ORIGINAL ARTICLE
Mediators of Inflammation in Asthma
A Forensic Perspective
Maria Laura Schirripa, MD,* Maria Pia Scarpelli, MD, and Cristian Palmiere, MD
Abstract: In the clinical setting, the role of systemic inflammation in pa-
tients with asthma has attracted increased attention, and some authors
showed that increased IL-6 and high-sensitivity C-reactive protein charac-
terized a group of asthmatic patients. In the realm of forensic pathology, a
postmortem diagnosis of asthmatic death can be extremely challenging.
The aim of this study was to determine the postmortem serum levels of
C-reactive protein, IL-6, and tumor necrosis factor in a series of severe
acute bronchial asthma deaths that underwent medicolegal investigations.
A total of 35 autopsy cases were retrospectively selected and included
deaths in asthmatic subjects (related and unrelated to severe acute bronchial
asthma, in situations characterized or not by systemic inflammation) as
well as deaths in nonasthmatic individuals (in situations characterized or
not by systemic inflammation). Our findings suggest that IL-6 is selectively
increased in the systemic circulation of individuals with asthma, irres-
pective of whether the cause of death depends on a fatal asthma attack,
compared with other biomarkers. Accordingly, postmortem serum IL-6
values in cases of death during severe acute bronchial asthma can be mea-
sured and considered of diagnostic relevance to estimate the magnitude of
the systemic inflammation responses characterizing the disease.
Key Words: asthma, systemic inflammation, postmortem biochemistry,
autopsy
(Am J Forensic Med Pathol 2017;38: 153158)
A sthma is a heterogeneous, chronic inflammatory disease of
the airways characterized by inconstant and mostly reversible
respiratory pathway obstruction based on a chronic bronchial in-
flammatory reaction. Symptoms (cough, rhonchus, wheezing,
chest tightness, and/or shortness of breath) vary and are correlated
to expiratory flow limitation. An estimated 300 million people
worldwide experience asthma. Prevalence of this disease has been
increasing over the last 40 years, and it is one of the most common
chronic diseases among young adults in the Western society.14
Asthma has traditionally been described as a T-helper typ. 2
(Th2) lymphocyte-mediated condition in which allergen presenta-
tion by antigen-presenting cells to naive T cells results in Th2
cell differentiation.1,5,6
Immunoglobulin E (IgE) is one of the key contributors to the
proinflammatory cascade in allergic asthma. Allergens enter the
airways and are presented by antigen-presenting cells to T lym-
phocytes, which initiate the cell-mediated immune response.
The Th2 cells and their associated cytokine milieu stimulated B
cells to produce IgE antibodies and proallergic cytokines.1,7
Manuscript received September 5, 2016; accepted January 22, 2017.
From the *Medicina Legale Parma, Parma, Italy; and CURML, University
Center of Legal Medicine, Lausanne University Hospital, Lausanne,
Switzerland.
The authors report no conflict of interest.
Reprints: Cristian Palmiere, MD, CURML, University Center of Legal
Medicine, Lausanne University Hospital, Chemin de la Vulliette 4 1000,
Lausanne 25, Switzerland. E-mail: cristian.palmiere@chuv.ch.
Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0195-7910/17/38020153
DOI: 10.1097/PAF.0000000000000306
Am J Forensic Med Pathol Volume 38, Number 2, June 2017
Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved.
The classic paradigm in the early asthmatic response is mast
cell degranulation induced by antigen-mediated cross-linking of
IgE bound to the surface high affinity IgE receptor. Free IgE re-
leased from B cells binds to the high affinity IgE receptor on the
surface of mast cells and basophils. The receptor bound IgE is
then cross-linked by an allergen and triggers degranulation
as well as release of prostaglandins, leukotrienes, histamine,
tryptase, chymase, and cytokines, which all lead to the early
allergic response.1,810
Asthma is characterized by episodic symptoms and variable
airflow obstruction that occur either spontaneously or in response
to environmental exposure. Severe asthma affects up to 10%
of the asthma population and remains poorly understood with
few therapeutic options. Unfortunately, asthma deaths still occur,
although why some patients succumb to asthma and others do
not is unknown.11,12
In the clinical setting, asthma endotypes have been defined
based on distinct pathophysiological features, therefore reflecting
the corresponding mechanisms. More recently, the role of sys-
temic inflammation in patients with asthma has attracted increased
attention. For instance, Wood et al13,14 showed that increased sys-
temic inflammation markers (IL-6 and high-sensitivity C-reactive
protein [CRP]) characterized a group of asthmatic patients with
neutrophilic airway inflammation, and was associated with worse
clinical outcome.
In the realm of forensic pathology, a postmortem diagnosis of
asthmatic death can be extremely challenging in the absence of
suggestive circumstantial data and patient medical information.
Indeed, macroscopic features of pulmonary hyperinflation and
mucus plugging in the airways can sometimes be modified by
attempted resuscitation. Analogously, microscopic findings do
not always correlate with the severity of clinical manifestations.
Indeed, relatively innocuous morphological features may be found
in witnessed asthmatic deaths, whereas more impressive macro-
scopic and microscopic findings may be incidental in deaths that
have unrelated causes.15,16
Postmortem serum levels of mast cell-derived tryptase have
occasionally been measured in patients who died of acute, severe
bronchial asthma. By contrast, systemic inflammation markers
have never been measured in cases of fatal asthma in the
forensic setting.17,18
The aim of this study was to determine the postmortem se-
rum levels of CRP, IL-6, and tumor necrosis factor (TNF-)
in a series of severe acute bronchial asthma deaths that underwent
medicolegal investigations. Our goal was to characterize the post-
mortem serum levels of the tested biomarkers and therefore eval-
uate the usefulness of their determination for diagnostic purposes
in cases of fatal asthma attacks.
MATERIALS AND METHODS
Study Design and Study Populations
The present study was carried out in 2016, concerning med-
icolegal autopsies performed between 2008 and 2016. A total of
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Schirripa et al
35 autopsy cases (25 male subjects and 10 female subjects) with a
mean age of 46 years (range, 1271 years) were retrospectively
selected and included the following:
four cases of death in asthmatic subjects (allergic asthma and
short duration attacks), in which the cause of death was deter-
mined to be severe acute bronchial asthma;
eight cases of death in asthmatic subjects (allergic asthma), in
which the cause of death was considered to be unrelated to se-
vere acute bronchial asthma and unrelated to systemic inflam-
mation. The causes of death in this group were suicide by
hanging or gunshot wounds and sudden (arrhythmic) cardiac
death. All these cases were characterized by a survival time less
than 1 hour;
seven cases of death in asthmatic subjects (allergic asthma) in
situations characterized by systemic inflammation (multiple
traumas with a survival time greater than 8 hours). The cases se-
lected for this group consisted of road traffic victims (crash-
involved cyclists or pedestrians) and high falls admitted to hos-
pital. In all these cases, multiple traumas led to progressive,
multiple organ failure and the cause of death was determined
to be multiple traumas. The cause of death was considered to
be unrelated to severe acute bronchial asthma;
eight cases of death in nonasthmatic and nonatopic individuals,
in whom the cause of death was considered to be unrelated to
systemic inflammation. The causes of death in this group were
suicide by hanging or gunshot wounds, and sudden (arrhythmic)
cardiac death. All these cases were characterized by a survival
time less than 1 hour; and
eight cases of deaths in nonasthmatic and nonatopic individuals
in situations characterized by systemic inflammation (multiple
traumas with a survival time greater than 8 hours). The cases
selected for this group were similar to those selected in the
asthmatic individuals, consisting of road traffic victims
(crash-involved cyclists or pedestrians) and high falls admitted
to hospital. In all these cases, multiple traumas led to progressive,
multiple organ failure, and the cause of death was determined to
be multiple traumas.
All cases selected for the study originated from forensic prac-
tice and underwent medicolegal autopsies as requested by local
inquiring authorities (the public prosecutor). Postmortem interval,
defined as the time between death (or body discovery) and periph-
eral blood sampling at autopsy, ranged from 16 to 50 hours.
Laboratory analyses, including CRP, IL-6, and TNF- deter-
mination, were performed as part of medicolegal investigations.
Availability of postmortem serum was the most important crite-
rion for case inclusion. Police reports, medical records, and clini-
cal histories of the deceased (including allergy details and asthma
severity as well as data pertaining to medical asthma treatments)
were consistently reviewed before conclusions were made. Investi-
gated atopic diseases and allergies included atopic dermatitis, aller-
gic rhinitis, rhinosinusitis, asthma, atopic and allergic conjunctivitis,
and keratoconjunctivitis, eczema, urticaria, drug allergies, food
allergies, and multiple allergies.
Postmortem Investigations
Unenhanced computed tomography scans were performed
before any manipulation of the corpses in all cases included in
this study.
Complete, conventional medicolegal autopsies, histology,
toxicology, and biochemical investigations were carried out in
all cases.
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Am J Forensic Med Pathol Volume 38, Number 2, June 2017
Medicolegal autopsies were jointly performed by 2 forensic
pathologists (at least 1 is board certified) as in accordance with both
local standards and international guidelines for medicolegal cases.
Conventional histology included hematoxylin-eosin stains
of brain, heart, lung, liver, and kidney samples. Representative
samples of the myocardium and coronary arteries were obtained
during autopsy for each case. Tissue samples were embedded in
wax, cut into 5 m sections and then stained with hematoxylin-
eosin stain. All samples were observed using light microscopy.
Assessment of asthma severity grading from absent, mild, moder-
ate, and severe was performed based on histological evaluation of
lung sections. Subjective grading used in this study was a combi-
nation of the severity of various histological features (mucus plugs
in airway lumen, airway wall inflammation with neutrophil and/or
eosinophil and/or mast cell infiltrates, subepithelial basement
membrane thickening, smooth muscle cell hypertrophy, mucous
gland hyperplasia, and vascular congestion).
Death from asthma was defined as macroscopic evidence of
lung hyperinflation and overexpansion, macroscopic evidence of
mucus plugging, histological evidence of features of asthma, and
exclusion of alternative causes of death based on all postmortem
investigation findings.
Biochemical investigations systematically included measure-
ment of mast cell tryptase, total IgE, and specific IgE to inhalant
allergens, CRP, IL-6, and TNF-. All these parameters were mea-
sured in postmortem serum from femoral blood.
Sample Collection
Peripheral blood from the femoral veins was systematically
collected for toxicology and postmortem biochemistry as soon
as possible, upon arrival of the bodies at the morgue, and before
the autopsy. Femoral blood samples were collected by aspiration
with sterile needles and syringes from the femoral vein(s). Blood
samples were drawn after clamping the vein(s) at the proximal end
and lifting the lower limb(s) for several minutes. Samples were
stored in tubes containing sodium fluoride and preservative-free
gel serum separator tubes. These were centrifuged immediately
after collection at 3000g for 15 minutes. After centrifugation,
the separated supernatant substance (postmortem serum) was col-
lected and stored in preservative-free tubes. No specimens were
excluded because of insufficient sample volume. Postmortem se-
rum samples were transferred to the laboratories immediately after
collection. When analyses were delayed, samples were stored
at 20C.
Laboratory Assays
Mast cell tryptase and total IgE were measured with a commer-
cial fluoroenzyme immunoassay method (Pharmacia & Upjohn,
Fisher Scientific, Thermo Fisher Scientific, Pittsburgh, Pa).
Phadiatop test was systematically used to detect the presence
of IgE specific to inhalant allergens. Results were expressed as
positive or negative.
The level of CRP (immunoturbidimetric Tina-quant CRP)
was determined by Roche standard methods using the Roche
Modular P system (Roche Diagnostics GmbH, Mannheim,
Germany). Results were expressed in milligrams per liter.
Both IL-6 and TNF- measurements were performed using a
commercially available multiplex beads immunoassay, based on
the Luminex platform (Fluorokine MAP Multiplex Human Cyto-
kine Panel; R&D Systems, Minneapolis, Minn) according to the
supplier's instructions. Results were expressed in picogram
per milliliter.
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Am J Forensic Med Pathol Volume 38, Number 2, June 2017
Increased postmortem serums CRP, IL-6, and TNF-, sug-
gesting the presence of generalized inflammation, were chosen
based on former medicolegal investigation results.
Ethics
All relevant ethical issues were identified and discussed with
the local ethical committee. All cases included in this study
underwent medicolegal autopsies as requested by the inquiring au-
thorities. Postmortem serum is routinely collected during autopsy
for toxicological and/or biochemical purposes in our facility.
Moreover, postmortem biochemical analyses are routinely per-
formed as part of medicolegal investigations. All biological sam-
ples were anonymized before the analysis and analyzed in the
same laboratory. Hence, no ethical approval was necessary to
perform biochemical analyses in the collected cases.
Statistical Analysis
Data were analyzed using GraphPad Prism software 6.0
(GraphPad Software, Inc, La Jolla, Calif ) as a statistical unit. Con-
centrations of mast cell tryptase and total IgE were compared
nonparametrically by the Mann-Whitney U test. The P values that
are less than 0.05 were considered statistically significant.
RESULTS
Table 1 summarizes the measured ranges for CRP, IL-6, and
TNF- in the studied groups. Further laboratory investigations
failed to provide additional information in interpreting these data,
and results were not reported.
In the group of severe acute bronchial asthma deaths, mast
cell tryptase concentrations ranged from 58 to 120 ng/mL (clinical
reference value in the laboratory where the analysis was per-
formed, 13 ng/mL). Total IgE concentrations ranged from 139 to
818 kU/L (clinical reference value in the laboratory where the
analysis was performed, 550 kU/L). Phadiatop test was positive
in all cases. Lung hyperinflation, mucus plugs in the airway
lumen, smooth muscle cell hypertrophy, submucosal gland hyper-
plasia, vascular congestion, and airway wall inflammation includ-
ing neutrophils, eosinophils, and mast cells of various degrees
were observed in all cases.
Postmortem serum IL-6 levels were significantly increased
in all asthmatic deaths (irrespective of the cause of death) and
nonasthmatic deaths with systemic inflammation.
Statistically significant differences could not be observed
either between asthma death versus asthmatics with other causes
of death or between asthma death versus nonasthmatics with
severe inflammation.
Analogously, no statistically significant differences could be
noticed between asthmatics with systemic inflammation and
nonasthmatics with systemic inflammation.
By contrast, postmortem serum CRP and TNF- concentra-
tions were significantly increased exclusively in both asthmatic
and nonasthmatic deaths with a generalized inflammatory response
TABLE 1. Summary of Measured Ranges for CRP, IL-6, and TNF- in the Studied Groups
Tested Biomarkers and Studied Population
Asthmatics severe acute bronchial asthma deaths (n = 4)
Asthmatics suicide and arrhythmic death (n = 8)
Asthmatics systemic inflammation (n = 7)
Nonasthmatics suicide and arrhythmic death (n = 8)
Nonasthmatics systemic inflammation (n = 8)
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Mediators of Inflammation in Asthma
compared with the other studied groups, thus confirming the ex-
istence of underlying systemic inflammatory processes at the
time of death (P < 0.05 for all comparisons). No statistically sig-
nificant differences were noticed in either parameter between
asthmatics with severe inflammation and nonasthmatics with
severe inflammation.
Globally considered, these results seem to suggest that IL-6
could be selectively increased in the systemic circulation of indi-
viduals with chronic asthma (irrespective of whether the cause
of death depends on a fatal asthma attack) compared with other
systemic inflammatory and proinflammatory biomarkers. These
findings might therefore indicate that bronchial asthma is charac-
terized by a condition of persistent IL-6mediated generalized
inflammation that is to some extent comparable, from a biochem-
ical point of view, to other situations of forensic interest in which
systemic inflammation is a distinctive pathophysiological feature.
DISCUSSION
Cytokines are glycoproteins synthesized and released by a
variety of (although not exclusively by) inflammatory cells, which
play an important role in orchestrating the inflammatory response
in several conditions including bronchial asthma. The cytokine
family consists of interleukins, chemokines (chemotactic cyto-
kines), TNF, colony-stimulating factor, interferons, growth factors,
and suppressor factors. Their properties encompass regulation of
the amplitude as well as the duration of immune and inflammatory
responses, paracrine activity at very low concentrations, and inter-
action with high-affinity receptors on the cell surface.19,20
Severe acute asthma can be precipitated by different triggers
including inhaled allergens, irritants, and viruses. Asthma triggers
can cause airway inflammation, provoke acute bronchocons-
triction, or both. Acute severe asthma can affect diverse patients
with different clinical features in terms of severity, stability,
outcome, and response to available treatments. This phenotypic
diversity can be accounted for by distinct inflammatory mecha-
nisms underpinned by peculiar molecular pathways. This patient
heterogeneity, and the variety of triggering agents, is such that it
is therefore impossible to identify a typical inflammatory profile
for severe acute asthma.21,22
Cytokine networks play a decisive role in coordinating
asthma inflammation. Indeed, differences in cytokine patterns that
are involved in cell recruitment and T-cell regulation account for
different inflammation features. Proinflammatory cytokines such
as IL-6 and TNF- act by amplifying the inflammation response
and thus determine disease severity. Growth factors are responsi-
ble for the persistence of certain inflammatory cells and structural
changes that occur in the lungs of asthmatic patients. Cytokines
sources are plural, including lung epithelial cells and inflamma-
tory cells. Some cytokines, such as TNF-, act as amplifiers of
the inflammatory response through their ability to activate the
transcription factor nuclear factor-B, a key activator of cytokine
and chemokine gene expression.23,24
IL-6, pg/mL CRP, mg/L TNF-, pg/mL
389808 616 39205
425726 812 51191
398881 29135 80506
25149 416 11152
525782 31156 105487
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Schirripa et al
In addition to cytokines, the acute phase reactant CRP is also
associated with systemic inflammation and tissue damage. A
number of studies have demonstrated that increased levels (mea-
sured by high-sensitivity assays in most cases) may be observed
in the presence of airflow obstruction, thus indirectly indicating
airway inflammation severity in asthma.2536
Eosinophilic inflammation is a characteristic feature of some
(but not all) patients with severe asthma, and TNF- has been
demonstrated to play a central role in promoting eosinophilia in
asthma. The TNF- is produced by a variety of inflammatory cells
including neutrophils, in response to various stimuli such as infec-
tious agents and allergens. The TNF- regulates the recruitment of
eosinophils by increasing the expression of adhesion molecules on
vascular endothelium. It is also a potent activator of these cells.3742
Silvestri et al39 observed high levels of serum TNF- in conjunction
with elevated circulating leukocytes and neutrophils in severe
asthma compared with cases with mild-to-moderate disease and
healthy controls, possibly suggesting an increased production of this
cytokine from the airways and the involvement of a neutrophil-
derived cytokine pattern in severe asthma. These authors postulated
that the role of TNF- in severe asthma was therefore to amplify
airway inflammation and enhance airway hyperresponsiveness.
The IL-6 production from alveolar macrophages was report-
edly increased in patients with asthma and an increased expression
of IL-6 gene and protein was demonstrated in the bronchial epi-
thelial cells of asthmatic patients. Mast cells and eosinophils,
which are increased in asthmatic airways, are reported to release
IL-6, which exhibits a variety of immune and proinflammatory
effects including T-cell activation, IL-4induced IgE synthesis,
and mast cell survival. The IL-6, like other inflammatory cyto-
kines, has been shown to be elevated in different lung diseases
and has long been considered a byproduct of ongoing inflamma-
tion in the lung. However, recent studies have supported a dissoci-
ation of IL-6 from other proinflammatory biomarkers in the lung,
suggesting that it may play an active role in the pathogenesis of
asthma by mediating a specific aspect of the disease.41,4347 Peters
et al41 observed significantly increased plasma IL-6 levels in a
subgroup of patients with asthma that may suggest systemic
IL-6 inflammation as a mediator of disease severity.
Forensic pathologists may occasionally face situations in
which a death may have occurred because of fatal bronchial
asthma. Two different patterns of fatal asthma have been described
in clinical and forensic literature. The greater number of these
deaths (80%85%) occurs in individuals who have a severe,
poorly controlled disease and gradually deteriorated over days or
weeks (the so-called slow onset-late arrival or typ. 1 scenario of
asthma death). A variation of this pattern is a history of unstable
disease, which is partially responsive to treatment, upon which a
major attack is superimposed. In a small proportion of individuals
(15%20%), death can be sudden and unexpected, without
obvious antecedent, long-term asthma control deterioration (the
so-called sudden unset or typ. 2 scenario of asthma death). In
the typ. 1 scenario (long-duration attacks), death occurs 8 hours
or more after symptom onset. Morphological findings in these
cases consist of increased mucus secretion and extensive airway
plugging (likely reflecting a more cumulative change) by dense,
tenacious mucus mixed with inflammatory and epithelial cells as
well as an intense eosinophilic infiltration of the airway mucosa
and submucosa. In typ. 2 scenarios (short-duration attacks), death
occurs within a few hours after symptom onset. Morphological
findings in these cases consist of increased airway smooth muscle
shortening (presumably a short-duration event), empty airways
(no mucus plugs) in some cases, and in almost all subjects a
greater proportion of elastase-positive neutrophils than eosino-
phils infiltrating the airway mucosa and submucosa.4852
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Am J Forensic Med Pathol Volume 38, Number 2, June 2017
The CRP, IL-6, and TNF- have been occasionally investi-
gated in the forensic setting, although never in relation to fatal
asthma. Postmortem serum CRP levels have been shown as re-
duced, on average, by 35% compared with antemortem values.
This may possibly indicate molecule proteolysis because of
decompositional changes along with insignificant postmortem
molecule release from hepatocytes in the early postmortem pe-
riod. Increased CRP levels in postmortem serum samples are
therefore considered to reliably reflect the existence of ongoing
inflammatory processes at the time of death.53,54
Tsokos et al54 observed increased IL-6 values in the postmor-
tem serum of a series of sepsis cases, along with significant eleva-
tions in postmortem serum IL-6 concentrations compared with
antemortem values, potentially suggesting IL-6 release after death
from cells storing the molecule because of autolysis and
decompositional changes. On the other hand, subsequent studies
have found that postmortem serum IL-6 levels can be considered
useful indices of trauma severity and systemic inflammation.5558
The TNF- has only been sporadically investigated in the
forensic setting. Perskvist et al59 found that TNF- expression
was enhanced in cardiomyocytes during heart failure, thus confirm-
ing the role played by this molecule in controlling the inflammatory
response of various etiologies. Conversely, Mimasaka et al58 and
Schrag et al60 failed to observe significantly increased postmortem
serum TNF- in sepsis or trauma cases (Table 2).
The results of the study presented herein tend to be in agree-
ment with those reported in former investigations in the clinical
setting. They indicate that postmortem serum IL-6 levels are
increased in individuals with chronic asthma, irrespective of
whether the cause of death is because of a fatal asthma attack.
These data would therefore corroborate the conclusions of clinical
investigations performed in patients with chronic asthma, which
speculated that IL-6induced systemic inflammation may play a
specific role in the pathogenesis of the disease in a distinct sub-
group of asthmatic patients.
This is the first study, to our knowledge, to investigate the
biochemical profile of severe acute bronchial asthma deaths with
specific regard to the biochemical markers of systemic inflamma-
tion in a series of cases that had undergone forensic investigations.
We were unable to find similar studies pertaining to postmortem
serum IL-6, CRP, and TNF- levels in cases of asthma deaths in
the forensic setting with which to compare our results.
Our present study has some limitations. The most important is
the relatively small number of studied cases, which may limit the
accuracy of our research. However, precise selection criteria were
applied during the recruitment process in all study groups and sub-
groups to minimize heterogeneity in the study populations.
TABLE 2. Postmortem Usefulness of the Measured Biomarkers
Investigated
Biomarker Postmortem Levels
53,54
CRP Postmortem levels reflect the existence of
inflammatory processes at the time of death
Postmortem levels reduced on average by 35%
compared with antemortem level
IL-65458 Useful postmortem indices of trauma severity and
systemic inflammation
Significant elevation of postmortem levels
compared with antemortem level
TNF-58,59 Not significantly increased in sepsis or trauma cases
in postmortem serum
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Am J Forensic Med Pathol Volume 38, Number 2, June 2017
Prospective investigations including a greater number of subjects
would therefore be needed to confirm our findings.
Thus, even though further studies are required to confirm
these preliminary observations, our results seem to indicate that
death in asthmatics is characterized by a biochemical profile
marked by significantly higher postmortem serum from femoral
blood IL-6 levels compared with CRP and TNF- concentrations.
Accordingly, postmortem serum IL-6 values in cases of death
during severe acute bronchial asthma can be measured and possi-
bly considered of diagnostic relevance in combination with data
obtained from other investigations to estimate the magnitude of
the systemic inflammation responses characterizing the disease.
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