Leptin independently predicts development of sepsis and its outcome
Jacobsson et al. Journal of Inflammation
Leptin independently predicts development of sepsis and its outcome
Sofie Jacobsson 0 3
Peter Larsson 0 3
Göran Johansson 0 3
Margareta Norberg 2
Göran Wadell 1
Göran Hallmans 5
Ola Winsö 0 3
Stefan Söderberg 4
0 Department of Surgical and Perioperative Sciences, Anesthesiology and Intensive Care Medicine, Umeå University Hospital, Umeå University , S-901 85 Umeå , Sweden
1 Department of Clinical Microbiology, Umeå University , Umeå , Sweden
2 Department of Public Health and Clinical Medicine, Epidemiology and Global Health, Umeå University , Umeå , Sweden
3 Department of Surgical and Perioperative Sciences, Anesthesiology and Intensive Care Medicine, Umeå University Hospital, Umeå University , S-901 85 Umeå , Sweden
4 Department of Public Health and Clinical Medicine, Medicine, Umeå University , Umeå , Sweden
5 Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University , Umeå , Sweden
Background: Sepsis is a life-threatening condition and obesity is related to the clinical outcome. The underlying reasons are incompletely understood, but the adipocyte derived hormones leptin and adiponectin may be involved. Methods: Patients aged 18 years or more with documented first time sepsis events were included in a nested case-referent study if they had participated in previous health surveys. Two matched referents free of known sepsis were identified. Circulating levels of leptin and adiponectin were determined in stored plasma, and their impact on a future sepsis event and its outcome was evaluated. Results: We identified 152 patients (62% women) with a sepsis event and a previous participation in a health survey. Eighty-three % had also blood samples from the acute event. Hyperleptinemia at health survey associated with a future sepsis event (OR 1.77, 95% CI 1.04-3.00) and with hospital death. After adjustment for BMI leptin remained associated with sepsis in men, but not in women. High levels in the acute phase associated with increased risk for in hospital death in women (OR 4.18, 95% CI 1.17-15.00), while being protective in men (OR 0.05, 95% CI 0.01-0.48). Furthermore, leptin increased more from baseline to the acute phase in men than in women. Adiponectin did not predict sepsis and did not relate to outcome. Conclusions: Hyperleptinemia independently predicted the development of sepsis and an unfavourable outcome in men, and inertia in the acute response related to worse outcome.
Sepsis; Leptin; Adiponectin; Obesity; Case-referent study; Sex
Sepsis is a life threatening condition with an increasing
incidence globally [
]. In parallel, the prevalence of
obesity is increasing, and obesity is common among sepsis
patients and has been associated with both worse and
favourable outcomes [
]. The underlying reasons are
incompletely understood, but the adipose tissue may be
an important modulator of inflammation and immunity
via production of vasoactive substances such as
cytokines and other peptides collectively known as
The adipokines leptin and adiponectin are involved in
the inflammatory process, and they may modulate key
processes during sepsis development such as cytokine
production, immune cell proliferation and endothelial
function through interaction with other cytokines and
their receptors [
However, there are conflicting results regarding these
adipokines and the outcome from sepsis [
Although adipokines have been associated with the
prognosis of sepsis, it is not clear if adipokines promotes
an infectious process to become septic or are related to
the outcome of the septic event [
In this study, we aimed to assess the risk for sepsis and
its outcome related to circulating levels of adipokines both
at baseline and at the acute phase. Furthermore, if these
associations differed between sexes.
Between 1 March 1988 and 31 October 2008, a total of 797
patients were admitted with a diagnosis of sepsis at the
Intensive Care Unit, Umeå University Hospital, Sweden.
The diagnosis of sepsis and the severity of sepsis were
confirmed retrospectively by reviewing hospital records,
including results from biochemical, microbiological, and
Prior to the septic event, 152 of the 797 had participated
in one of four population-based health studies in
Northern Sweden: the Västerbotten Intervention Program (VIP),
the Northern Sweden MONItoring Of trends and
Determinants in CArdivascular Disease (MONICA)
survey, the Mammary Screening Program (MSP), and the
Northern Sweden Maternity Cohort (NSMC). The
contribution of cases from each survey was 81 (VIP), 4
(MONICA), 43 (MSP), and 24 (NSMC).
VIP is an ongoing community intervention program
targeting cardiovascular disease and diabetes
]. Subjects are asked to participate in a health
survey at their primary health centre at the ages of
30, 40, 50 and 60 years. However, those aged 30 are
no longer invited because of a lack of resources. The
participation rate was initially 55% but has increased
and is now approximately 65%. The total number of
unique individuals surveyed in VIP was 85,600 as of
31 December 2009.
MONICA consists of randomly selected individuals
aged 25–74 years from the counties of Norr- and
Västerbotten, who were invited to participate in a
health study. The study has been repeated six times
until 2009 and 10,300 unique persons participated
(74% of those invited) [
Data for the MSP cohort, consisting of 28,700 women,
were collected between 1995 and 2006 when the women
attended their regular mammography exam and were
asked to donate blood samples for research. In addition,
anthropometric measurements were taken.
In VIP, MONICA and MSP, participants were asked to
donate blood to the Northern Sweden Biobank for future
research, and blood was stored at −80 °C until further
analysis. Participants were fasting before sampling for a
minimum of 4 h (extended to 8 h in 1992).
The Northern Sweden Maternity Cohort (NSMC)
consists of all women in the study area who were screened for
rubella immunity during pregnancy, and the total number
of participants were 91,000 as of 31 December 2009.
Remaining samples from rubella screening as well as from
routine clinical serological and viral analyses have been
stored at −20 °C since 1975 at the Department of Virology,
For each septic case, two referents from the same
cohort without any episode of sepsis and being alive
at the date of the case admission to ICU were
chosen and matched for age (±2 years), gender, and
time of blood sampling (±30 days). Matching on
smoking (y/n) was incomplete due to missing
information, mainly in the MSP.
In addition, 128 out of 152 patients had also retrievable
samples collected at ICU admission (the acute phase).
The study protocol was approved by the Regional
Ethical Review Board in Umeå and by the Swedish
National Computer Data Inspection Board, and complies
with the Declaration of Helsinki. All participants gave
written informed consent for future use of data and
The septic event (acute phase)
Patients aged 18 years or older with a diagnosis of sepsis
within 24 h after admittance to the intensive care unit
(ICU) were included.
For patients with multiple admissions due to sepsis,
only the first event was included. Sepsis, severe sepsis or
septic shock was defined according to standard
]. Acute Physiology, Age and Chronic Health
Evaluation (APACHE) II score was calculated and used
for assessment of severity of illness at admission [
Sequential Organ Failure Assessment Score (SOFA) as a
marker for organ dysfunction and disease severity was
calculated at admission [
]. Data on height and weight
were recorded, if present, and body mass index (BMI)
was calculated as weight (kg) divided by height (m)
squared. Data on length of stay, mortality, referral
patterns, and reasons for admission, co-morbidities, and
sources of infection, primary infection sites and
causative microorganisms were collected. Microbiological
cultures were considered relevant if acquired within 48 h
before or after admission to the ICU. Pre-existing
diseases were defined according to Knaus et al. [
Clinical examinations at baseline (health survey)
In VIP and MONICA, participants were asked to
complete a health questionnaire about their living
conditions and cardiovascular risk factors, and anthropometry
and blood pressure were measured. An oral glucose
tolerance test with measurements of fasting and post-load
glucose levels was routinely performed in VIP and in
60% of the MONICA participants but was not obtained
in MSP and in NSMC. Diabetes and intermediate forms
of glucose intolerance were determined according to
WHO guidelines [
In the MONICA and MSP surveys, blood pressure
was recorded in the sitting position after 5 min of rest,
initially using a mercury sphygmomanometer but since
2004 by using semi-automatic devices (Omron M7,
Omron Corp., Kyoto, Japan). In the VIP survey, blood
pressure was measured after 5 min of rest in the
recumbent position until 1 September 2009 and thereafter in
the sitting position using devices as above. The
measurements obtained in the recumbent position were adjusted
according to a sex- and age-specific formula [
Hypertension was defined as systolic BP ≥140 mmHg and/or
diastolic BP ≥90 mmHg and/or on anti-hypertensive
Weight was measured without shoes in light indoor
clothing and recorded to the nearest 0.2 kg. Height was
measured to the nearest centimetre, without shoes, and
BMI was calculated.
Subjects were categorized as daily smokers, ex-smokers
or non-smokers. Total serum cholesterol was measured
using a bench-top analyser (ReflotronR, Boehringer
Mannheim GmbH Diagnostica, Mannheim, Germany) at
the time of the health survey (VIP, until 1 September 2009)
or by an enzymatic method (Boehringer Mannheim GmbH
Diagnostica, Mannheim, Germany) at a central laboratory
(MONICA and VIP after 1 September 2009). Cholesterol
values obtained using the bench-top method were adjusted
to the results measured at the central laboratory.
No clinical examinations were performed in the NSMC.
Leptin and adiponectin were analysed in stored plasma
obtained at the baseline health survey with a
doubleantibody radioimmunoassay method (Millipore
Corporation, Billerica, MA, USA). The detectable level of the
assays is 0.5 ng/mL. The total coefficient of variation
(CV) for leptin was 4.7% at both low (2–4 ng/mL) and
high (10–15 ng/mL) levels. For adiponectin, the total
CV was 15.2% at low levels (2–4 μg/mL) and 8.8% at
high (26–54 μg/mL) levels.
Data are presented as numerical values or percentages.
Non-normally distributed data were loge-transformed prior
to analysis. Continuous data are presented as (geometric)
means with 95% confidence intervals (CI). Pearson
correlation or Spearman’s rho was used for test of associations.
For comparisons, Fisher’s exact, Student t, or
Mann–Whitney U-tests were used when appropriate. Paired sample
ttest was used for intra-individual comparison. Since cases
and referents had the same follow-up time within strata in
this nested and matched case-referent study, logistic
regression analysis (rather than Cox regression) using the
conditional maximum likelihood routine designed for matched
analysis was uses to estimate odds ratios (OR) and 95% CIs,
and the influence of studied variables on future sepsis
(stratified sex) was tested in univariable and multivariable
models. Missing continuous values (BMI and serum
cholesterol) were replaced with the cohort- and sex-specific
median values representing the referents and missing values
for categorical variables were treated as a separate category
(not shown in tables). Non-conditional logistic regression
analysis was used to calculate the risk for in-hospital death.
Leptin and adiponectin were tested both as continuous
(loge-transformed) and categorical (quartiles) variables.
Cut-offs for quartiles were based on the cohort and
sexspecific distribution of the baseline adipokine levels
amongst referents (risk for sepsis) or amongst cases (risk
for death). A p-value <0.05 was considered significant, and
all p-values reported are two-sided. No adjustment was
made for multiple testing. SPSS ver. 22 was used for
Subject with future sepsis had marginally higher BMI
and lower total cholesterol than matched referents
(Table 1). Prevalences of diabetes and hypertension,
fasting and post-load blood glucose levels did not differ
between cases and their referents. Circulating levels of
leptin and adiponectin did not differ between cases and
their referents. As expected, women had higher leptin
(P < 0.001) and adiponectin (P < 0.001) levels (Figs. 1
and 2, respectively).
The acute event was classified as sepsis in 26%, as
severe sepsis in 52% and as septic shock in 22%, with no
differences between men and women (Table 2). The ICU
mortality was 18% and the hospital mortality was 21%.
The median time between survey participation and event
was 6.5 years (IQR 7.7). The mean age at sepsis onset
was 56.1 years in women and 61.0. years in men.The
frequency of co-morbidities, including diabetes, steroid
treatment, and renal insufficiency at the time of the
sepsis event was similar in men and women (Table 2).
At baseline, BMI correlated with high circulating levels
of leptin (r = 0.36, P < 0.001), and with low circulating
levels of adiponectin (r = −0.24, P < 0.001). In contrast,
BMI did not associate with leptin (r = −0.05, P = 0.60)
or with adiponectin (r = −0.05, P = 0.44) in the acute
phase. Furthermore, leptin and adiponectin levels in the
acute phase did not correlate with severity of disease
expressed as APACHE- (leptin; P = 0.95, adiponectin;
P = 0.79) or SOFA- scores (leptin; P = 0.88, adiponectin;
P = 0.94). Leptin and adiponectin did not correlate at
baseline (P = 0.14) or in the acute phase (P = 0.92).
Predictors of sepsis at baseline
High circulating levels of leptin predicted a first-ever
sepsis event (OR 2.04, 95% CI 1.30–3.2, P = 0.002) and
retained predictive value after adjustment for BMI (OR
1.89, 95% CI 1.14–3.13, P = 0.01) and in the fully adjusted
model (OR 1.77, 95% CI 1.04–3.00, P = 0.03) (Fig. 2).
None of the included confounders remained significantly
associated with sepsis in the fully adjusted model (data
Values reported are means (¤geometric means) or percentages (%) with 95% CI. Hypertension was defined as systolic BP > 140 mmHg and/or diastolic
BP > 90 mmHg and/or antihypertensive treatment. Reduced glucose tolerance included any of IFG, OGT or DM
Abbreviations: DM diabetes mellitus, IFG impaired fasting glucose, IGT impaired glucose tolerance (see text for definitions of DM, IFG and IGT), HDL high density
lipoprotein, BP blood pressure
not shown). The septic event was graded as sepsis, severe
sepsis or septic shock, and a graded response was seen in
that there were stronger BMI-independent associations
between hyperleptinemia and more severe forms of sepsis
compared to milder forms of sepsis. Furthermore, leptin
predicted sepsis-related in-hospital deaths (Fig. 2). Stratified
for sex hyperleptinemia predicted sepsis in both men (OR
2.39, 95% CI 1.18–4.86, P = 0.02) and women (OR 1.83,
95% CI 1.02–3.27, P = 0.04). This association remained in
men after adjustment for BMI (OR 2.60, 95% CI 1.20–5.61,
P = 0.02), but not in women (P = 0.36). Furthermore, leptin
predicted independently in-hospital death in men (OR 6.41
95% (1.32–31.1, P = 0.02). Adiponectin levels were not
associated with the development of sepsis in any model (data
Changes in leptin and adiponectin levels between baseline and the acute phase
Contrary to baseline, there were no differences in
leptinor adiponectin levels between men and women in the
acute phase (leptin; P = 0.26, adiponectin; P = 0.36),
(Fig. 3). However, the increase in both leptin- and
adiponectin levels between baseline and the acute phase
were significantly higher in men than in women (leptin
P = 0.001, adiponectin P = 0.02). Leptin levels increased
from baseline to the acute phase in surviving men
(P = 0.001) whereas surviving women decreased their
leptin levels from baseline to the acute phase (P = 0.02)
(Fig. 4a). There was no significant change in leptin levels
from baseline to the acute phase in non-survivors (men;
P = 0.09, women; P = 0.31) (Fig. 4a).
Adiponectin levels increased from baseline to the
acute phase in both surviving and non-surviving men
whereas surviving and non-surviving women
decreased their adiponectin levels from baseline to the
acute phase, however the changes were not
statistically significant (Fig. 4b).
Predictors of in-hospital death
High leptin levels expressed as the highest three quartiles
compared to the lowest quartile predicted death
irrespective of disease severity (APACHE II or SOFA score) in
women (OR 4.18, 95% CI 1.17–15.00, P = 0.03), whereas
high leptin levels in men were associated with a decreased
risk of death (OR 0.05, 95% CI 0.01–0.48, P = 0.01) (Fig. 5).
Adjustment with SOFA score gave similar point estimates.
Furthermore, leptin levels were dichotomised using a
single cut-off for both men and women (10 ng/mL). Levels
above 10 ng/mL were significantly associated with in
hospital death, OR 2.48, 95% (1.06–5.77, P = 0.035), which
remained after adjustment for APACHE II; OR 2.68, 95%
CI (1.08–6.65), P = 0.033, but not after adjustment for
SOFA score, OR 2.15 95% CI (0.86–5.39), P = 0.10.
This risk for in-hospital death remained in women,
OR 7.48, 95% CI (2.30–24.28), P = 0.001, but not in
men, OR 0.49, 95% CI (0.12–1.95), P = 0.31. When
analyzed as a continuous loge-transformed variable, high
leptin in the acute phase predicted in-hospital death
independently of APACHE II-score in women (OR 1.58,
95% CI 1.01–2.48, P = 0.04), whereas the protective
effect of high leptin levels in men did not remain
significant (OR 0.80, 95% CI 0.42–1.49, P = 0.48).
APACHE II and SOFA scores remained associated
with in-hospital death after adjustment for leptin levels
in the acute phase (P < 0.001 for both APACHE and
Adiponectin did not associate with in-hospital death,
neither as a categorical variable, nor as a continuous
variable (Fig. 5).
To our knowledge, this is the first study to
prospectively analyse serum levels of leptin and adiponectin in
patients who subsequently develop sepsis. Furthermore,
we are not aware of any previous studies of
intraindividual changes in adipokine levels from a non-septic
basal state to an acute septic state and the associations
with outcome with a possible sex-difference.
Here we report that high levels of circulating leptin at
baseline independently predicted a first-ever sepsis event,
possibly with a sex-related difference. Furthermore,
there was a graded response, with stronger
associations between hyperleptinemia at baseline and more
severe forms of sepsis compared to milder forms of
sepsis. In contrast to baseline, levels of adipokines did
not differ between men and women in the acute
phase, primarily due to a higher increase in adipokine
levels in men than in women. Furthermore, increased
leptin levels in the acute phase were associated with
better survival in men but not in women.
In contrast, adiponectin at baseline was not
associated with the development of sepsis and adiponectin
levels in the acute phase were not associated with
Our results are consistent with earlier reports showing
that high leptin levels are related to better outcome in
acute sepsis [
15, 16, 18, 30
]. However, we saw this
association in men.
In contrast, we found that high leptin levels at baseline
predicted sepsis with an unfavourable outcome. This
apparent contradiction might reflect the pleiotropic
properties of adipokines. Leptin and adiponectin are
adipocyte-derived cytokines with pro- and
antiinflammatory effects, linking adipose tissue with
metabolism and inflammation [
]. Baseline leptin and
adiponectin levels reflect the metabolic conditions at the
time and are determined by nutritional status and
correlate to the amount of fat mass, where leptin
increase and adiponectin decrease with increasing obesity.
These aberrations relate to the development of
cardiovascular disease (CVD) and diabetes [
], possibly by
inducing endothelial dysfunction [
Hyperleptinemia also induces a low-grade
pro-inflammatory state where cells in the innate immune system
are activated and release cytokines. Furthermore,
activation of the innate immune system induces leptin secretion.
Thus, there are bidirectional loops between the
inflammatory response and leptin. A key-feature in the sepsis
syndrome is the acute systemic inflammation with capillary
leakage and vasoplegia, which leads to severe hypotension
and septic shock. It is reasonable to believe that patients
with obesity-induced low grade inflammatory state with
impaired endothelial function, may have an unfavourable
outcome from a superimposed infection with
accompanying endothelial activation and the consequent
development of severe sepsis or septic shock [
]. However, in
the acute phase, the ability to secret sufficient amounts of
adipokines may be beneficial by activating the immune
In the acute phase, the expected association
between BMI and leptin was not seen, and the
difference in circulating levels between men and women
was attenuated, indicating that leptin is not only a
simple measure of obesity but also a complex
hormone with acute-phase properties [
equalization of adipokine levels between sexes in the
acute phase was mainly due to a greater increase in
men. Equalization in leptin levels between sexes have
also been reported in children with sepsis and that
children with higher increases in leptin levels had an
unfavourable outcome . An additional increase in
leptin levels from initially high levels at baseline may
not be beneficial from a physiologic perspective or
may indicate leptin resistance [
in changes in adipokine levels in the acute septic
state between men and women may in part explain
conflicting results from previous studies.
We found sex-differences in the predictive value of
leptin with stronger association in men. The design of
this study does not allow an explanation for these
gender differences, but may be due to sex-differences
in leptin signalling [
] and we have reported
similar sex-related differences in leptins ability to
predict stroke and diabetes [
This study has limitations. The cases were not entirely
representative of all consecutive patients admitted to the
ICU as participation in a health survey prior to the
sepsis event was mandatory. Two of the health surveys, the
MSP and the NSMC, included only women. Further, the
mean age in the NSMC was low, which explains why
most our cases were (younger) women. This contrasts
with most sepsis studies with a majority of men [
However, we believe that the matching procedure with
the cases and their two referents with the same sex and
within the same cohort, as well as being able to compare
inter individual adipokine levels in health (baseline
survey) with levels in the acute septic condition (acute
phase) is a strength to this study.
The protocol for these health surveys did not
include analysis of CRP, HbA1c, C-peptide or insulin
and it has not been done in the present study due to
limited sample volumes.
We did not exclude patients with diabetes, renal
failure, patients with steroid treatment, or those with
other immunosuppressive conditions; conditions that
may affect adipokine levels. We thus believe that our
selection represents the clinical reality. Further, the
frequency of co-morbidities that could affect
adipokine levels did not differ between men and women.
Although there is a strong correlation between
circulating levels of adipokines and BMI, there is a significant
inter-individual variation. As our prediction analysis is
adjusted for BMI, the results indicate that leptin has
effects independent from just being a measure of the
amount of adipose tissue, an effect more pronounced in
men. Despite shortcomings as a measure of fat mass,
BMI still used because of its simplicity and
reproducibility. The rationale for matching on smoking status was
the higher risk of perioperative infectious complications
related to smoking, and that smoking influence leptin
]. This matching was not complete due to
missing information, especially in the NSMC cohort.
Repeated analysis after omitting the NSMC- or MSP
cohort did not alter the results and leptin remained
predictive of an event of sepsis.
Due to reduced sample size in the acute sepsis event
(n = 128) the chosen cohort- and sex specific cut of
levels for adipokines (Q1 vs Q2–4) differ from the cut of
levels in the prediction analysis (Q4 vs Q1–3) (baseline
samples n = 152). Using cut offs of 10 ng/mL for leptin
as used by others gave similar results as using
cohortand sex specific Q1 vs Q2–4, with risk for in-hospital
death in women and protection in men (although not
significant). However, 10 ng/ml is a high leptin level in
men and most patients will end up in the comparator
group using this approach. As leptin physiology probably
differs between men and women we argue that
sexspecific cut-offs are important and the strengths of our
study is the sample size which allows us to stratify the
analysis for sex.
Circulating levels of leptin and adiponectin show
diurnal variation and sampling at the baseline survey
did not take this into account. However, if any effect
this would diminish the associations found in this
study. Furthermore, the samples from the pre-sepsis
investigation do represent population-based levels and
we have previously shown that individual leptin levels
are stable over long periods of time in men and
women and in different ethnicities [
]. Leptin is also
stable after long-time storage of samples [
We conclude that hyperleptinemia at baseline predicts a
first-ever sepsis event, even after adjustment for BMI and
other known cardiovascular risk factors. There is a graded
response between high levels of leptin at baseline and
sepsis severity. In contrast, hyperleptinemia in the acute
phase relates to a reduced risk for in-hospital death in
men whereas hyperleptinemia relates to an increased risk
in women. Furthermore, we found that inertia in the
leptin response to sepsis in the acute phase was related to
worse outcome, which is an intriguing finding that could
be of outermost importance for the understanding of the
triggers of an adequate immune response to a
The authors wish to express their gratitude to the Västerbotten Intervention
Project (VIP), the Northern Sweden MONICA project, the Mammary Screening
Project, the Maternity Cohort of Northern Sweden, and the Medical Biobank
and the funds that support these groups. We thank Åsa Ågren, Hubert
Sjödin, Anna-Maja Åberg, Lennart Styrke and Eva Liedgren for expert
technical assistance and Margareta Danielsson for performing the laboratory
Funding that enabled collection, analysis, interpretation of data and writing
the manuscript was received from the County Council of Västerbotten,
Umeå University, The Swedish Medical Society, Capio, and the Kempe
Foundation supported this study. SSö was supported by the Swedish Heart
and Lung Foundation, and by the County Council of Västerbotten (ALF).
Availability of data and materials
All results and data are kept in the section for Anesthesiology and Intensive
Care Medicine, Department of Surgical and Perioperative Science, Umeå
University. These will be made available from the corresponding author on
Conflict of interest
No competing financial interests exist.
SS and PL designed the study, SJ extracted and evaluated patient data and
performed statistical analyses. GJ contributed with statistical analyses
including presentation of data in tables and figs. GH, MN and GW
contributed to aspects related to the cohort design. SJ, OW and SS drafted
the manuscript, and all authors revised the manuscript critically for important
intellectual content. All authors approved the final version and are
accountable for all aspects of the manuscript.
Ethics approval and consent to participate
The study protocol was approved by the Regional Ethical Review Board in
Umeå, diary number 06-144 M, 2010–40-32 and 2011/19–32 M and by the
Swedish National Computer Data Inspection Board, and complies with the
Declaration of Helsinki. All participants gave written informed consent for
future use of data and blood samples at the moment of the baseline survey.
Consent for publication
Data was de-identified, after collection, and therefore there was no consent
required from individual patients, according to the ethical approval.
The authors declare that they have no competing interests.
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