardiac index; CNS = central nervous system; Cr = creatinine; CRP = C-reactive protein;
FiO2 = fraction of inspired oxygen; GCS = Glasgow Coma Scale; HR = heart rate; INR = International Normalized Ratio; MAP = mean arterial pressure; PCT = procalcitonin; PaO2 = arterial partial
pressure of oxygen; PLT = platelets; SBP = systolic blood pressure; SIRS = systemic inflammatory response syndrome; SOFA = Sequential Organ Failure Assessment; SVO2= mixed venous oxygen
saturation; T = temperature; TBSA = total body surface area; UOP = urine output; VR = ventilatory rate; WBC = white blood cell count.
a
Either documented or suspected.
b
No discrete number of symptoms was published; the stated goal was to facilitate bedside diagnosis instead of creating standardized diagnostic criteria [19].
c
Defined as SBP <90 mm Hg or reduction in SBP ‡40 mm Hg.
 DETECTING BURN INFECTION AND SEPSIS 5

(Fig. 1) [23]. The following are notable examples of candi-

date serum biomarkers.
PCT (ng/mL), suPAR (ng/mL)

10
and Lactate (mmol/L)

CRP Procalcitonin. Procalcitonin (PCT) is a serum protein with

8
considerable potential for use in the detection of sepsis in pa-
6 tients with severe burn injuries. Measurement of PCT has
PCT
Lactate gained attention in the critical care setting because of its notably
4
consistent correlation with the course of bacterial infection. It is
2
an endocrine hormone of the thyroid gland and precursor to
IL-6
TNF- calcitonin that plays an indirect role in calcium metabolism and
IL-10
0 has undetectable serum concentrations under normal condi-
0 1 2 6 12 24 48 72
Time (hours) tions. However, during a systemic inflammatory response and
in the presence of microbial endotoxin, it is released into the
FIG. 1. Time course of sepsis biomarker elevation after circulation by non-endocrine tissues including the lung, kidney,
pathogen exposure. Borrowed and modified with permis- and omentum [24]. Unlike other serum biomarkers, the utility
sion from University of California Davis Department of Pa- of PCT lies in its responsiveness to both inflammatory medi-
thology [23]. CRP = C-reactive protein, IL-6 = interleukin 6, ators and bacterial lipopolysaccharide (LPS) [24,25]. Similarly,
IL-10 = interleukin 10, PCT = procalcitonin, TNF-a = tissue fungal toxins elicit an increase in PCT, but to a lesser extent
necrosis factor alpha.
than bacterial LPS because of activation of an alternative cy-
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tokine response involving interferon (IFN)-g [26]. Although

Sepsis-3, the ISBI practice guidelines published in 2018 af-
terward re-affirmed the previously instituted ABA consensus
definitions as standard of care in burn patients [8]. Ironically, a
prospective study by Yan et al. [22] published the same year
compared the predictive value of ABA criteria, the afore-
mentioned Mann-Salinas criteria, and Sepsis-3 in adult burn
patients, discovering that they correctly predicted sepsis in
59%, 28%, and 85% of patients, respectively, at 48 hours prior
to clinical diagnosis of sepsis. Although at this time the evi-
dence most supports Sepsis-3 for the reliable diagnosis of burn
sepsis, this has not been formally embraced in treatment
guidelines and remains to be corroborated.
Serum biomarkers investigated for early
detection of sepsis
The lack of robust clinical criteria capable of timely and
specific diagnosis of burn sepsis as well as the magnitude of
clinical impact imparted by early treatment has triggered a
massive undertaking to search for methods for the early de-
tection and diagnosis of sepsis. A wide spectrum of inflam-
matory and molecular serum biomarkers identifiable early in
the course of infection has already undergone investigation
PCT is useful in the detection of bacterial and fungal infections,
its measurement is limited in detecting viruses, likely because
of the highly potent viral inhibition of tumor necrosis factor
(TNF)-a by IFN-g, effectively suppressing measurable PCT.
With regard to bacterial sepsis, a meta-analysis in 2019 by
Kondo et al. [27] showed an AUROC of 0.84 with a pooled
sensitivity of 80% and specificity of 75% (Table 3). Although
a sizable proportion of the literature acknowledges PCT’s
diagnostic accuracy in early detection of bacterial sepsis in
the critically ill, its clinical utility has been called into
question. Notably, Jensen et al. [28] in 2011 published the
results of the Procalcitonin and Survival Study (PASS) ran-
domized clinical trial, which recruited 1,200 critically ill
patients to evaluate the effectiveness of PCT-guided early
antibiotic therapy in improving sepsis survival. This strategy
yielded an absolute risk reduction of 0.6% contrasted with the
standard of care, which was not statistically significant.
Nonetheless, mounting evidence exists for the diagnostic
value of PCT in the care of burned patients. The relation
between PCT and sepsis has been explored throughout the
past three decades, and studies continue to report evidence in
favor of PCT’s diagnostic utility in burn patients. One such
investigation assessed the diagnostic capabilities of PCT

Table 3. Accuracy of Serum Biomarkers for Detection of Sepsis in Burn Injury

Studied
Sensitivity Specificity exclusively in
Marker (%) (%) AUROC burn patients Predictive value Type of study
PCT 80 75 0.84 N Sepsis in ICU Meta-analysis [27]
74 88 0.92 Y Early sepsis Meta-analysis [30]
77 65 0.83 Y Early sepsis Meta-analysis [31]
CRP 80 61 0.73 N Early sepsis Meta-analysis [36]
92 58 0.82 Y Sepsis Prospective [54]
IL-6 68 73 0.80 N Sepsis Meta-analysis [38]
IL-8 75–80 75–80 0.88 Y Sepsis Prospective [42]
IL-10 85 84 0.87 Y Sepsis; death Prospective [55]
92 93 NR Y Sepsis; survival Observational [56]
TNF-a 68 88 0.93 N Sepsis in neonatal infants Meta-analysis [56]
mRNA (RT-PCR) 91 80 NR N Sepsis in ICU Observational [53]
CRP = C-reactive protein; IL = interleukin; mRNA = messenger RNA; N = no; NR = not reported; PCT = procalcitonin; RT-PCR = reverse
transcriptase polymerase chain reaction; TNF-a = tumor necrosis factor; Y = yes.
 6 TORRES ET AL.
compared with C-reactive protein (CRP), erythrocyte sedi-
mentation rate (ESR), and white blood cell (WBC) count. Not
only was PCT found to have excellent diagnostic accuracy in
the prediction of infection, but it also was the only serum marker
that displayed an observable difference between septic and
non-septic cases [29]. Two recently completed meta-analyses
demonstrated findings in burn sepsis largely consistent with
each other and earlier works, with an AUROC of 0.92 [30] and
0.83 [31]. Furthermore, a later study determined that elevated
serial measurements of PCT during the first five days after burn
injury were strongly associated with the development of sepsis
[32]. In addition to its diagnostic ability, contrasting concen-
trations of PCT may be able to help distinguish gram-negative
from gram-positive bacterial infection, with significantly higher
concentrations indicating gram-negative infections [33].
C-Reactive Protein. C-reactive protein (CRP) is a thor-
oughly studied acute-phase reactant and serum biomarker of
inflammation that is produced primarily in the liver and up-
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regulated by interleukin-6 (IL-6) [34]. Its concentration cor-
relates strongly with burn size, and higher concentrations tend
to be found in women and non-survivors [35]. Beyond these
findings, its utility for the detection of sepsis is not supported,
as demonstrated in a meta-analysis of nine studies published
in 2018 by Tan et al. [36], reporting a sensitivity of 0.80 and
specificity of 0.61. Jeschke et al. [35] carried out the largest
cohort study to date specifically for sepsis detection in burned
patients, with a total of 918 pediatric enrollees included in the
analysis. The investigation confirmed that CRP was unable to
predict sepsis at any change in threshold between 0 and 20 mg/
dL. Although widely available, its use is not recommended in
routine burn critical care.
Interleukins 6, 8, and 10. Interleukin (IL)-6 is a major
acute-phase reactant released by T cells and macrophages at the
site of injury, and its utility in the diagnosis of infection has
been well studied [37,38]. In a meta-analysis of 20 studies on
adults with SIRS, IL-6 was determined to be of diagnostic value
comparable to that of PCT in its ability to detect sepsis, with IL-
6 having a pooled sensitivity of 0.68 and specificity of 0.73
[38]. In burned patients, patterns of elevated concentrations are
biphasic, peaking at both early and late time points after severe
burns. Monitoring for persistently high concentrations of IL-6
may raise suspicion of upcoming sepsis in patients with burns
[39]. However, IL-6 remains questionable in its clinical utility
for the detection of sepsis. Tsalik et al. [40] studied a cohort of
336 adults with suspected sepsis, and IL-6 was demonstrated to
have an insignificant value in discriminating between severity
of infection compared with PCT and CRP.
Interleukin-8 is a pro-inflammatory cytokine that is notably
released during the acute period of injury and acts as a potent
attractant for neutrophils, promoting their migration into the
affected area [41]. Investigations have highlighted a clinical
value in IL-8 that is primarily prognostic rather than diagnostic,
in which a relation exists between its serum concentration and
the likelihood of sepsis and survival. In a large cohort study by
Kraft et al., IL-8 was measured in 468 pediatric burn patients
with TBSA of >30%, in which concentrations above a threshold
of 234 pg/mL indicated a higher likelihood of multiorgan dys-
function, sepsis, and death [42]. Persistently elevated IL-8 cor-
relates with a poorer prognosis and high possibility of infection
in burn patients [39].
Interleukin-10 mediates the immune response to infection,
primarily inhibiting inflammatory activities of macrophages
and Th1, NK, and B cells in an attempt to downregulate the
pro-inflammatory state [43]. Assessment of IL-10 in isolation
from other serum biomarkers has limited utility, yet it may
provide further insight into the prognostic trajectory of burn
injury and sepsis. Similar to findings in IL-8, burn patients
who develop sepsis tend to have remarkably higher concen-
trations of IL-10, which remain elevated for as long as 14 days
after injury and into the development of infection [44,45].
Tumor Necrosis Factor-a. During the acute period after a
severe burn, macrophages on location participate in the immune
response by secreting tumor necrosis factor (TNF)-a which
upregulates the activity of pro-inflammatory cytokines [46].
Because TNF-a also is released after infection, studies have
explored its value in the recognition of sepsis. Significantly
elevated concentrations of TNF-a were measured in burned
patients at the time of admission, with a second elevation of
TNF-a occurring later in the hospital course [44,46]. Subsequent
studies reported that lower ratios of TNF-a to IL-10 were highly
predictive of repeated episodes of infection and were correlated
inversely with burn size [47]. However, the utility of TNFa in
the detection of sepsis still is limited because of conflicting data
in some populations. For example, TNF-a concentrations do not
become elevated in elderly patients regardless of sepsis devel-
opment during the first 30 days after the burn, which may be
related to a latent or impaired host immune response [48].
Molecular Markers. In recent years, emerging interest has
developed for cellular and molecular laboratory techniques in
the detection of sepsis in burned patients based on encour-
aging findings in the fields of genomics and transcriptomics.
By using widely available genomics assays to identify sets of
relevant genetic markers, these tools may provide highly
accurate and reliable means of early recognition of sepsis. For
example, carriers of particular alleles relating to expression
of interleukins, TNF-a, and Toll-like receptor 4 have a higher
risk of sepsis and death after severe burns [49–51].
Epigenetic processes, such as DNA methylation and histone
modification, may also be useful in early detection of sepsis and
can specify the bacterial etiology [52]. Studies on transcribed
mRNA and smaller, non-coding microRNA that are involved in
the pro-inflammatory state indicate the potential of a diagnostic
pattern for identifying sepsis. One study measured expression
of a panel of seven cytokine genes using real-time reverse
transcriptase polymerase chain reaction together with non-
linear neural network analysis and demonstrated that they
could predict sepsis accurately as early as four days prior to
onset with a sensitivity and specificity of 91.4% and 80.2%,
respectively [53]. Proteomics and metabolomics are two
additional fields of analysis where pattern recognition and
molecular expression can be utilized for sepsis recognition.
Conclusions
Early intervention is critical to improve outcomes of sep-
sis, but early treatment necessitates early detection. Despite
the existence of criteria specific for burn sepsis published by
the American Burn Association, they have not been reliable
in prospective studies beyond the contemporary Sepsis-3
criteria. Investigation of serum biomarkers of sepsis also has
 DETECTING BURN INFECTION AND SEPSIS
yet to produce a gold standard or widely implemented assay.
Hope persists that reliable criteria and assays will be identi-
fied for the early detection of burn sepsis. Meanwhile, a
thorough understanding and appropriate application of the
available diagnostic criteria and assays are paramount in
providing care of severe burns.
Acknowledgments
We thank Dr. Nam K. Tran and the University of Cali-
fornia Davis Department of Pathology for allowing us to
reproduce a modified version of Figure 1 [23].
Author Disclosure Statement
The authors have no disclosures related to this article.
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Address correspondence to:
Dr. Joshua M. Peterson
Division of Plastic Surgery
Department of Surgery
University of Texas Medical Branch
301 University Boulevard
6.124 McCullough Building
Galveston, TX 77555-0724
USA
E-mail: jopeters@utmb.edu