EVIDENCE-BASED MANAGEMENT OF ACUTE

PANCREATITIS

PhD Thesis

Doctoral School of Pharmacological and Pharmaceutical Sciences

Head of the doctoral school: Erika Pintér, MD, PhD, DSc

Szilárd Gódi, MD
First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary

Supervisors:
Áron Vincze, MD, PhD, Med. habil
First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
Péter Hegyi, MD, PhD, DSc
Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

Pécs, 2020
1. Table of contents

1. Table of contents ......................................................................................................... 1

2. List of abbreviations ................................................................................................... 3
3. Introduction ................................................................................................................. 4
3.1 Incidence ................................................................................................................. 4
3.2 Pathomechanism and aetiology ............................................................................... 5
3.3 Diagnostic criteria ................................................................................................... 7
3.4 Complications, severity and mortality .................................................................... 7
3.4.1 Local complications.......................................................................................... 7
3.4.2 Systemic complications .................................................................................... 8
3.4.3 Infectious complications ................................................................................... 9
3.4.4 Severity and mortality ...................................................................................... 9
3.5 Management .......................................................................................................... 10
3.5.1 Evidence-based guidelines ............................................................................. 10
3.5.2 Cornerstones of clinical management ............................................................ 11
3.5.3 Centralized care .............................................................................................. 12
3.5.4 Antibiotic use.................................................................................................. 13
3.6 Determinants of disease course ............................................................................. 15
4. Objectives and hypotheses ....................................................................................... 18
5. Methods...................................................................................................................... 19
5.1 Study design and data sources............................................................................... 19
5.2 AP Registry ........................................................................................................... 19
5.2.1 Background and objectives............................................................................. 19
5.2.2 Sites of recruitment......................................................................................... 19
5.2.3 Eligibility and data collection ......................................................................... 19
5.2.4 Data validation................................................................................................ 20
5.2.5 Data extraction................................................................................................ 20
5.2.6 Statistical considerations ................................................................................ 20
5.2.7 Ethical considerations ..................................................................................... 21
5.3 International survey ............................................................................................... 21
5.3.1 Background and objectives............................................................................. 21
5.3.2 Data collection ................................................................................................ 21
5.4 Systematic review ................................................................................................. 22

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 5.4.1 Background and objectives............................................................................. 22
5.4.2 Data sources and eligibility ............................................................................ 22
5.4.3 Selection, data collection and risk of bias assessment ................................... 22
6. Results ........................................................................................................................ 24
6.1 Centralized care ..................................................................................................... 24
6.1.1 Characteristics of the study population .......................................................... 24
6.1.2 Severity, mortality, complications and length of hospital stay ...................... 24
6.1.3 Therapeutic approach and interventions ......................................................... 26
6.1.4 Cost of care ..................................................................................................... 26
6.2 Antibiotic use ........................................................................................................ 26
6.2.1 Systematic review ........................................................................................... 26
6.2.2 International survey ........................................................................................ 28
6.2.3 Registry analysis ............................................................................................. 28
6.3 Metabolic syndrome and acute pancreatitis .......................................................... 35
6.3.1 Characteristics of the study population .......................................................... 35
6.3.2 Association of components of metabolic syndrome with disease outcomes .. 35
7. Discussion .................................................................................................................. 39
7.1 Scope and main findings ....................................................................................... 39
7.2 Explanation and elaboration .................................................................................. 39
7.2.1 Centralized care .............................................................................................. 39
7.2.2 Antibiotic use.................................................................................................. 41
7.2.3 Metabolic syndrome ....................................................................................... 43
7.3 Strengths and limitations ....................................................................................... 44
8. Conclusions and perspectives .................................................................................. 46
9. Acknowledgements ................................................................................................... 47
10. References ................................................................................................................ 48
11. Scientometrics and list of publications.................................................................. 63
12. Appendix .................................................................................................................. 66

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2. List of abbreviations IAP: International Association of
AB: antibiotic Pancreatology
ALI: acute lung injury ICU: intensive care unit
ANC: acute necrotizing collection IL-1β: interleukine-1β
ANOVA: analysis of variance IL-1β-R: interleukine-1β receptor
ANP: acute necrotizing pancreatitis IPN: infected pancreas necrosis
AP: acute pancreatitis MAP: mild acute pancreatitis
APA: American Pancreatic Association MetS: metabolic syndrome
APACHE II: acute physiology and chronic MODS: multi-organ dysfunction syndrome
health examination II MRI: magnetic resonance imaging
APFC: acute peripancreatic fluid collection MSAP: moderately severe acute pancreatitis
ARDS: acute respiratory distress syndrome Nuclear factor-κB: NFκB
AUC: area under the curve OR: odds ratio
BISAP: bedside index of severity in acute PC: pancreatic centre
pancreatitis PCT: procalcitonin
BMI: body mass index Pro-IL-1β: the ’pro’ form of interleukine-1β
CECT: contrast-enhanced computed PRSS1: human cationic trypsinogen
tomography Q1-Q3: 25-75% quartiles
CI: 95% confidence interval RCT: randomized controlled trials
CRA: clinical research administrator ROC: receiver operation characteristic
CRF: case report form SAP: severe acute pancreatitis
CRP: C-reactive protein SD: standard deviation
CT: computed tomography SD: surgical department
CTSI: computed tomography severity index SE: standard error of the mean
DAMP: damage-associated molecular pattern SIRS: inflammatory response syndrome
ER: emergency unit SPINK1: serine protease inhibitor Kazal type 1
ERCP: endoscopic retrograde TIMD: territorial internal medical department
cholangiopancreatography TLRs: toll-like receptors
EUS: Endoscopic ultrasound TNF-R1: tumour necrosis factor-receptor 1
FNAB: fine-needle aspiration biopsy TNF-α: tumour necrosis factor-α
GRADE: Grading of Recommendations TPC: tertiary pancreas centre
Assessment, Development and Evaluation US: ultrasonography
HDL-C: high-density lipoprotein-cholesterol WBC: white blood cell count
HPSG: Hungarian Pancreatic Study Group WON: walled-off necrosis

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3. Introduction

Pancreatitis is the inflammation of the pancreas, which includes a continuum of

disorders from acute pancreatitis (AP) through early chronic pancreatitis to chronic
pancreatitis (1). AP, a potentially life-threatening condition, is one of the leading causes
of emergency visits and hospital admissions among gastrointestinal disorders in
developed countries (2). Disease-specific curative therapies are still lacking, which
provides the ground for intensive research in various areas of pancreatology, including
diagnostics, prognostics and therapeutic implications (3).

3.1 Incidence

The most extensive evidence on incidence of AP was provided by a thorough meta-

analysis (2016) based on ten population-based cohort studies identified through
systematic literature search (4). According to this report, crude incidence of AP proved
to be 33.74 cases per 100,000 person-years (95% confidence interval [CI]: 23.33–48.81
cases). Incidence of AP ranged from 15.00 cases in Denmark to 83.70 cases in Sweden
per 100,000 person-years across studies. If we consider the European studies, crude
incidence of AP was 28.93 cases per 100,000 person-years (CI: 16.64–50.30 cases).
Observations raised concerns about a rising trend in incidence of AP diagnosis (Figure
1), which might be explained by the better access to diagnostic tools and by the trend of
acquired (mainly lifestyle-related) risk factors (5-7).

Figure 1. Incidence of acute pancreatitis between 2002 and 2013 in the US. P-values indicate a significant increase
in incidence, shown by the dashed trend lines. The increment in incidence was observed in both males and females.
Reprinted from ’Temporal Trends in Incidence and Outcomes of Acute Pancreatitis in Hospitalized Patients in the
United States From 2002 to 2013’, by Brindise et al., 2019, Pancreas.

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 Reliable data on incidence of AP in Hungary are still lacking. According to the
unofficial report of the Hungarian Central Statistical Office, approximately 5,000–5,500
cases are diagnosed annually, which corresponds to an estimated crude incidence of 50–
55 cases per 100,000 person-years.

3.2 Pathomechanism and aetiology

Mechanisms triggering and driving pancreatic inflammation are extensively

studied, yet, some steps of initiation and progression have remained unexplored. In the
process, we differentiate genetic susceptibility from acquired factors (mainly
environmental risk factors). Nevertheless, according to the ’multiple hits on multiple
targets’ theory, the combination of potentially harmful factors (’hits’) are required to
impair different cellular/molecular structures (’targets’) to initiate the development of AP
(8).
Genetic susceptibility is driven by genes encoding pancreatic proteases or
regulators of proteases. The gain-of-function or loss-of-function defects lead to premature
activation of pancreatic digestive enzymes (the family of zymogens, from which
trypsinogen should be highlighted), mediating pancreatic damage via autodigestion. One
example is the loss-of-function mutation of a trypsin inhibitor, serine protease inhibitor
Kazal type 1 (SPINK1). Another example could be the gain-of-function mutation of
human cationic trypsinogen (PRSS1), becoming prone to early activation (9-11). Several
types of mutations are characterized at http://www.pancreasgenetics.org/.
There are numerous environmental or acquired factors which are implicated in the
pathomechanism of AP. Biliary pathologies, including but not limited to gallstone disease
and microlithiasis, are thought to be responsible for 40–60% of AP cases via triggering
reflux of bile to or retention of pancreatic juice in the pancreatic ducts, leading to early
activation of digestive enzymes (12). Alcohol abuse is the second most common factor in
the Western world accounting for 25–30% of AP cases where alcohol and its toxic
metabolites lead to direct acinar and ductal cell damage as well as premature enzyme
activation (13). Other aetiological factors include hypertriglyceridaemia (considered
causative above 11 mmol/L, the third most common aetiology in the Western countries
whereas the second most common aetiology in Japan), drugs (mainly chemotherapeutics
and immunosuppressants), iatrogenic injury (endoscopic retrograde
cholangiopancreatography [ERCP], surgery), trauma, infections, hypoxia and ischaemia,
hypercalcaemia and pancreatic malformations. If none of the known aetiological factors

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is identified in the background during a thorough investigation, idiopathic AP can be
diagnosed (10–30% of the cases) (14).
Here, we introduce a model describing the development and course of AP. No
matter what factors are in the background, activation of pancreatic digestive enzymes is
an early step in which intracellular Ca2+ spike is a critical moment (this is the so-called
calcium-dependent protease activation; another ancillary mechanism is the cathepsin B-
dependent protease activation). Premature protease activation of any cause leads to injury
of pancreatic acinar and ductal cells, by which the mechanisms of cell death are activated.
The type of cell death can be necrosis, apoptosis, autophagy, necroptosis or pyroptosis.
Protease activation and cell death form a vicious cycle by accelerating each other (some
theories pose that cell death precedes protease activation, others scientists presume that
protease activation comes first). Cell fragments and the released inflammatory mediators
activate leukocytes, leading to inflammation in which Nuclear factor-κB (NFκB) pathway
plays a key role. The process is illustrated in Figure 2. As a consequence,
monocytes/macrophages and neutrophil granulocytes migrate to the pancreatic
parenchyma, producing a large amount of various pro- and anti-inflammatory cytokines,
chemokines and other mediators, which maintain and aggravate the vicious cycle of cell
death and protease activation. In the meantime, amylase and lipase are released from the
dying parenchymal cells to the circulation, serving as indicators of AP. The release of
inflammatory mediators is responsible for the escalation of local immune response into
systemic inflammatory response syndrome (SIRS), with an abrupt rise in C-reactive
protein (CRP). Finally, since cytokines are vasoactive mediators, the cytokine storm
causes distributive vasoplegic shock and multi-organ dysfunction syndrome (MODS) in
severe cases (9, 15, 16).

Figure 2. Relationship between cell

death and immune response in acute
pancreatitis. DAMP: damage-
associated molecular pattern, IL-1β:
interleukine-1β, IL-1β-R: interleukine-
1β receptor, NFκB: Nuclear factor-κB,
Pro-IL-1β: pro form of interleukine-1β,
TLRs: toll-like receptors, TNF-R1:
tumour necrosis factor-receptor 1, TNF-
α: tumour necrosis factor-α. Reprinted
and adapted from ’Genetics, Cell
Biology, and Pathophysiology of
Pancreatitis’ by Mayerle et al., 2019,
Gastroenterology.

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3.3 Diagnostic criteria

Although there were several international initiations to define AP and AP-related

concepts in adults, the most widely accepted system is the 2012 revised Atlanta
Classification (17). Based on the diagnostic criteria of this classification, the diagnosis of
AP requires at least two of the followings (’two out of three criteria’):
1) abdominal pain consistent with AP (acute onset of a persistent, severe, epigastric
pain often radiating to the back);
2) serum lipase activity or amylase activity at least three times greater than the upper
limit of normal; and
3) characteristic findings of AP on contrast-enhanced computed tomography
(CECT), magnetic resonance imaging (MRI) or transabdominal ultrasonography
(US).

3.4 Complications, severity and mortality

The disease course of AP varies: some cases are mild (almost asymptomatic) while
the critically-ill patients require intensive care. Following the revised Atlanta
Classification, we grade the severity of AP based on local and systemic complications
(17).

3.4.1 Local complications

Local status can be assessed based on findings on CECT. Cases can be divided by
the presence of pancreatic and/or peripancreatic necrosis into acute interstitial
oedematous pancreatitis or acute necrotizing pancreatitis (ANP).
If fluid accumulates in the surrounding area of (but not in) the pancreas without
necrosis, a definable wall and within four weeks after onset of AP, the condition is termed
as acute peripancreatic fluid collection (APFC). If the (peri)pancreatic fluid contains
liquid and solid components derived from pancreatic necrosis, the condition is termed as
acute necrotizing collection (ANC).
If encapsulated fluid collection develops four weeks after the onset of interstitial
oedematous AP (which is usually round or oval, locates mostly outside the pancreas and
has no solid containment), the condition is termed as pancreatic pseudocyst. If the
(peri)pancreatic necrosis develops a well-defined wall (usually four weeks after onset of
ANP), the condition is termed as walled-off necrosis (WON).
If pancreas visualisation is permitted, US is sufficient to establish the diagnosis of
AP. However, CECT outperforms US in detecting necrosis or other local complications

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(18). The revised Atlanta Classification recommends CECT while the Appropriateness
Criteria released by the American College of Radiology recommends CECT or MRI for
the diagnosis of local complications. Documentation of local complications is not
necessary in the early phase of AP, the ideal timing of imaging for this purpose is 5–7
days after onset (definitely later than 72 hours) (17, 19).
Considering the time frames in the definitions (>4 weeks after onset for
pseudocyst and WON) and the fact that follow-up imaging is often missing, the true
incidence of local complications is hard to be estimated. ANP might develop in 20–40%
and WON in 1–9% of the cases (for details, see the review of Rana et al.) (20). However,
a recent prospective observational study performing CECT at 5–7-day, 1-month and 3-
month after onset detected a surprisingly high incidence of ANP (81%) and consequent
WON (58.7%) (21). Another study recorded similarly high incidence of APFC (42.7%)
and pseudocysts (6.3%) (22). Of note, these numbers should be treated with caution as a
lot depends on the study population (e.g. the proportion of recurrent, acute-on-chronic or
severe cases).

3.4.2 Systemic complications

Systemic complications are considered to be the consequence of cytokine storm.

Newly developing organ failure (most commonly, acute respiratory failure, kidney failure
or heart failure), as well as the deterioration of pre-existing chronic conditions (such as
the decompensation of chronic heart failure), should be taken into account on assessment.
The Modified Marshall Score is the recommended tool to determine organ failure (23).
Transient (resolves within 48 hours) and persistent organ failure (lasts longer than 48
hours) should we distinguished (discussed under the heading ’3.4.4 Severity and
mortality’). If organ failure affects more than one organ system, it is termed MODS (a
synonym is multiple organ failure).
Lung injury (acute lung injury [ALI] or acute respiratory distress syndrome
[ARDS]) with subsequent respiratory failure is the most common systemic complication
of AP (probably due to the release of pancreatic phospholipase A2). Any organ failure
develops up to 5–15% of patients: incidence of respiratory, renal and heart failure was 9,
7 and 4% in a study, respectively (24). Comparable incidences were calculated from data
in our earlier cohort of 600 AP cases from Hungary (25).

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3.4.3 Infectious complications

Site of infections can be extrapancreatic and pancreatic; both have the potential to
evolve into sepsis. Common extrapancreatic infections include acute cholangitis,
pneumonia, catheter-related and line infections, urinary tract infections. The most
common form of pancreatic infections is the infected pancreas necrosis (IPN). 50% of
IPN develops within seven days after onset, and its prognosis is poor with a mortality rate
reaching 30% (vs the 13% with sterile necrosis) (26, 27). IPN can be diagnosed with
computed tomography (CT)- or US-guided fine-needle aspiration biopsy (FNAB),
followed by Gram stain/culture. However, strategies based on non-invasive diagnostics
are becoming more popular: conservative treatment with empirical antibiotics (AB)
(followed by ’rescue’ FNAB in deteriorating cases) gains more and more attention (28).

3.4.4 Severity and mortality

Unlike the original 1992 Atlanta

Classification, the revised 2012 Atlanta
Classification re-defines disease severity
of AP based on the development and
duration of organ failure and the
development of local complications (17,
Figure 3. Mortality of acute pancreatitis by
29). The classification differentiates mild, severity. MAP: mild acute pancreatitis, MSAP:
moderately severe acute pancreatitis, SAP: severe
moderately severe and severe AP (MAP, acute pancreatitis. Reprinted and adapted from
’Prospective, Multicentre, Nationwide Clinical Data
MSAP and SAP, respectively), the three- from 600 Cases of Acute Pancreatitis’ by Párniczky et
grade severity is detailed in Table 1. MAP al., 2016, PloS One.

and MSAP are associated with low mortality (<1%) whereas SAP has high mortality
approximating 30% (Figure 3) (25). Although these criteria are more exact than other
classification systems, the revised Atlanta Classification was not designed to grade
severity on-admission so that it conveys little meaning to practitioners. This problem
derives from the duration-based definition of organ failure (transient vs persistent) and
the (un)reliability of early assessment of local complications (discussed under the heading
’3.4.1 Local complications’). The severity of AP should be re-assessed multiple times
during hospitalization, at discharge and follow-up visit.
SAP, MSAP and MAP account for approximately 5–15, 15–30 and 60–75% of the
cases, respectively (30-32). If we consider Hungarian data, these proportions were 8.8,
30.0 and 61.2% in our previous study, respectively (25).

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Table 1. The revised Atlanta Classification for disease severity
Grade of severity Criteria
MAP No organ failure
No local complications
MSAP Transient organ failure (resolves within 48 hours) and/or
Local or systemic complications without persistent organ
failure
SAP Persistent organ failure (lasts longer than 48 hours)
MAP: mild acute pancreatitis, MSAP: moderately severe acute pancreatitis. SAP: severe acute pancreatitis

Although tremendous efforts

were made to reduce mortality of AP,
yet, the disease has remained
potentially life-threatening with a
fatality rate of 1–5% (32-34): AP is
responsible for 1.6 deaths (CI 0.85–
1.58) per 100,000 person-years (4).
Hungarian data showed an overall
mortality of 2.8% in our previous study
(25). Nevertheless, the tendency is
Figure 4. Mortality of acute pancreatitis in the US. The
promising: mortality was reduced solid line represents overall mortality, the dashed line
represents the mortality of those who developed acute kidney
from 1.8 to 1.1% in the US between failure as systemic complication. Reprinted from ’Acute
pancreatitis: Trends in outcomes and the role of acute kidney
2003 and 2012 (shown in Figure 4) (6, injury in mortality – A propensity-matched analysis’ by
Devani et al., 2018, Pancreatology.
34). Although specific therapies are
still not available, early recognition of deteriorating cases and more effective intensive
care substantially contributed to this improvement.
There are many classification systems designed to predict mortality or severity of
AP. The most commonly used include but are not limited to the bedside index of severity
in acute pancreatitis (BISAP) (33), the computed tomography severity index (CTSI) (35),
the modified CTSI (36), Ranson (37) and the acute physiology and chronic health
examination II (APACHE II) (38). All of these scoring systems are moderate to good
predictors of severity as well as mortality (39).

3.5 Management

3.5.1 Evidence-based guidelines

The Working Group International Association of Pancreatology/American

Pancreatic Association (IAP/APA) Acute Pancreatitis Guidelines released an evidence-

10
based guideline on the management of AP in 2013 (40), which, after update and
adaptation, was translated to and published in Hungarian language by the Hungarian
Pancreatic Study Group (HPSG) in 2015 (41). The guideline panel of IAP/APA consisted
of multidisciplinary experts from many fields involved in the care of AP. The panel
formulated pre-defined questions, then performed a systematic literature search to collect
all question-related evidence. Based on the data, recommendations were made adhering
to the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) system quantifying the quality of evidence (as very low, low, moderate or high)
and the strength of recommendation (as weak or strong) (42).
In addition to the IAP/APA guideline (40), evidence-based guidelines were released
by the American College of Gastroenterology (2013) (43) and the Japanese Society of
Hepato-Biliary-Pancreatic Surgery (2015) (44), while other organizations including but
not restricted to the American Gastroenterological Association (2018) (45), the World
Society of Emergency Surgery (2019) (46), the Canadian Medical Association (2016)
(47) and the Italian Association for the Study of the Pancreas (2015) (48) released their
guidelines as well.

3.5.2 Cornerstones of clinical management

1. The diagnosis should be established based on the ’two out of three criteria’ (as
discussed above).
2. Patients should be admitted to centres specialized for care in gastroenterology or
pancreatology.
3. Aetiology should be thoroughly investigated.
4. Early fluid resuscitation is an essential part of management.
5. Close monitoring in the initial phase and admission to intensive care in time can
save lives.
6. Preventive ABs or probiotics should not be given.
7. Changes in electrolytes and inflammatory markers should be monitored in the
early phase.
8. Endoscopic ultrasound (EUS) / magnetic retrograde cholangiopancreatography /
ERCP and same-admission cholecystectomy should be considered in the case of
biliary aetiology or plasmapheresis in the case of hypertriglyceridemic aetiology.
9. Enteral feeding should be initiated in SAP.

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 10. If invasive intervention is required due to local complications, the step-up
approach is recommended.
11. Patients should be screened for local complications at discharge and follow-up
visit.
12. AP is often recurrent so that lifestyle changes are required.

3.5.3 Centralized care

Medicine evolves rapidly, which process is well-reflected by the exponential slope

of the curve describing the propagation of data on certain conditions. Being up-to-date
about many fields of science has become a demanding challenge (49). Besides, to provide
state-of-the-art care, accumulating extensive theoretical knowledge alone is not enough:
active management of cases is required, allowing to put theories into practice. To sum up,
the key to success depends on the knowledge and the number of cases treated (these
together may be called expertise). These encouraged the establishment of units
specialized in providing care for a narrow spectrum of conditions, giving birth to the
concept of centralization of care. The efficacy of centralization is plausible to be
generalizable to all treatable diseases with a potential risk of severe complications in the
fields of both conservative and operative medicine.
Centre volume (that is, the number of cases admitted to or procedures performed in
a unit) and physician volume (that is, the number of cases treated or procedures performed
by a physician) are important determinants of quality of care. Research implicated that
the latter may be more important than the former, at least in the field of operative medicine
(50). Adjusted mortality of pancreatic resection was 12% lower in very high-volume vs
very low-volume hospitals, and similar tendencies were observed regarding other
operations (51). In another study, 30-day survival of patients with oesophageal, gastric
and pancreatic cancer significantly improved with the higher number of cases operated
(3.4, 7.2 and 4.1% reduction of mortality with each case added, respectively) (52). The
efficacy of centralization in operative care can be illustrated through several other
examples in- and outside the scope of gastrointestinal surgery (53-60).
The role of centralization in non-surgical fields of gastroenterology, such as in
gastrointestinal endoscopy, was recognized by the European Society of Gastrointestinal
Endoscopy as well. The physician volume is particularly important in the learning phase
of one’s carrier. Higher centre and physician volume were found to favourably impact
quality indicators of ERCP (including the rate of post-ERCP pancreatitis) (61-65) or

12
colonoscopy in cancer screening (66), recurrence after ablation of Barrett’s dysplasia (67)
or the success rate of transjugular intrahepatic portosystemic shunt insertion (68).
Interestingly, the volume-mortality relationship may not apply to variceal bleeding (69-
71).
Although we have evidence for the beneficial effect of centralization in AP as well,
evidence-based guidelines make heterogenous recommendations that are of low quality
of evidence (indicated with ’C’). This means that further research is very likely to have a
substantial impact on our confidence in the estimate, either proving or disproving it (42).
The American guideline recommends referral to a specialist unit for cases with idiopathic
AP (conditional recommendation, low quality of evidence) (43) while the Japanese
guideline (1C) and IAP/APA guideline (GRADE 1C, strong agreement) recommend
referral for SAP (40, 44). Besides, the latter expands the indication of referrals for those
patients requiring interventional radiologic, endoscopic or surgical intervention (GRADE
1C, strong agreement) (40). Only the IAP/APA guideline attempts to define specialist
units (GRADE 2C, weak agreement) (40):
’A specialist center in the management of acute pancreatitis is defined as a high
volume center with up-to-date intensive care facilities including options for organ
replacement therapy, and with daily (i.e. 7 days per week) access to interventional
radiology, interventional endoscopy with EUS and ERCP assistance as well as surgical
expertise in managing necrotizing pancreatitis’ (Section E, Statements 14).
Current evidence warrants further investigation about the role of centralized care in
AP.

3.5.4 Antibiotic use

The three leading evidence-based guidelines make recommendations about the use
of ABs in AP cases without confirmed pancreatic/extrapancreatic infections (termed as
preventive or prophylactic use of ABs), as follows:
• ’Intravenous antibiotic prophylaxis is not recommended for the prevention of
infectious complications in acute pancreatitis. (GRADE 1B, strong agreement)’ by
the IAP/APA Evidence-Based Guidelines for the Management of Acute
Pancreatitis (Section F, Statement 17) (40).
• ’Routine use of prophylactic antibiotics in patients with severe acute pancreatitis
is not recommended (strong recommendation, moderate quality of evidence)’ and
’The use of antibiotics in patients with sterile necrosis to prevent the development

13
 of infected necrosis is not recommended (strong recommendation, moderate quality
of evidence)’ by the American College of Gastroenterology Guideline:
Management of Acute Pancreatitis (Statements 21, 22) (43).
• ’The prophylactic administration of antibiotics is not necessary in mild acute
pancreatitis, since the incidence and mortality rates of infectious complications
from mild acute pancreatitis are low. (1A) and ’The prophylactic administration of
antibiotics in severe acute pancreatitis and necrotizing pancreatitis may improve
the prognosis, if carried out in the early phases of pancreatitis (within 72 h of
onset). (2B)’ by the Japanese Guidelines for the Management of Acute Pancreatitis:
Japanese Guidelines 2015 (Section I, Statement 17) (44).
Based on these recommendations, prophylactic use of ABs is not recommended
generally in AP (moderate quality of evidence), MAP (high quality of evidence) or SAP
(moderate quality of evidence). The Japanese and the US guidelines disagree on the
prophylactic use of ABs in ANP: the former may attribute some benefit for early
prophylactic AB treatment, whereas the latter does not recommend prophylactic use of
ABs.
The question as to whether prophylactic ABs should be given has been debated for
decades: several randomized controlled trials (RCT) were conducted in the past 50 years.
According to a recent (2017) meta-analysis performed by the Cochrane Collaboration,
prophylactic ABs did not yield statistically significant benefit regarding short-term (<3
months) mortality (odds ratio [OR]: 0.81, CI: 0.57–1.15), rate of organ failure (OR: 0.78,
CI: 0.44–1.38), rate of IAP (OR: 0.82, CI: 0.53–1.25) or rate of sepsis (OR: 0.42, CI:
0.11–1.60) based on the data of 17 RCTs in AP. Findings were consistent in ANP and
SAP as well based on the data of ten and nine RCTs, respectively. It must be noted,
however, that the grade of evidence was rated as very low for all outcomes due to the
limitations of the studies, which means that future studies carry the potential to change
these associations (72). Although the leading guidelines were released earlier than this
meta-analysis, their recommendations are in line with its findings (except for that in the
Japanese guideline attributing potential benefit to early prophylactic use of ABs in SAP).
According to our previous research, 77.1% of patients received ABs during hospital
stay. Considering the estimated incidence of pancreatic and extrapancreatic infections
(30–35%), this number is twice as high as expected. However, the majority of the patients
received ABs for prophylaxis, indicating a significant AB overuse. Interestingly, there
was no difference in the outcomes of patients receiving prophylactic ABs and those

14
receiving therapeutic ABs to control confirmed pancreatic or extrapancreatic infections
(SAP accounted for 7.2 vs 7.8% in the groups with prophylactic vs therapeutic AB use,
respectively) (25).
Choosing the population which may benefit from AB treatment is a hard choice.
Many biomarkers used as pervasive indicators of an ongoing infection (white blood cell
count [WBC] and acute-phase proteins, e.g. cytokines, CRP and even procalcitonin
[PCT]) can change during the natural course of AP, posing difficulty in distinguishing
inflammation of sterile and infective origins (73-75). Currently, reliable non-invasive
biomarkers are still lacking.

3.6 Determinants of disease course

There are many on-admission variables which were implicated to be associated with
a more severe disease course in AP. The associations of age, comorbidities, aetiology of
AP, smoking and obesity with severity and mortality of AP were extensively studied.
In a meta-analysis from 33 studies, our research team concluded that ageing is
associated with a higher proportion of SAP (each year increase between 20 and 70 years
of age was associated with an increment of 0.193% in incidence of SAP). In contrast, we
observed a biphasic linear association between age and mortality (the inclination of the
slope increased above 57.5 years of age) (76). When we analysed the joint effect of ageing
and comorbidities with multivariate analysis in our cohort of AP cases, we found that
comorbidities are responsible for the increment in mortality in elderly, but both ageing
and comorbidities are essential regarding severity (Figure 5). A Charlson Comorbidity
Score >2 was independently associated with two times increased frequency of SAP (OR:
2.10, CI: 1.08–4.09) and with four times higher mortality (OR: 4.48, CI: 1.57–12.80). Out
of the comorbidities investigated, mortality was significantly positively associated with
pre-existing congestive heart failure, peripheral vascular disease, cerebrovascular disease,
moderate/severe renal disease, moderate/severe liver disease and metastatic tumour.
Interestingly, diabetes mellitus was not associated with worse prognosis (77).

15
Figure 5. A model describing the joint effect of ageing and comorbidities on mortality (A) and severity (B) of
acute pancreatitis. Comorbidities seem to be responsible for the prominent excess in mortality with ageing (with a
cut-off point at 57.5 years, indicated by the dashed line), whereas ageing and, to a lesser extent, comorbidities are both
important regarding severity. Adapted and reprinted from ’Aging and Comorbidities in Acute Pancreatitis II.: A
Cohort-Analysis of 1203 Prospectively Collected Cases’ by Szakács et al., 2018, Frontiers in Physiology.

Although the disease course becomes similar after initiation of the cascade of
cytokine storm, hypertriglyceridaemic aetiology seems to be associated with a more
severe disease course (25, 78-80). Unlike alcoholic and biliary aetiologies which have
limited influence on severity and mortality (25, 81-84).
Among lifestyle factors,
alcohol intake is considered to
be a causative factor of AP (8).
Smoking (alone or with regular
alcohol intake) aggravates the
disease course, increases the
Figure 6. Effects of obesity on the outcomes of acute pancreatitis.
risk of recurrent AP and
The analysis was adjusted for age, sex, comorbidities and aetiology.
facilitates the transition from *indicates p<0.05. Reprinted from ’The association between obesity
and outcomes in acute pancreatitis: an individual patient data meta-
AP to chronic pancreatitis (8, analysis’ by Smeets et al., 2019, Eur J Gastroenterol Hepatol.

25, 85, 86). Considering that obesity has become increasingly common in developed
countries, its potential modifying effect on disease course has come to light. An individual
patient data-level meta-analysis aggregated the population of four cohorts of AP cases
and found that obesity proved to be an independent predictor of multiple organ failure
(Figure 6) (87). Findings from a study-level meta-analysis (19 studies, 9,997 cases)
indicated that patients with a body mass index (BMI)>25 kg/m2 (i.e. overweight and
obesity) tend to be almost three times more likely to develop SAP compared to those with
normal BMI (OR: 2.87, CI: 1.90–4.35). Moreover, BMI>30 kg/m2 (i.e. obesity) was a
significant risk factor of mortality compared to normal BMI (OR: 2.89, CI: 1.10–7.36)
(88). However, we should take into account that obesity is mostly part of metabolic
16
syndrome (MetS). In 2006, a harmonized definition of MetS was released, nominating
waist circumference, hypertriglyceridaemia, high-density lipoprotein-cholesterol,
hypertension and diabetes mellitus as its components (two out of the five criteria should
be met, see Table 2) (89). MetS is a common comorbid condition in AP; its prevalence
varies from 18 to 62.8% across studies (30, 90, 91). Besides, it was implicated to be a
potential prognostic factor of the disease course.
Table 2. The components of metabolic syndrome
Measure Categorical cut points
Elevated waist circumference Region-specific, ≥94 cm for males and
≥80 cm for females in Caucasians
Elevated triglycerides (drug treatment for >1.7 mmol/L
elevated triglycerides is an alternate
indicator)
Reduced HDL-C (drug treatment for <1.0 mmol/L for males, <1.3 mmol/L for
reduced HDL-C is an alternate indicator) females
Elevated blood pressure (antihypertensive ≥130 mm Hg for systolic and/or ≥85 mm
drug treatment in a patient with a history Hg for diastolic
of hypertension is an alternate indicator)
Elevated fasting glucose (drug treatment >5.6 mmol/L
of elevated glucose is an alternate
indicator)
HDL-C: high-density lipoprotein-cholesterol.

17
4. Objectives and hypotheses

1. We aimed to compare the efficacy and cost-effectiveness of centralized care vs

non-centralized care in AP through the example of two tertiary hospitals from two
Hungarian cities. Based on the pre-existing data, we hypothesize that the outcomes
of centralized care will outperform that of non-centralized care.
2. We aimed to assess guideline adherence and identify the indicators of right AB
use in AP. Based on the data from our previous cohort study, we assume that there
is a significant AB overuse across Hungary. Based on prior international data, CRP
is unlikely to be a reliable indicator of infections. In contrast, PCT is assumed to
have a better diagnostic performance.
3. We aimed to investigate the effects of MetS on the disease course of AP with a
particular focus on the effects of the components alone and in combination. Since
many comorbidities, including obesity, are known to affect disease course, we
hypothesize that components will be independent risk factors of adverse outcomes
of AP while their joint effect will be more pronounced than their effect alone.

18
5. Methods

5.1 Study design and data sources

We performed three retrospective cohort studies (92-94), where the primary source
of data was the Hungarian Registry for Pancreatic Patients (in the followings, AP
Registry) (discussed under the heading ’5.2 AP Registry’). Ancillary data were collected
from an international survey to assess worldwide guideline adherence regarding AB use
in AP (discussed under the heading ’5.3 International survey’). We performed a
systematic review of papers in medical databases to assess strategies how high-quality
studies defined/suspected pancreatic infection and to review if we have high-quality
evidence supporting the efficacy of biomarker-guided AB therapy (discussed under the
heading ’5.4 Systematic review’).

5.2 AP Registry

5.2.1 Background and objectives

HPSG is dedicated to improving the care of pancreatic diseases in Hungary by

surveillance of patient care as per the principles of evidence-based medicine. Following
these objectives, HPSG established multiple patient registries of pancreatic diseases
including AP, chronic pancreatitis, pancreatic cancer and autoimmune pancreatitis (for
more information, visit https://tm-centre.org/hu/). The AP Registry was established in
2011 and had been operating consecutively since then. The registry should be considered
as a multicentre observational study with detailed, systematic prospective data collection
but without pre-defined clinical questions.

5.2.2 Sites of recruitment

The registry is free to join for all centres providing care for AP patients after
claiming local ethical permission for operation. Centres should dedicate a local principal
investigator who is liable for patient recruitment, consenting, data collection, upload and
quality. In most centres, clinical research administrators (CRA) facilitate the work.

5.2.3 Eligibility and data collection

After establishing the diagnosis of AP as per the 2012 Atlanta Classification,

patients are offered to participate in the registry. When the written informed consent is
signed in duplicate, the patient is considered eligible for inclusion. Patients are allowed
to withdraw consent to participate any time; in this case, all data shall be removed from
the database, and all biological samples shall be destroyed.

19
 Data are recorded by the treating physician, the nursing staff and CRAs onto regular
hospital files or directly onto paper-based case report forms (CRF), depending on the data
type. All paper-based files are then converted to electronic CRFs and uploaded to the
secured server of the Centre for Translational Medicine (Hungary) via an online registry
platform.
Data are collected on admission (A form) and during hospitalization daily (B forms,
one/day). The A form contains relevant data about medical history (including but not
limited to previous pancreatic diseases, comorbidities, regular medications, history of
smoking and alcohol consumption), AP-related complaints, findings on physical
examination, vital parameters, laboratory studies, imaging, on-site medications,
endoscopic, surgical and radiological interventions, fluid resuscitation and nutrition. B
forms contain all fields of the A form except for those related to medical history and
aetiology of AP. Besides, disease outcomes including mortality, severity and
complications are recorded.

5.2.4 Data validation

To ensure data quality, a four-level quality control system was developed. The first
revision of the forms is performed by the CRA of the recruiting site, followed by the
revision of the medical doctor in charge. The third revision is made by the principal CRA
of the registry, and, finally, the principal investigator closes the case. Amendments and
acquisition of missing data can be requested on revisions.

5.2.5 Data extraction

Centres uploading data in the registry are encouraged to raise research questions
and form the corresponding hypotheses. If these questions are judged to merit further
investigation, the list of data required to perform statistical analysis is claimed and
downloaded from the server in a tabularized format where all information is numerically
coded. Data extraction is followed by problem-tailored analysis.

5.2.6 Statistical considerations

In our studies, we investigated data quality by counting missing data for each
variable of interest first. For outcome variables and baseline demographic factors (age
and sex), data quality reached or approached 100%.
After choosing the variables for analysis, descriptive statistics are performed. For
categorical variables, we calculated frequencies (%). For continuous variables, we

20
investigated distribution with Q-Q plots and calculated mean with standard deviation
(SD) or standard error of the mean (SE) for normally distributed variables and median
with 25–75% quartiles (Q1–Q3) and/or range for non-normally distributed variables.
Based on descriptive statistics, the included population was compared to the whole
population of the registry to test the representativity of the sample.
In univariate comparative analyses of categorical variables, we calculated ORs with
CIs and/or compared the groups with the chi2-, the Z- or the Fisher’s exact tests with
Bonferroni correction of the p-values (if needed). For continuous variables, we used the
independent sample t-test, the Welch test or the Mann-Whitney test, depending on the
distribution and the variance of the sample. If multiple groups were compared, we used
the one-way analysis of variance (ANOVA) with posthoc Tukey test or the Kruskal-
Wallis test followed by the Holm p-value adjustment, depending on the distribution of
the data.
In multivariate analyses, we used logistic regression and calculated adjusted ORs.
Available-case analysis was used for missing data.
To investigate the diagnostic accuracy of biomarkers, we constructed receiver
operation characteristic (ROC) curves and calculated area under the curves (AUC).
The analyses were carried out with the SPSS (Versions 23, 24 and 25, IBM, New
York, NY, USA) and the R Studio (Version 1.1.453, fmsb package).

5.2.7 Ethical considerations

The operation of the AP Registry was approved by the Scientific and Research
Ethics Committee of the Medical Research Council (Hungary) under registration number
22254-1/2012/EKU. All investigations were carried out adhering to the Declaration of
Helsinki ethical guidelines (updated in October 2013, Fortaleza, Brazil).

5.3 International survey

5.3.1 Background and objectives

The IAP includes the worlds’ leading pancreatologists from top pancreas centres.
With this survey, we aimed to assess international trends of AB use in AP.

5.3.2 Data collection

In November 2017, an invitation for data collection was sent to the members of the
IAP. The following data were collected: gender, aetiology, mortality and severity of AP,
and details of AB therapy irrespectively of its indication.

21
5.4 Systematic review

5.4.1 Background and objectives

Systematic reviews are the mainstays of evidence-based medicine. The number of

publications exceeds one million yearly. Even if someone narrows the focus on a specific
topic, it is almost impossible to keep pace with the release of the most recent papers.
Summary publications, especially guidelines and systematic review (with or without
meta-analysis) aim to overcome this issue by delivering reliable information, the
essentials of knowledge in a quickly and easily digestible format (49). The key to their
success relies on full reproducibility by using the standard and transparent methodology
proposed by the flagship of evidence-based medicine, the Cochrane Collaboration
(available at https://www.cochrane.org/). With this systematic review, we aimed to gather
all information about the guidance on and strategies of AB use in AP.

5.4.2 Data sources and eligibility

We searched three medical databases (MEDLINE via PubMed, Embase and

CENTRAL) systematically up to July 2018 with the following query: ’pancreatitis AND
(antibiotic OR antibiotics OR carbapenem OR imipenem OR meropenem OR ertapenem
OR doripenem OR aminoglycoside OR amikacin OR gentamicin OR cephalosporin OR
cefepime OR ceftriaxone OR ceftazidime OR cefoperazone OR cefixime OR cefuroxime
OR cephalexin OR ceftobiprole OR cefazolin OR cefalotin OR glycopeptide OR
vancomycin OR teicoplanin OR penicillin OR amoxicillin OR ampicillin OR oxacillin OR
piperacillin OR mezlocillin OR ticarcillin OR sulbactam OR tazobactam OR clavulanate
OR fluoroquinolone OR ciprofloxacin OR levofloxacin OR moxifloxacin OR ofloxacin
OR pefloxacin OR metronidazole OR tigecycline OR linezolid OR daptomycin’. We did
not impose any restrictions (e.g. to language or publication date) on the search.
The query was designed to identify all papers which discuss guidance on and
strategies of AB use in AP. To obtain the highest level of evidence, we included only
RCTs.

5.4.3 Selection, data collection and risk of bias assessment

First, yields of the search from all databases were combined in a reference manager
software, EndNote (version X7.4, Clarivate Analytics, Philadelphia, PA, USA). The
software is capable of removing the duplicate references automatically. Then, we

22
screened the remaining records for eligibility following a standard three-step selection by
title, abstract and full-text.
Eligible papers were subjected to thorough data collection along with our pre-
defined data collection sheet. The following data were extracted: characteristics of the
study population (definition of AP, demography, aetiology), definitions of suspected and
definitive pancreatic and extrapancreatic infections, interventions (drug regimens and/or
guidance of therapy) and study setting.
Selection and data collection were carried out by two investigators independently
in duplicate, discrepancies were resolved by involving a third party.
Since our question of interest did not concern the primary objective of the RCTs
(typically, the efficacy of AB ’A’ vs AB ’B’ on the course of AP, mainly on infection
control), risk of bias assessment could not be carried out with the tool dedicated to
assessing RCTs (i.e. the Cochrane Risk of Bias Tool).

23
6. Results

6.1 Centralized care

6.1.1 Characteristics of the study population

Between 1 January 2016 and 31 December 2016, 195 and 160 patients were treated
in Healthcare Model A (providing centralized care) and Healthcare Model B (providing
non-centralized care), respectively. Logistics of patient referral is illustrated in Figure 7.
In Healthcare Model A, nine emergency units (ER) referred patients directly to the
pancreatic centre (PC). In Healthcare Model B, one ER referred patients to territorial
internal medicine departments (TIMD), a tertiary pancreatic centre (TPC), a surgical
department (SD) or directly to the intensive care unit (ICU).

Figure 7. The models of centralized (A) and non-centralized care (B) of acute pancreatitis. The arrows with solid
line represent the direction of regular patient referral; those with dash line occasionally represent referrals. The number
of patients in each unit is shown in squares. ER: emergency unit, ICU: intensive care unit, PC: pancreatic centre, SD:
surgical department, TIMD: territorial internal medical department, TPC: tertiary pancreas centre. The figure is the
author’s own work.

Baseline characteristics of the study population are summarized in Table 3. Of note,

there was no statistically significant difference in age and sex between the groups. The
leading aetiology was the biliary origin in both centres.

6.1.2 Severity, mortality, complications and length of hospital stay

Mortality was significantly lower in Healthcare Model A vs Healthcare Model B

(1.0 vs 6.3%, respectively; p=0.007). SAP developed in 7.1 vs 11.9% in Healthcare Model
A vs Healthcare Model B, the difference did not attain the level of statistical significance
(p=0.310) (Figure 8). We observed no difference regarding local and systemic
complications between the groups (Table 4).
Length of hospital stay was significantly shorter in Healthcare Model A vs
Healthcare Model B (median 6 days [Q1–Q3: 5–9] vs 8 days [Q1–Q3: 6–11], respectively;
p=0.020).

24
Table 3. Characteristics of the study population
Healthcare Model A Healthcare Model B
(centralized, n=195) (non-centralized, n=160)
Age (mean±SD in years) 57.0±17.2 57.3±16.5
Sex (male%) 56 57
Aetiology (%)
Biliary 42.1 33.3
Alcoholic 15.4 8.3
Hypertriglyceridaemic 2.1 6.4
Alcoholic + 4.1 7.7
Hypertriglyceridaemic
Other combined 8.2 5.8
Post-ERCP 3.1 3.2
Other 7.2 15.4
Idiopathic 17.9 19.9
ERCP: endoscopic retrograde cholangiopancreatography; SD: standard deviation.

Figure 8. Severity and mortality in Healthcare Model A (providing centralized care) and Healthcare Model B
(providing non-centralized care). Pie charts show the distribution of severity, and bar charts show overall and
severity-stratified mortality. Severity was graded by the 2012 Atlanta Classification. MAP: mild acute pancreatitis,
MSAP: moderately severe acute pancreatitis, SAP: severe acute pancreatitis. The figure is the author’s own work.

Table 4. Complications
Healthcare Model A Healthcare Model B p-value
(N0, % of total) (N0, % of total)
No complication 150 (76.8) 118 (73.8) 0.337
Local complications 43 (22.1) 35 (21.8) 0.872
Systemic complications 21 (10.5) 27 (16.9) 0.177

25
6.1.3 Therapeutic approach and interventions

The proportion of ERCPs, necrosectomy or guided drainage did not differ between
groups (Table 5). However, enteral feeding was more frequently used in Healthcare
Model A, whereas AB use was less frequent in this group (p<0.001 for both comparisons).
Patients with MAP, MSAP and SAP received ABs in 35.3% (n=54), 64.3% (n=18) and
92.9% (n=13) in Healthcare Model A and in 70.3% (n=83), 91.3% (n=21) and 100.0%
(n=19) in Healthcare Model B, respectively; AB use was significantly lower in Healthcare
Model A regarding MAP and MSAP (p<0.05 for both) but not significantly different
regarding SAP (p=0.424)
Table 5. Therapeutic approach and interventions.
Healthcare Model A Healthcare Model B p-value
(N0, % of total) (N0, % of total)
ERCP 85 (43.6) 59 (36.9) 0.143
Necrosectomy 1 (0.5) 2 (1.3) 0.793
Radiology or EUS-guided 8 (4.1) 2 (1.2) 0.118
drainage
Enteral feeding 179 (91.8) 36 (22.5) <0.001
Antibiotic use 85 (43.6) 123 (76.9) <0.001
EUS: endoscopic ultrasonography, ERCP: endoscopic retrograde cholangiopancreatography
6.1.4 Cost of care

The average cost of care per capita was 964 Euro in Healthcare Model A, whereas
it was 1,285 Euro is Healthcare Model B with a difference of 25% between groups. This
calculation is limited to medication use, disposables, procedures and investigations but
does not include the costs of staff and hospital stay.

6.2 Antibiotic use

6.2.1 Systematic review

We conducted a systematic review to assess if any RCT investigated biomarker-

guided AB treatment in AP and how RCTs defined suspected or definitive pancreatic
infections. After careful search and selection, 23 studies proved to be eligible, one of
which reported on PCT-guided ABs treatment, the other 22 tested prophylactic AB use.
The flowchart of the selection process is shown in Figure 9.

26
Figure 9. The flowchart of the selection process. RCT: randomized controlled trial. Reprinted from ’Antibiotic
Therapy in Acute Pancreatitis: From Global Overuse to Evidence Based Recommendations’ by Párniczky et al., 2019,
Pancreatology.

Supplementary Table 1 summarizes the baseline characteristics of the studies

included. The only RCT investigating the guidance of AB therapy was a two-arm study
in SAP. On the intervention arm, the administration of ABs was driven if PCT level
exceeded 0.5 ng/ml, and the AB treatment was stopped if the level fell below 0.5 ng/ml.
On the control arm, ABs were given for two weeks for all patients, then continued if any
infection was confirmed. While the clinical efficacy of the strategies was found to be
equal, the PCT-guided treatment proved to be more cost-effective (24,401±2,631 vs
27,813±2,529 US dollars for the PCT-guided vs control groups, respectively; p<0.001)
(95).
In the remaining 22 studies testing the efficacy of AB treatment vs various control
groups, the definitions for pancreatic infection was substantially heterogeneous (96-117).
Generally, the definitions were based on laboratory and clinical factors (alone or in
combination). These factors included CRP (in five studies), elevated WBC (in two

27
studies), fever (in two studies), SIRS/organ failure/sepsis (in three studies) and air bubbles
within the pancreatic necrosis on CECT (in two studies). Surprisingly, none of the studies
used PCT to define suspected or definitive infection. A change in inflammatory
biomarkers (i.e. a rise following an initial decrease) was taken into consideration only in
two studies.
Taken together, there is no evidence-based consensus on how to define pancreatic
infection and how to guide AB therapy in AP.

6.2.2 International survey

Figure 10. shows the findings of our international survey on the frequency of AB
use in AP. Data were collected across 23 countries from 9,869 patient. The global
tendency showed significant overuse of ABs. It exceeded 80% in Asia (based on Chinese
and Taiwanese data), approached 80% in Eastern Europe whereas it was only
approximately 30% in Western Europe. In Hungary, the AB use was 74.7%.

Figure 10. Map of antibiotic use worldwide. In average, 57.2% of patients with acute pancreatitis received antibiotics.
Reprinted from ’Antibiotic Therapy in Acute Pancreatitis: From Global Overuse to Evidence Based Recommendations’
by Párniczky et al., 2019, Pancreatology.
6.2.3 Registry analysis

6.2.3.1 Characteristics of the study population

Altogether, 962 of 1,070 patients from the AP Registry were eligible for inclusion.
We set up groups based on AB treatment and status of infection, as shown by Figure 11.

28
Figure 11. Study subgroups. Groups 1 and 2 did not, whereas Groups 3–5 did receive antibiotics. Infection was
suspected based on clinical signs and symptoms. Prophylactic (Group 3), empirical (Group 4) and targeted (Group 5)
antibiotic treatment were defined if no infection was suspected, infection was suspected without positive culturing and
infection was verified with culturing, respectively. Group 4 was divided into 4A (suspected infection without culturing
performed) and 4B (suspected infection with negative culturing). AB: antibiotic, Neg.: negative, Pos.: Positive, Susp.:
Suspected. The figure is the author’s own work.
Mortality and SAP accounted for 1.8 and 5.5% in the study population,
respectively. The leading aetiology was the biliary origin (42.1%), followed by idiopathic
AP (21.5%) and alcoholic AP (18.8%). Distribution of AB use by aetiology is
summarized in Table 6. Most of the patients received ABs irrespective of aetiology.
Table 6. Antibiotic use by aetiology.
Aetiology N0 of patients Antibiotic use
(% of total) (%)
Biliary 405 (42.1) 82
Alcoholic 181 (18.8) 65
Hypertriglyceridaemic 23 (2.4) 78
Post-ERCP 28 (2.9) 71
Idiopathic 207 (21.5) 70
Other 87 (9.0) 69
Combined 31 (3.2) 84
ERCP: endoscopic retrograde cholangiopancreatography.
6.2.3.2 Mortality, severity and length of hospital stay

Mortality of AP was 2.2 and 0.8% in patients who received (Groups 3–5) or did not
receive ABs (Groups 1, 2), respectively; without significant difference between the
groups. MAP, MSAP and SAP accounted for 79.9, 18.9 and 1.2% (Groups 1, 2) vs 62.4,

29
30.6 and 7.0% (Groups 3–5), respectively (p<0.001). Length of hospital stay was
significantly longer for those receiving ABs (13.4±0.5 vs 8.3±0.3 days for Groups 3–5
and Groups 1, 2, respectively; p<0.001).
Table 7 summarizes mortality, severity and length of hospital stay across groups.
The rate of SAP and mortality were the highest while the length of hospital stay was the
longest in Group 5. SAP was more common in Group 5 (positive culturing) compared to
Group 4B (negative culturing) (p=0.028), but the difference in mortality did not attain the
level of statistical significance. Also, SAP was more common in Group 4B (negative
culturing) compared to Group 4A (no culturing) (p=0.007). Group 1 and Group 2 (neither
received ABs) did not differ in outcomes significantly.
Table 7. Mortality, severity and length of hospital stay across groups.
Group Mortality Severe course Length of hospital stay
(%) (%) (days)
No antibiotic use
Group 1 0.8 0.8 8.3±0.4
Group 2 0.8 1.6 8.2±0.4
Antibiotic use
Group 3 0.8 5.8 12.3±1.1
Group 4A 1.4 2.4 10.7±0.3
Group 4B 3.9 10.8 18.6±1.5
Group 5 6.6 28.9 22.9±1.6
Definition of groups is described in Figure 11.
6.2.3.3 Details of antibiotic treatment

If we consider those patients receiving ABs (that is, Groups 3–5), the therapy was
started in 74% of the cases on the first day and in 11% on the second day of hospital stay.
These numbers were similar across groups. 52% of the cases were treated with a single
AB; the others received combined AB treatment. In 75% of the cases, the initial treatment
was continued while the remaining individuals required at least one switch in AB therapy
(21 and 4% required one and two switches, respectively). In general, AB switch was
associated with a more severe disease course.
Distribution of ABs across groups by status of infection and by severity of AP are
shown in Table 8. Almost 30% of the cases received cephalosporins alone, followed by
the combination of ciprofloxacin with metronidazole and cephalosporin with
metronidazole. The pattern was similar in the subgroup of MAP, whereas imipenem was
favoured in SAP.

30
6.2.3.4 Biomarkers and the initiation of antibiotic treatment

Figure 12A–D shows the on-admission levels of amylase, lipase, CRP and WBC
across groups by status of infection. Patients receiving ABs (Groups 3–5) have
significantly higher amylase, lipase, CRP and WBC compared to those not receiving ABs
(Groups 1, 2). Patients with positive culturing (Group 5) did not have significantly higher
amylase, lipase, CRP or WBC compared to those who did have negative culturing (Group
4b). Those receiving prophylactic ABs (Group 3) had significantly higher levels of
amylase, lipase, CRP and WBC compared to those not receiving ABs and were not
suspected of having infection (Group 1).
Figure 12E–H shows the on-admission levels of amylase, lipase, CRP and WBC
across groups by severity. CRP but not amylase and lipase differed significantly by
severity: the highest CRP level was measured in SAP, whereas the lowest in MAP (Figure
12G).

6.2.3.5 Changes in biomarkers during the disease course

Figure 13 shows the changes in CRP and WBC across groups by status of infection.
Regarding CRP, only the comparison of Groups 4a vs 4b attained the level of significance
(Figure 13D), while we observed no significant difference regarding WBC (Figure 13F–
J). Considering the changes in PCT, we observed a tendency when comparing Groups 4b
vs 5 (p=0.052), indicating a higher level of PCT in those with positive culturing.
When we tested if these biomarkers can distinguish cases with infection from those
without infection, AUCs were poor for CRP and WBC (AUC=0.510 and 0.454,
respectively) and fair for PCT (AUC=0.729) (Figure 14).

6.2.3.6 Outcomes and pathogens of cases with infections

IPN had spiking high mortality (25.0%). Other sources of infection (biliary,
urogenital, pulmonary) were associated with moderate-high mortality ranging from 8.3
to 14.3%. Pathogens were dominantly Staphylococci (34.2%), Enterococci (27.4%),
Clostridium difficile (22.4%), Escherichia coli (18.4%), Pseudomonas (13.2%) and
Klebsiella species (9.2%).

31
Table 8. Distribution of antibiotics across groups by status of infection and by severity of acute pancreatitis.
Single AB Dual AB
Ciprofloxacin Cephalosporin
Triple AB
Cephalosporin Ciprofloxacin Imipenem Other + + Other
metronidazole metronidazole
Distribution across groups (%)
Group 3 30.0 15.8 6.7 0.0 22.5 18.3 3.3 3.3
Group 4a 34.0 13.6 2.6 2.1 23.3 18.6 3.3 2.4
Group 4b 18.6 11.8 15.7 4.9 15.7 19.6 5.9 7.8
Group 5 18.4 11.8 14.5 6.6 13.2 13.2 11.8 10.5
Distribution across severity (%)
Mild 31.9 15.4 3.1 1.6 24.6 18.1 2.5 2.9
Moderate 27.7 11.4 8.6 3.2 17.3 19.1 7.7 5.0
Severe 16.0 6.0 26.0 10.0 6.0 14.0 10.0 12.0
Summary (%) 29.5 13.5 6.4 2.6 21.0 18.1 4.6 4.2
Values are given in % of row total. Definition of groups is described in Figure 11. AB: antibiotic.

32
Figure 12. On-admission laboratory markers by antibiotic therapy and status of infection (A–D) and by severity of acute pancreatitis (E–H). In non-AB groups, day-matched controls
were selected. Values are given as mean ± standard deviation. For the definitions of groups, see Figure 11. (A) Average amylase in non-AB group (510.01 ± 57.91 U/L) compared to AB group
(1004.15 ± 50.22 U/L) differed significantly (p<0.001). (B): There was a significant difference (p<0.001) between average lipase in non-AB (815.83 ± 96.73 U/L) and AB (2298.72 ± 207.82 U/L)
groups. (C) CRP level showed a significant difference between non-AB and AB groups (52.16 ± 4.91 mg/L vs 86.4 ± 4.2 mg/L, p<0.001), (D) similar trends were detected with regards to WBC
levels (10.32 ± 0.28 G/L vs 13.8 ± 0.2 G/L, p<0.001). (E) Average amylase (1015.25 ± 55.10 U/L, 957.41 ± 83.33 U/L, 1077.48 ± 397.02 U/l) and (F) lipase (2303.05 ± 219.19 U/L, 2286.82 ±
378.21 U/L, 2131.42 ± 1377.75 U/L) did not differ across mild, moderate and severe cases, respectively. (G) Average CRP (68.77 ± 4.32 mg/L, 104.56 ± 8.71 mg/L, 181.7 ± 27.26 mg/L) and (H)
WBC (12.83 ± 0.21 G/L, 15.11 ± 0.49 G/L, 16.5 ± 0.98 G/L) positively correlated with the severity of acute pancreatitis. AB: antibiotic, CRP: C-reactive protein, WBC: white blood cell count.
Reprinted from ’Antibiotic Therapy in Acute Pancreatitis: From Global Overuse to Evidence Based Recommendations’ by Párniczky et al., 2019, Pancreatology.

33
Figure 13. Changes in biomarkers during disease course across groups by antibiotic treatment and status of infection. (A) All groups (for illustrative purpose only), (B) Groups 1 vs 2, (C)
Groups 1 vs 3, (D), Groups 4a vs 4b and (E) Groups 4b vs 5 with the corresponding p-values embedded in the figures. Group are indicated with numbers in the figures, for the definitions of groups,
see Figure 11. The horizontal axis represents the days of hospital stay (A: admission). CRP: C-reactive protein, WBC: white blood cell count. Adapted and reprinted from ’Antibiotic Therapy in
Acute Pancreatitis: From Global Overuse to Evidence Based Recommendations’ by Párniczky et al., 2019, Pancreatology.

34
Figure 14. Procalcitonin and infections in acute pancreatitis. (A) Changes of procalcitonin level during disease
course in Groups 4b vs 5 with the corresponding p-value embedded in the figure. (B) Diagnostic accuracy of
procalcitonin in discriminating pancreatic infections: area under the curve was 0.729, indicating a fair discriminative
ability. PCT: procalcitonin. Adapted and reprinted from ’Antibiotic Therapy in Acute Pancreatitis: From Global
Overuse to Evidence Based Recommendations’ by Párniczky et al., 2019, Pancreatology.

6.3 Metabolic syndrome and acute pancreatitis

6.3.1 Characteristics of the study population

A total of 1,435 cases were identified in the AP Registry, of which 1,257 were
included in the analysis (for sites of recruitment, see Supplementary Figure 1). The study
population proved to be representative of the total population of the registry regarding
age, sex, severity of AP, mortality, length of hospital stay and complications. All cases
had available information about hypertension and obesity (defined as a BMI≥30 kg/m2),
1,127 cases about diabetes mellitus and 1,036 cases about hyperlipidaemia. All four
variables were available for 906 cases. Baseline characteristics of the population are
summarized in Table 9. Obesity, hypertension, hyperlipidaemia and diabetes mellitus
accounted for 29.5, 60.0, 33.6 and 16.4% of the cases.

6.3.2 Association of components of metabolic syndrome with disease outcomes

Table 9 summarizes the characteristics of the study population, and Table 10 shows
the outcomes of patients with and without the components of MetS in univariate analysis.
Mortality was similar across groups. Obesity and hypertension were associated with a
more severe disease course (OR: 2.15, CI: 1.31–3.54 and OR: 2.39, CI: 1.30–4.38,
respectively), more systemic complications (OR: 1.99, CI: 1.30–3.05 and OR: 2.83, CI:
1.64–4.88, respectively) and longer hospital stay (12.1 vs 10.4 days with p=0.008 and
11.8 vs 10.5 days with p=0.020, respectively). Local complications were rather more

35
common with hyperlipidaemia (OR: 1.55, CI: 1.17–2.05). Interestingly, diabetes mellitus
was not associated with untoward outcomes of AP.
Based on the data of 906 patients having had available data for all the four variables,
189 patients (20.9%) had no components of MetS, 294 (32.5%) had obesity, 560 (61.8%)
had hypertension, 316 (34.9%) had hyperlipidaemia, and 162 (17.9%) had diabetes
mellitus. In logistic regression analysis adjusted for age and other components of MetS,
obesity predicted renal failure (OR: 2.98, CI: 1.33–6.66); hypertension predicted SAP
(OR: 3.41, CI: 1.39–8.37), systemic complications (OR: 2.64, CI: 1.27–5.51) and renal
failure (OR: 7.46, CI: 1.61–34.49); hyperlipidaemia predicted local complications (OR:
1.51, CI: 1.10–2.07) and new diagnosis of DM (OR: 2.55, CI: 1.26–5.19); whereas
diabetes mellitus was not a significant predictor of any outcomes. The presence of two,
three, or four components of MetS significantly increased the rate of untoward outcomes
by 9.5, 24.1, and 66.7%, respectively.

36
Table 9. Characteristics of the study population.
Total Obesity Hypertension Hyperlipidaemia Diabetes mellitus
(n=1,257)
No Yes No Yes No Yes No Yes
(n=886) (n=371) (n=451) (n=676) (n=687) (n=349) (n=1051) (n=206)
Demography
Age (mean±SD, 55.7±17 55.4±17.7 56.3±15.2 46.2±15.2 63.8±14.1* 56.4±17. 54.0±14.5* 54.5±17. 61.7±13.9*
years) 8 3
Female (% of total) 42.9 40.7 48.0* 38.1 48.2* 44.4 35.2 43.6 39.3
CCI (mean±SD, 1.4±1.6 1.3±1.6 1.6±1.7 0.9±1.4 1.7±1.7 1.3±1.6 1.7±1.8 1.0±1.4 2.9±1.7
point)
Aetiology (% of total)
Biliary 37.8 33.6 47.7* 31.3 44.1 41.3 26.4 38.2 35.9
Alcoholic 18.5 21.1 12.1 20.2 12.4 21.4 17.2 19.0 15.5
Hypertriglicerdaemic 3.7 3.0 5.4 3.3 3.7 0.1 12.9* 2.8 8.7*
Alcoholic + 1.8 1.9 1.6 1.6 1.9 0.0 6.6 1.8 1.9
Hypertriglicerdaemic
Post-ERCP 2.6 3.0 1.6 3.1 2.8 2.9 0.9 2.6 2.9
Combined 8.0 7.1 10.0 11.1 7.0 7.7 7.2 7.9 8.3
Idiopathic 20.5 22.0 17.0 21.5 20.7 18.8 23.8 20.6 20.4
Other 7.1 8.1 4.6 8.0 7.4 7.7 5.2 7.2 6.3
*indicates a statistically significant difference between groups in univariate analysis (condition vs no condition). ERCP: endoscopic retrograde cholangiopancreatography, SD: standard deviation.

37
Table 10. Disease outcomes.
Total Obesity Hypertension Hyperlipidaemia Diabetes mellitus
(n=1,257)
No Yes No Yes No Yes No Yes
(n=886) (n=371) (n=451) (n=676) (n=687) (n=349) (n=1051) (n=206)
Severity (% of total)
Mild 69.6 69.9 69.0 70.1 69.5 73.5 64.2* 69.7 68.9
Moderate 25.1 26.1 22.6 26.8 23.4 22.1 29.5 24.9 25.7
Severe 5.3 4.1 8.4* 3.1 7.1* 4.4 6.3 5.3 5.3
Mortality 2.4 2.1 3.0 1.3 3.1 2.3 1.4 2.5 1.9
Length of hospital 10.9±9.3 10.4±8.6 12.1±10.6* 10.5±7.9 11.8±10.1* 10.5±9 11.4±10.3 10.7±9 11.8±10.6
stay (mean±SD, days)
Complications (% of total)
Local 29.0 28.6 30.2 29.5 28.3 25.3 34.7* 29.1 28.6
Fluid collection 25.0 24.7 26.7 23.9 25.3 22.1 29.8* 24.9 27.2
Pseudocyst 7.6 7.8 7.3 6.9 9.3 6.0 10.6* 7.6 7.8
Necrosis 8.0 7.1 10.2 7.8 8.0 8.2 8.9 8.3 6.8
New onset diabetes 3.8 3.5 4.6 2.7 4.1 3.6 5.2 4.6 N/A
mellitus
Systemic 7.6 6.0 11.3* 3.8 10.1* 6.6 9.5 7.0 10.2
Respiratory failure 4.6 3.5 7.3* 2.0 6.1* 4.5 4.9 4.1 7.3
Heart failure 1.8 1.4 3.0 0.7 2.5* 1.9 2.0 1.9 1.5
Renal failure 2.7 1.4 5.9* 0.7 4.1* 2.2 4.6* 2.8 2.4
*indicates a statistically significant difference between groups in univariate analysis (condition vs no condition). N/A: not applicable, SD: standard deviation.

38
7. Discussion

7.1 Scope and main findings

In this dissertation, findings from three cohort studies covering different aspects of
the management of AP were introduced. We aimed to investigate the effects of centralized
care, features and indications of AB use and the associations between the components of
MetS and outcomes of AP. In our first study, centralized care proved to be superior
regarding outcomes, quality indicators and cost of care (92). In our second study, early
rise in CRP proved to be inaccurate for guiding the initiation of AB therapy, whereas PCT
was a more promising biomarker (93). In the third study, MetS and its components
predisposed patients to develop a more severe disease course (94).

7.2 Explanation and elaboration

7.2.1 Centralized care

To our best knowledge, five studies investigated the role of hospital volume on the
outcomes of AP (7, 118-121). The definition for high hospital volume varied across
studies fundamentally: cut-offs for annual case numbers ranged from 16 to 118. In
contrast in our study, 195 cases were treated in the specialist unit (centralized care), and
only 81 cases were treated in the tertiary pancreatic centre in the non-centralized setting
(the others were treated in smaller wards receiving ≤30 cases, as shown by Figure 7).
Comparing our centres to the international data, Healthcare Model A should be taken as
a high volume centre whereas
Healthcare Model B consists of
of a moderate volume and
multiple low volume centres.
Four studies provided
evidence that a higher hospital
volume has a favourable impact
on mortality of AP (for an Figure 15. The association between hospital volume and in-
example, see Figure 15) (7, 118, hospital mortality. The higher the hospital volume, the lower the
in-hospital mortality. In our study, in-hospital mortality was 1 and
119, 121), the fifth found no 6.3% with annual case numbers 195 and 160 in Healthcare Models
A and B, respectively (represented by the larger black dots with the
benefit (120). Length of hospital corresponding letters in the figure). Of note, only 81 patients were
treated in the tertiary pancreatic centre in Healthcare Model B.
stay consistently reduced in four Adapted and reprinted from ’The effect of hospital volume on patient
outcomes in severe acute pancreatitis’ by Shen et al., 2012, BMC
studies (7, 118-120). Cost of Gastroenterology.

39
care was reduced in one study (7); however, another one reported no change (120). The
benefit of a higher hospital volume remained stable even after propensity matching and/or
adjustment for significant covariates, such as baseline disease severity (patients with SAP
are probably more likely to be referred to a centre of higher progressivity level thereby
increasing adverse outcomes, the phenomenon is termed as ’referral bias’ (122)). It must
be noted, however, that our study did not investigate the effect of hospital volume directly
since this is only one component of centralized care. In our study, better guideline
adherence (i.e. evidence-based care, reflected by the lower rate AB use and the higher
rate of nasoenteral nutrition) served with an additional benefit for patients, making our
study setting unique.
To sum up, providing care of AP in specialised units (i.e. centralization) is
supported by several theoretical and practical arguments.
1) Both hospital volume and physician volume can exceed that of general units
multiple times: along the ’Practice makes one better’ principle, management skills
(i.e. expertise) can be gained with the increasing number of cases.
2) Access to state-of-the-art facilities and services, including multidisciplinary
consultations, is usually better in specialized units. Instant availability of ICU
should be highlighted. Besides, access to diagnostic and therapeutic endoscopic
procedures is a must-have-item in specialist units: EUS/ERCP should be performed
by an expert operator for selected cases of biliary AP (123), and endoscopic
debridement/stent insertion might be required for certain cases of local
complications.
3) Adherence to evidence-based guidelines is better in specialist units as treating
physicians are motivated to keep pace with changes in recommendations. Although
most efforts for pharmacological interventions failed to achieve success in AP (72),
pre-existing comorbidities can be decompensated, thereby requiring further care.
Secondary prevention aiming to reduce the rate of recurrent AP might be more
structured by providing the required intervention through strict follow-up of cases
(such as same-admission cholecystectomy in biliary AP (124), encouragement for
alcohol withdrawal in alcohol-induced AP (125) or lipid-control in
hypertriglyceridaemic AP (126)).
4) Specialized units contribute to research activity to a considerable extent, which
provides further financial and infrastructural access and promote guideline
adherence (49). A good example could be the operation of the AP Registry, which

40
 requires to acquire extremely detailed past
medical history and strict recording of vital
signs, laboratory parameters, finding on
physical examination and imaging daily.
These arguments are entirely in line with the
principles of evidence-based medicine regarding
decision making: evidence from research should
be complemented with personal expertise and the
patient’s preferences to make the optimal decision
Figure 16. The model of evidence-based
(Figure 16). medicine. Centralized care in specialist units
allows to meet ’Optimal choice’. The figure
7.2.2 Antibiotic use is the author’s own work.

In 1975, two RCTs were published which investigated the efficacy of prophylactic
AB use in AP (98, 103), writing the first pages of the saga of ABs in AP. Although now
we consider prophylactic AB use ineffective (72), defining the population which benefits
from ABs has remained an open debate. Although extrapancreatic infections, e.g. acute
cholangitis, obviously require treatment (40, 43, 44), identifying those who already have
or are particularly vulnerable to develop IPN is challenging.
Considering the direct and indirect strategies implemented to verify IPN and justify
AB use, even the top-quality studies used inconsistent definitions, as indicated by our
systematic review (see Supplementary Table 1). Despite the known drawbacks
(invasivity, costs, difficult sampling, need for imaging-guidance), FNAB followed by
culturing should be considered the single direct method for detecting bacteria from IPN
and initiating targeted AB treatment, though empirical AB therapy is pervasively used
(40, 43, 44). A meta-analysis of 14 studies reported that the incidence of IPN could be as
high as 21% (314 cases of IPN out of 1,478 cases of AP) and IPN posed a considerable
burden of mortality (127). In our data analysis of 962 AP cases, 76 had a culturing-
confirmed infection (7.9%), which is considerably lower than the reported average. Of
note, the number of cases with negative culturing was low as well (102 cases, 10.5%). A
total of 420 cases (43.4%) were considered to show signs of suspected infection and were
treated accordingly with ABs, which rather reflects that our practice follows the empirical
treatment strategy instead of the culturing-based targeted AB therapy (Figure 11).
Nevertheless, no RCTs have compared FNA-guided vs empirical initiation of ABs.

41
 In line with our preliminary publication (25), our study indicated that 74.7% of
cases received ABs during hospital stay in Hungary. In the context of the fraction of cases
with confirmed or suspected infection, this number is almost double of the expectations.
Findings from the Western countries fell far from that reported in Hungary while most
Asian countries performed similarly as we did (map of worldwide AB use is shown in
Figure 10). These findings are in line with previous observations from Japan (74%) (128),
India (67%) (129), the UK (58%) (130) and the US (41%) (131) and findings of a
summary publication from 2016 (41–88%) (132). If we consider AB use as an indicator
of guideline adherence, Hungary performed poorly. Regular in-hospital audits and
establishment of specialist units may facilitate guideline adherence regarding AB use, as
shown by our study on the efficacy of centralized care (92).
AB overuse has long-lasting implications: it encourages the emergence of AB-
resistant bacteria, thereby reducing the available treatment options not only in AP but also
in other medical conditions (133). The background of AB over- or misuse is multifactorial
but the development of SIRS with elevating WBC, CRP and, sometimes, rising body
temperature – as the consequence of sterile inflammation – resembles an ongoing
infection, deciphering clinicians. To address this issue, biomarker research tended to
focus on new and newly emerging laboratory parameters (such as CRP, PCT, cytokines
and chemokines) assumed to have the potential of distinguishing IPN from sterile ANP
(see the paper of Quenot et al. for an up-to-date review on biomarkers (134)). In these
studies, the level of biomarkers often showed a statistically significant difference between
cases with and without IPN with varying diagnostic performance across studies. AUC for
CRP ranged from 76 to 86% whereas that of PCT often exceeded 90%. In a meta-analysis
of 7 studies, sensitivity and specificity of PCT proved to be 80 and 91%, respectively;
with an AUC of 0.91 (135). Surprisingly, AUC for on-admission PCT was measured only
0.729 in our cohort of patients (Figure 14) while on-admission CRP had an even worse
poor diagnostic performance. The difference between our results might root in the
selection of the sample: earlier studies often included patients from ICU so that the pre-
test probability of having IAP was substantially higher. Besides, a lot of patients in our
database did not have valid PCT measurement; therefore, our confidence in the
representativity of this result is low.
Biomarker-guided initiation of AB therapy is an enticing possibility. Convincing
quality of evidence on safety and efficacy can only be obtained from RCTs. The single
study we found on PCT-guided AB therapy had a limited sample size to estimate the

42
effects on hard outcomes reliably; therefore, it should be considered a pilot study (95).
Another ongoing RCT from the UK under the acronym PROCAP has similar objectives
and presumably has more extensive resources (136). Further studies on the topic are very
welcomed.

7.2.3 Metabolic syndrome

According to data of the Hungarian Central Statistical Office, 40.3% of the

population had normal BMI, 35.8% had a BMI between 25 and 30 kg/m2 (i.e. overweight)
and 19.7% had a BMI>30 kg/m2 (i.e. obese) in 2017 (further data are available at
www.ksh.hu). In contrast, prevalence of obesity was almost 30% in our study. Indeed, it
is not surprising because obesity is known to increase the risk of AP: in a Chinese
prospective cohort study including more than half-million participants, waist
circumference was an independent risk factor of AP (adjusted hazard ratio [HR]: 1.35,
CI: 1.27-1.43) (137). Observations posed that the amount (and maybe the distribution) of
visceral fat is related to the severity of AP (138, 139). The theory on how obesity
aggravates the clinical course of AP involves the role of abundant peripancreatic adipose
tissue, which is vulnerable to necrosis, in which unsaturated fatty acids, cytokines,
chemokines and other biologically active molecules are released, triggering the cascade
of systemic effects (for details, see the review of Khatua et al. (140)). The previous results
were supported by our findings based on calculations from BMI instead of waist
circumference (as the latter is not routinely recorded in the AP Registry).
Hyperlipidaemia was reported to be associated with adverse disease course in multiple
studies (79, 141, 142) whereas, in our study, hyperlipidaemia was independently
associated only with the frequency of local complications. By mechanism, lipotoxicity
and endoplasmic reticulum stress were implicated (143). Surprisingly, we found no
association between diabetes mellitus and disease outcomes in this study, opposing other
evidence (144).
In line with other reports (30, 90, 91), the association between the effects of MetS
on adverse disease outcomes was convincing in our study as well. Considering the
individual effects of components of MetS, there is substantial heterogeneity in the
measured effects across the studies. This roots in the fact that the components of MetS do
associate with other prognostic factors (such as age or comorbidities), aggravating the
disease course. This question can only be approached with multivariate analysis (in our
study, with logistic regression) to control for confounding factors. However, studies

43
included various confounding factors in the analysis, potentially leading to divergent
conclusions. Consequently, the findings of studies in the literature should not be
considered comparable with each other.

7.3 Strengths and limitations

Although the AP Registry records are based on multicentre data, it must be noted
that the population of the registry is not nationwide; therefore, we do not have evidence
that it is undoubtedly representative of the whole Hungarian set of cases with AP (out of
the estimated 5,000–5,500 cases in the country, an average of 500–600 cases are uploaded
in the registry annually). Centres which cannot afford to employ CRAs may upload MAP
with shorter hospitalization more frequently because the longer the hospitalization, the
more B forms are required to be completed, imposing an extra administrative burden on
the medical staff. Consequently, data from the registry may underestimate the rate of SAP
and mortality.
Regarding internationality, the registry is open to join for all centres providing care
for AP (irrespective of the level of care or centralization). However, the majority of the
study population was recruited from Hungary (shown in Supplementary Figure 1). Of
note, baseline characteristics of the study population (age, sex, comorbidities) and disease
outcomes (mortality and severity) resemble that published in the literature.
Guideline adherence may differ across centres, so does diagnostic and therapeutic
approaches, both having the potential to modify disease outcomes. Local complications
are especially vulnerable to detection bias: while in our specialist unit, follow-up imaging
(US or CECT) is arranged for the 1-month visit, some centres do not invite patients for
follow-up at all. Therefore, incidence of local complications is probably underestimated,
affecting the categorization of disease severity (i.e. the differentiation between MAP and
MSAP, see Table 1 for definitions). Besides, transient and permanent organ failure are
sometimes hard to be distinguished (e.g. if one does not have data on kidney functions
prior to the acute episode, the length of recovery cannot be judged reliably). Access to
interventions may affect outcomes as well: centres cannot adhere to the step-up approach
if endoscopic or percutaneous interventions are not available (145). Limited laboratory
and imaging capacities (e.g. measurement of IgG4, detection of pancreatic malformations
or microlithiasis, identification of genetic mutations) may affect the investigation for rare
aetiologies so that classification bias might occur.

44
 The AP Registry is a unique source of data on AP cases with excellent data quality
for hard outcomes, ensured by the four-level quality control systems. The high total case
number (>1,000 cases) allows a detailed analysis of rare conditions as well. Although
data quality for disease outcomes (e.g. severity, mortality) and certain baseline parameters
(e.g. age, sex, aetiology, on-admission vital parameters) are almost 100%, other data are
not always systematically documented. Missing data limits the use of logistic regression
model because some potential confounding factors cannot be added or can be replaced
with imputation. Besides, from a statistical point of view, mortality and severity should
be considered rare events in AP, which reduce statistical power in the analysis even if the
total case number is high.
Theoretically, the comparison of centralized vs non-centralized care would have the
highest level of evidence from a cluster RCT. This setting is not feasible to be organized
due to various logistical and ethical reasons. However, since consecutive cases were
included in the analysis from both centres in this study, we assume that baseline factors
were approximately balanced between groups (as shown by the age and sex of the cases
in Table 3). The question if PCT-guided AB treatment is superior to standard of care or
other biomarker-guided treatment regarding efficacy and safety can be best answered
with a parallel RCT.

45
8. Conclusions and perspectives

1. Centralized care is superior to non-centralized care in AP regarding mortality,

severity and quality indicators of care, such as the use of ABs and enteral
feeding, while the cost of care is reduced by a quarter in the specialist unit.
Further research is needed to investigate which component(s) of centralized care
might be responsible for its benefit and which annual minimum volume of centres is
needed to observe improvement in care.
2. ABs are overused in AP both worldwide and in Hungary. Early AB treatment
should not be initiated based on initially elevated CRP because it does not
indicate infections reliably in AP. PCT shows fair diagnostic performance in
detecting infections so that it may be a better driver of AB therapy than CRP.
Further research is needed to clarify if changes in biomarkers, such as persistently
elevated or suddenly rising CRP, can establish the rationale for the initiation of AB
treatment. The diagnostic performance of other biomarkers of the acute-phase
response, e.g. cytokines and chemokines, warrants further investigation. Regular in-
house audits might help to reduce the unnecessary AB treatment, thereby the cost of
care in specialist units.
3. Components of MetS are present in a considerable fraction of AP patients and
are independent predictors of various outcomes. Hypertension predicts severity,
systematic complications and renal failure; obesity predicts renal failure, and
hyperlipidaemia predicts local complications and newly onset diabetes mellitus.
The more components of MetS a patient has, the worse the clinical outcome is.
Further research is needed to investigate the interplay of the components of MetS
during the clinical course of AP. In addition, the difference between well- and poorly
treated comorbidities should be assessed as well. Prognostic scores might benefit
from incorporating MetS or items of MetS.

46
9. Acknowledgements

I want to express my profound gratitude to my supervisor Áron Vincze for his

guidance and help during my clinical and scientific work. Without him, this work would
not have been possible.
I want to thank Péter Hegyi, who offered me the opportunity to participate in the
operation of the AP Registry actively and supported me throughout the entire work. The
efforts of all treating physicians and clinical research administrators who contributed to
data acquisition and upload of patients’ files must be acknowledged as well. The
operation of the AP Registry would not be possible without the financial support of an
Economic Development and Innovation Operative Programme Grant (GINOP 2.3.2.-15-
2016-00048) and a Human Resources Development Operative Programme Grant (EFOP-
3.6.2-16-2017-00006) of the National Research, Development and Innovation Office,
Hungary.
I want to thank the biostatistical team of the Center for Translational Medicine, led
by Nelli Farkas, for her help with the statistical analysis, and I am very grateful to Zsolt
Szakács for his contribution to the methodology and critical review of the projects.
Finally, I would like to thank my family members, who always encouraged and
supported me during my study.

47
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108. Maraví-Poma E, Gener J, Alvarez-Lerma F, Olaechea P, Blanco A, Domínguez-
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109. Nordback I, Sand J, Saaristo R, Paajanen H. Early treatment with antibiotics
reduces the need for surgery in acute necrotizing pancreatitis--a single-center randomized
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255x(01)80021-4.
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pancreatitis with imipenem. Surg Gynecol Obstet. 1993;176:480-3. DOI: not available.

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treatment of severe pancreatitis with imipenem: a prospective randomized clinical trial.
Scand J Gastroenterol. 2007;42:771-6. DOI: 10.1080/00365520601173855.
112. Sainio V, Kemppainen E, Puolakkainen P, Taavitsainen M, Kivisaari L, Valtonen
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1995;346:663-7. DOI: 10.1016/s0140-6736(95)92280-6.
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114. Spicak J, Hubaczova M, Antos F, Bartova J, Cech P, Kasalicky M, et al.
Antibiotics in the treatment of acute pancreatitis-findings from a randomized multi-centre
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115. Spicak J, Hejtmankova S, Cech P, Hoskovec D, Kostka R, Leffler J, et al.
Antibiotic Prophylaxis in Severe Acute Pancreatitis: Randomized Multicenter
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2003;57. DOI: not available.
116. Xue P, Deng LH, Zhang ZD, Yang XN, Wan MH, Song B, et al. Effect of
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1746.2008.05758.x.
117. Yang XN, Deng LH, Xue P, Zhao L, Jin T, Wan MH, et al. Non-preventive use
of antibiotics in patients with severe acute pancreatitis treated with integrated traditional
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He Xue Bao. 2009;7:330-3. DOI: 10.3736/jcim20090406.
118. Murata A, Matsuda S, Mayumi T, Yokoe M, Kuwabara K, Ichimiya Y, et al.
Effect of hospital volume on clinical outcome in patients with acute pancreatitis, based
on a national administrative database. Pancreas. 2011;40:1018-23. DOI:
10.1097/MPA.0b013e31821bd233.
119. Shen HN, Lu CL, Li CY. The effect of hospital volume on patient outcomes in
severe acute pancreatitis. BMC Gastroenterol. 2012;12:112. DOI: 10.1186/1471-230x-
12-112.
120. Hamada T, Yasunaga H, Nakai Y, Isayama H, Horiguchi H, Fushimi K, et al.
Impact of hospital volume on outcomes in acute pancreatitis: a study using a nationwide
administrative database. J Gastroenterol. 2014;49:148-55.

59
121. Kamal A, Sinha A, Hutfless SM, Afghani E, Faghih M, Khashab MA, et al.
Hospital admission volume does not impact the in-hospital mortality of acute pancreatitis.
2017;19:21-8.
122. Wu BU. The impact of hospital volume on outcomes in acute pancreatitis: a case
for centers of excellence? Gastroenterology. 2009;137:1886-8. DOI:
10.1053/j.gastro.2009.10.016.
123. Halász A, Pécsi D, Farkas N, Izbéki F, Gajdán L, Fejes R, et al. Outcomes and
timing of endoscopic retrograde cholangiopancreatography for acute biliary pancreatitis.
Dig Liver Dis. 2019;51:1281-6. DOI: 10.1016/j.dld.2019.03.018.
124. da Costa DW, Bouwense SA, Schepers NJ, Besselink MG, van Santvoort HC, van
Brunschot S, et al. Same-admission versus interval cholecystectomy for mild gallstone
pancreatitis (PONCHO): a multicentre randomised controlled trial. Lancet.
2015;386:1261-8. DOI: 10.1016/s0140-6736(15)00274-3.
125. Nordback I, Pelli H, Lappalainen-Lehto R, Järvinen S, Räty S, Sand J. The
recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized
controlled trial. Gastroenterology. 2009;136:848-55. DOI: 10.1053/j.gastro.2008.11.044.
126. Rawla P, Sunkara T, Thandra KC, Gaduputi V. Hypertriglyceridemia-induced
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127. Petrov MS, Shanbhag S, Chakraborty M, Phillips AR, Windsor JA. Organ failure
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128. Nakaharai K, Morita K, Jo T, Matsui H, Fushimi K, Yasunaga H. Early
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10.1016/j.jiac.2018.05.009.
129. Talukdar R, Ingale P, Choudhury HP, Dhingra R, Shetty S, Joshi H, et al.
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130. Baltatzis M, Mason JM, Chandrabalan V, Stathakis P, McIntyre B,
Jegatheeswaran S, et al. Antibiotic use in acute pancreatitis: An audit of current practice
in a tertiary centre. Pancreatology. 2016;16:946-51. DOI: 10.1016/j.pan.2016.08.012.
131. Koutroumpakis E, Slivka A, Furlan A, Dasyam AK, Dudekula A, Greer JB, et al.
Management and outcomes of acute pancreatitis patients over the last decade: A US

60
tertiary-center experience. Pancreatology. 2017;17:32-40. DOI:
10.1016/j.pan.2016.10.011.
132. Baltatzis M, Jegatheeswaran S, O'Reilly DA, Siriwardena AK. Antibiotic use in
acute pancreatitis: Global overview of compliance with international guidelines.
Pancreatology. 2016;16:189-93. DOI: 10.1016/j.pan.2015.12.179.
133. Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, et al.
Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 2013;13:1057-98.
DOI: 10.1016/s1473-3099(13)70318-9.
134. Quenot JP, Luyt CE, Roche N, Chalumeau M, Charles PE, Claessens YE, et al.
Role of biomarkers in the management of antibiotic therapy: an expert panel review II:
clinical use of biomarkers for initiation or discontinuation of antibiotic therapy. Ann
Intensive Care. 2013;3:21. DOI: 10.1186/2110-5820-3-21.
135. Mofidi R, Suttie SA, Patil PV, Ogston S, Parks RW. The value of procalcitonin at
predicting the severity of acute pancreatitis and development of infected pancreatic
necrosis: systematic review. Surgery. 2009;146:72-81. DOI: 10.1016/j.surg.2009.02.013.
136. Siriwardena AK, Jegatheeswaran S, Mason JM, Baltatzis M, Chan A, Sheen AJ,
et al. PROCalcitonin-based algorithm for antibiotic use in Acute Pancreatitis (PROCAP):
study protocol for a randomised controlled trial. Trials. 2019;20:463. DOI:
10.1186/s13063-019-3549-3.
137. Pang Y, Kartsonaki C, Turnbull I, Guo Y, Yang L, Bian Z, et al. Metabolic and
lifestyle risk factors for acute pancreatitis in Chinese adults: A prospective cohort study
of 0.5 million people. PLoS Med. 2018;15:e1002618. DOI:
10.1371/journal.pmed.1002618.
138. Yashima Y, Isayama H, Tsujino T, Nagano R, Yamamoto K, Mizuno S, et al. A
large volume of visceral adipose tissue leads to severe acute pancreatitis. J Gastroenterol.
2011;46:1213-8. DOI: 10.1007/s00535-011-0430-x.
139. O'Leary DP, O'Neill D, McLaughlin P, O'Neill S, Myers E, Maher MM, et al.
Effects of abdominal fat distribution parameters on severity of acute pancreatitis. World
J Surg. 2012;36:1679-85. DOI: 10.1007/s00268-011-1414-y.
140. Khatua B, El-Kurdi B, Singh VP. Obesity and pancreatitis. Current opinion in
gastroenterology. 2017;33:374-82. DOI: 10.1097/MOG.0000000000000386.
141. Ji T, Li X, Zhang X, Hui L, Shang F, Zhu X, et al. Evaluation of the Severity of
Hyperlipidemia Pancreatitis Using CT-measured Visceral Adipose Tissue. J Clin
Gastroenterol. 2019;53:e276-e83. DOI: 10.1097/mcg.0000000000001079.

61
142. Wang SH, Chou YC, Shangkuan WC, Wei KY, Pan YH, Lin HC. Relationship
between Plasma Triglyceride Level and Severity of Hypertriglyceridemic Pancreatitis.
PLoS One. 2016;11:e0163984. DOI: 10.1371/journal.pone.0163984.
143. Zeng Y, Wang X, Zhang W, Wu K, Ma J. Hypertriglyceridemia aggravates ER
stress and pathogenesis of acute pancreatitis. Hepatogastroenterology. 2012;59:2318-26.
DOI: 10.5754/hge12042.
144. Huh JH, Jeon H, Park SM, Choi E, Lee GS, Kim JW, et al. Diabetes Mellitus is
Associated With Mortality in Acute Pancreatitis. J Clin Gastroenterol. 2018;52:178-83.
DOI: 10.1097/mcg.0000000000000783.
145. Szakó L, Mátrai P, Hegyi P, Pécsi D, Gyöngyi Z, Csupor D, et al. Endoscopic and
surgical drainage for pancreatic fluid collections are better than percutaneous drainage:
Meta-analysis. Pancreatology. 2020;20:132-41. DOI: 10.1016/j.pan.2019.10.006.

62
11. Scientometrics and list of publications

Source: MTMT2. Date of update: 23th Jun 2020.

Impact factors

1. First author: 2.063

2. Cumulative: 52.075

Citations

1. Independent (from journal articles only): 166

2. Cumulative: 245
3. Hirsh index: 8

Publications directly related to the content of this PhD thesis (n=3, IF: 9.059)

1. Gódi S, Erőss B, Gyömbér Z, Szentesi A, Farkas N, Párniczky A, et al.

Centralized care for acute pancreatitis significantly improves outcomes. J Gastrointestin
Liver Dis. 2018;27:151-7. DOI: 10.15403/jgld.2014.1121.272.pan (Q2, IF: 2.063).
2. Párniczky A, Lantos T, Tóth EM, Szakács Z, Gódi S, Hágendorn R, et al.
Antibiotic therapy in acute pancreatitis: From global overuse to evidence based
recommendations. Pancreatology. 2019;19:488-99. DOI: 10.1016/j.pan.2019.04.003
(Q1, IF: 3.629).
3. Szentesi A, Párniczky A, Vincze Á, Bajor J, Gódi S, Sarlós P, et al. Multiple Hits
in Acute Pancreatitis: Components of Metabolic Syndrome Synergize Each Other's
Deteriorating Effects. Front Physiol. 2019;10:1202. DOI: 10.3389/fphys.2019.01202
(Q2, IF: 3.367).

Other publications (n=17, IF: 43.016)

1. Balázs A, Németh BC, Ördög B, Hegyi E, Hritz I, Czakó L, …Gódi S…, et al. A
Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a
Hungarian Cohort. Pancreas. 2016;45:541-5. DOI: 10.1097/mpa.0000000000000539
(Q1, IF: 2.967).
2. Farkas N, Hanák L, Mikó A, Bajor J, Sarlós P, Czimmer J, …Gódi S…, et al. A
Multicenter, International Cohort Analysis of 1435 Cases to Support Clinical Trial Design
in Acute Pancreatitis. Front Physiol. 2019;10:1092. DOI: 10.3389/fphys.2019.01092
(Q2, IF: 3.367).

63
3. Hágendorn R, Vincze Á, Izbéki F, Gajdán L, Gódi S, Illés A, et al. Development
of disturbance of consciousness is associated with increased severity in acute pancreatitis.
Pancreatology. 2020 [Accepted for publication] (Q1, IF: 3.629).
4. Halász A, Pécsi D, Farkas N, Izbéki F, Gajdán L, Fejes R, …Gódi S…,, et al.
Outcomes and timing of endoscopic retrograde cholangiopancreatography for acute
biliary pancreatitis. Dig Liver Dis. 2019;51:1281-6. DOI: 10.1016/j.dld.2019.03.018 (Q2,
IF: 3.570).
5. Kun J, Szitter I, Kemény A, Perkecz A, Kereskai L, Pohóczky K, …Gódi S…,, et
al. Upregulation of the transient receptor potential ankyrin 1 ion channel in the inflamed
human and mouse colon and its protective roles. PLoS One. 2014;9:e108164. DOI:
10.1371/journal.pone.0108164 (Q1, IF: 3.234).
6. Lakatos G, Balázs A, Kui B, Gódi S, Szücs Á, Szentesi A, et al. Pancreatic
Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian
Pancreatic Study Group. J Gastrointestin Liver Dis. 2016;25:219-25. DOI:
10.15403/jgld.2014.1121.252.pcr (Q2, IF: 1.837).
7. Madácsy L, Kurucsai G, Joó I, Gódi S, Fejes R, Székely A. Rescue ERCP and
insertion of a small-caliber pancreatic stent to prevent the evolution of severe post-ERCP
pancreatitis: a case-controlled series. Surg Endosc. 2009;23:1887-93. DOI:
10.1007/s00464-008-0199-z (Q1, IF: 3.307).
8. Márta K, Szabó AN, Pécsi D, Varjú P, Bajor J, Gódi S, et al. High versus low
energy administration in the early phase of acute pancreatitis (GOULASH trial): protocol
of a multicentre randomised double-blind clinical trial. BMJ Open. 2017;7:e015874.
DOI: 10.1136/bmjopen-2017-015874 (Q1, IF: 2.413).
9. Meczker Á, Mikó A, Gede N, Szentesi A, Párniczky A, Gódi S, et al.
Retrospective Matched-Cohort Analysis of Acute Pancreatitis Induced by 5-
Aminosalicylic Acid-Derived Drugs. Pancreas. 2019;48:488-95. DOI:
10.1097/mpa.0000000000001297 (Q1, IF: 2.920).
10. Mosztbacher D, Hanák L, Farkas N, Szentesi A, Mikó A, Bajor J, …Gódi S…, et
al. Hypertriglyceridemia-induced acute pancreatitis: A prospective, multicenter,
international cohort analysis of 716 acute pancreatitis cases. Pancreatology. 2020;20:608-
16. DOI: 10.1016/j.pan.2020.03.018 (Q1, IF: 3.629).
11. Pár G, Trosits A, Pakodi F, Szabó I, Czimmer J, Illés A, …Gódi S…, et al.
Transient Elastography as a Predictor of Oesophageal Varices in Patients With Liver
Cirrhosis. Orv Hetil. 2014;155:270-6. DOI: 10.1556/OH.2014.29824 (Q3, IF: -).

64
12. Párniczky A, Kui B, Szentesi A, Balázs A, Szűcs Á, Mosztbacher D, …Gódi S…,
et al. Prospective, Multicentre, Nationwide Clinical Data from 600 Cases of Acute
Pancreatitis. PLoS One. 2016;11:e0165309. DOI: 10.1371/journal.pone.0165309 (Q1,
IF: 2.806).
13. Pécsi D, Hegyi P, Szentesi A, Gódi S, Pakodi F, Vincze Á. The Role of Endoscopy
Registries in Quality Health Care. The First Data From the Hungarian Endoscopic
Retrograde Cholangiopancreatography (ERCP) Registry. Orv Hetil. 2018;159:1506-15.
DOI: 10.1556/650.2018.31145. DOI: not available (Q3, IF: 0.564).
14. Pécsi D, Paulovicsné KM, Czimmer J, Gódi S, Hunyady B, Illés A, et al. Livopan
szedációval szerzett tapasztalataink kolonoszkópia során. Centr Eur J Gastroenterol
Hepat. 2018;4:220-3 (Q: -, IF: - ).
15. Szakács Z, Gede N, Pécsi D, Izbéki F, Papp M, Kovács G, …Gódi S…, et al.
Aging and Comorbidities in Acute Pancreatitis II.: A Cohort-Analysis of 1203
Prospectively Collected Cases. Front Physiol. 2018;9:1776. DOI:
10.3389/fphys.2018.01776 (Q2, IF: 3.201).
16. Szentesi A, Tóth E, Bálint E, Fanczal J, Madácsy T, Laczkó D, …Gódi S…, et al.
Analysis of Research Activity in Gastroenterology: Pancreatitis Is in Real Danger. PLoS
One. 2016;11:e0165244. DOI: 10.1371/journal.pone.0165244 (Q1, IF: 2.806).
17. Szücs Á, Marjai T, Szentesi A, Farkas N, Párniczky A, Nagy G, …Gódi S…, et
al. Chronic pancreatitis: Multicentre prospective data collection and analysis by the
Hungarian Pancreatic Study Group. PLoS One. 2017;12:e0171420. DOI:
10.1371/journal.pone.0171420 (Q1, IF: 2.766).

65
12. Appendix

Supplementary Table 1. Characteristics of studies reporting on the guidance and initiation of antibiotic therapy in acute pancreatitis.
Studies reporting on the guidance of AB therapy
Study Country Population N0 of Interventions Definition for suspected
(recruitment pts. infection => intervention
period)
Qu et al. 2012 (95) China SAP (by Atlanta 1992) 71 PCT-guided (cut-off: 0.5 clinical signs and symptoms
(2009-2011) mg/ml) vs prophylactic ABs
Studies testing the efficacy of ABs
Barreda et al. 2009 Peru ANP (FNA confirmed) 58 imipenem vs two or more criteria of sepsis
(article in Spanish) (2005-2007) no ABs after the second week of
(96) onset => FNA => surgery
(culturing)
Bassi et al. 1998 Italy and ANP: CECT-confirmed 60 imipenem vs routine laboratory tests and
(97) Greek necrosis (at least 50%) and pefloxacin markers by Bassi 1994 =>
(1991-1997) CRP>100 mg/l FNA => surgery
Craig et al. 1975 The US upper abdominal pain for at 46 ampicillin vs fever >38.3°C => blood
(98) least 24 h + elevated serum no ABs culture
amylase (>160 U/dl) or
elevated urinary amylase
Delcenserie et al. France SAP: Alcoholic aetiology, CT- 23 ceftazidime, amikacin, not stated => FNA
1996 (99) (1988-1993) confirmed fluid collections metronidazole
vs no ABs
Dellinger et al. Multicenter ANP: 1, CECT-confirmed 100 meropenem vs clinical deterioration, routine
2007 (100) (Europe and necrosis (at least 30%) no ABs haematology and
North 2, CT-confirmed fluid biochemistry => FNA or
America) collections plus pancreatic surgical samples
(2003-2004) edema (Balthazar E) and

66
 (MOD score ≥2 and CRP>120
mg/l)
Finch et al. 1976 The US alcoholic OR idiopathic AP 58 ampicillin or cefalotin not stated => surgery
(101) (1971-1973) confirmed by symptoms + vs no ABs
amylase greater than 160
Somogyi U/100 ml
Garcia-Barassa et Spain AP: by Atlanta class 41 ciprofloxacin clinical deterioration, strong
al. 2009 (102) (1999-2003) ANP: CT-confirmed necrosis vs no ABs clinical suspicion => FNA
Howes et al. 1975 The US AP: symptoms + amylase 95 ampicillin or lincomycin clinical or bacteriological
(103) (1972-1974) vs no ABs evidence => AB

Isenmann et al. Germany AP: symptoms + (3x amylase 114 ciprofloxacin + SIRS OR MOF OR increase
2004 (104) (1999-2002) OR 3x lipase) metronidazole of CRP and clinically
SAP: AP + (CRP>150 mg/l vs no ABs suspected infection (OR
OR CECT-confirmed necrosis) expancreatic inf.) => FNA or
surgical sampling AND open-
labelled AB treatment
Luiten et al. 1995 The AP: symptoms + amylase > 102 cefotaxime + selective clinical suspicion (not
(105) Netherlands 1000 IU/l or laparotomy decontamination (colistin + detailed), fever ≥ 39°C for
(1990-1993) SAP: Imrie score ≥3 + CECT amphotericin + norfloxacin) blood culturing => FNA
(Balthazar grades D-E) vs
no ABs
Manes et al. 2003 Italy ANP: necrosis confirmed by 176 meropenem vs not stated (fever >38°C?) =>
(106) (1996-2001) CECT or by surgery + CRP imipenem FNA => surgery
>120 mg/l
Manes et al. 2006 Italy AP (no definition) 59 early vs persistent fever (>38°C),
(107) (2002-2005) late treatment increased CRP, leukocytosis,
and lack of improvement
under appropriate therapy, or

67
 air bubbles in the necrosis
(CECT) => FNA => surgery

Maravi-Poma et al. Spain AP: abdominal pain + 3x 92 long vs short treatment signs of sepsis or organ
2003 (108) (not stated) amylase/3x lipase failure for at least 3 days =>
ICU + severe ANP: CTSI>4 FNA
Nordback et al. Finland AP: symptoms + 3x amylase + 58 imipenem vs following an initial decrease,
2001 (109) (1995-1999) CT no ABs a recurrent parallel increases
ANP: CRP > 150 mg/l within in inflammation variables
48 h, CT-confirmed necrosis (temperature, white blood cell
count (+30%), CRP level
(+30%)) => surgery
recurrent non-parallel
increases => FNA => surgery
Pederzoli et al. Italy ANP: CECT-confirmed 74 imipenem vs suspected infected necrosis,
1993 (110) (1989-1991) necrosis no ABs infected pseudocyst, abscess
=> FNA => surgery
Rokke et al. 2007 Norway SAP: symptoms + 3x amylase 73 imipenem vs clinical, radiological or
(111) (1997-2002) + CT; CRP>120 mg/l within no ABs laboratory signs of infection
24 h or >200 mg/l within 48 h => AB => surgery (if
or CT-confirmed necrosis indicated by the attending
doctor)
Sainio et al. 1995 Finland SAP: CRP>120 mg/l within 48 60 cefuroxime vs persistent fever, rise in CRP,
(112) (1989-1993) h, low pancreatic contrast- no ABs or fluid collections detected
enhancement on CECT, by CT => FNA
alcoholic aetiology
Schwarz et al. 1997 Germany ANP 26 ofloxacin + metronidazole FNA for all participants
(article in German) (1991-1994) vs regularly in control group
(113) no ABs

68
 Spicak et al. 2002 Czech SAP: symptoms + 3x amylase 63 ciprofloxacin + control group: temperature
(article in Czech) Republic + CT (Atlanta (local compl.!) metronidazole vs no ABs 38°C for at least 24 h or
(114) (1999-2001) or CRP>150 mg/l infection => AB empirically,
later culturing
Spicak et al. 2003 Czech SAP: symptoms + 3x amylase 41 meropenem vs no ABs control group: temperature
(article in Czech) Republic + CT (Atlanta: CRP>190 mg/l 38.5°C for at least 24 h or
(115) (2001-2002) AND peripancreatic fluid) infection=> AB empirically
suspicion => FNA
Xue et al. 2009 China SAP (by Bangkok World 56 imipenem vs a second continuous increase
(116) (2007) Congress of Gastroenterology no ABs in temperature ≥38.5°C or
in Thailand 2002): CECT- white blood cell count
confirmed necrosis > 30% ≥20x109/L or CRP≥30% or
clinical deterioration =>
culture from the suspected
organ + CECT => air bubbles
in necrosis => FNA
Yang et al. 2009 China SAP: organ failure OR Ranson 54 imipenem vs no ABs suspected pancreatic infection
(article in Chinese) > 3, APACHE II > 8, Balthazar => AB change by resistance
(117) CT grade II or above and surgery
APACHE II: acute physiology and chronic health evaluation, AB: antibiotic, ANP: acute necrotizing pancreatitis, AP: acute pancreatitis, CRP: C-reactive protein, ICU: intensive care unit, CT:
computed tomography, CECT: contrast-enhanced computed tomography, FNA: fine-needle aspiration, MOD: multiple organ dysfunction, MOF: multi-organ failure, PCT: procalcitonin SAP:
severe acute pancreatitis, SIRS: systemic inflammatory response syndrome.

69
Supplementary Figure 1. Sites of recruitment of the study population of the AP
Registry

Grey circles on the map represent the sites of recruitment.

70
 ORIGINAL PAPER Available from: http://www.jgld.ro/wp/archive/y2018/n2/a7
DOI: http://dx.doi.org/10.15403/jgld.2014.1121.272.pan

Centralized Care For Acute Pancreatitis Significantly Improves

Outcomes

Szilárd Gódi1, Bálint Erőss1,2, Zsuzsanna Gyömbér3, Andrea Szentesi2,3, Nelli Farkas2,4, Andrea Párniczky2,5, Patrícia Sarlós1,2,
Judit Bajor1, József Czimmer1,2, Alexandra Mikó2, Katalin Márta2, Roland Hágendorn1, Zsolt Márton1, Zsófia Verzár6, László
Czakó3, Zoltán Szepes3, Áron Vincze1,2*, Péter Hegyi1,2,3,7* on behalf of the Hungarian Pancreatic Study Group

1) 1st Department of Medicine, ABSTRACT

University of Pécs Medical
School, 7624 Pécs, Aims: In this observational study, we investigated whether specialized care improves outcomes for acute
2) Institute for Translational pancreatitis (AP).
Medicine, University of Pécs Methods: Consecutive patients admitted to two university hospitals with AP were enrolled in this study
Medical School, 7624 Pécs, between 1 January 2016 and 31 December 2016 (Center A: specialized center; Center B: general hospital).
3) 1st Department of Medicine, Data on demographic characteristics and AP etiology, severity, mortality and quality of care (enteral nutrition
University of Szeged, 6720 and antibiotic use) were extracted from the Hungarian Acute Pancreatitis Registry. An independent sample
Szeged, t-test, Mann–Whitney test, chi-squared test or Fisher’s test were used for statistical analyses. Costs of care
4) Institute of Bioanalysis, were calculated and compared in the two models of care.
University of Pécs Medical Results: There were 355 patients enrolled, 195 patients in the specialized center (Center A) and 160 patients in
School, 7624 Pécs, Hungary the general hospital (Center B). There was no difference in mean age (57.02 ±17.16 vs. 57.31 ±16.50 P=0.872)
5) Department of and sex ratio (56% males vs. 57% males, P=0.837) between centres, allowing a comparison without selection
Gastroenterology, Heim Pál bias. Center A had lower mortality (n=2, 1.03% vs. n=16, 6.25%, p=0.007), more patients received enteral
Children’s Hospital, 1098 feeding (n=179, 91.8%, vs. n=36, 22.5%, p<0.001) and fewer patients were treated with antibiotics (n=85,
Budapest, 43.6% vs. n=123, 76.9%, p=0.001). In Center A the median length of hospitalization was shorter (Me 6, IQR
6) Department of Emergency 5–9 vs. Me 8, IQR 6–11, p=0.02) and the costs of care were by 25% lower.
Medicine, University of Pécs Conclusion: Our data suggests that treatment of AP in specialized centers reduces mortality, length of
School of Medicine, 7624 Pécs, hospitalization and thus might reduce the costs.
7) MTA-SZTE Momentum
Gastroenterology Key words: acute pancreatitis – costs – specialized center – outcome – mortality.
Multidisciplinary Research
Group, Hungary Abbreviations: ACG: American College of Gastroenterology; AP: Acute pancreatitis; ER: Emergency Unit;
IAP/APA: International Association of Pancreatology and the American Pancreatic Association; ICU: Intensive
Care Unit; LOH: Length of hospitalization; SD: Surgical Department; TIMD: Territorial Internal Medical
Address for correspondence: Departments; TPC: Tertiary Pancreas Center.
Péter Hegyi
Institute for Translational
Medicine, University of Pécs INTRODUCTION todiseases, where patients are directly admitted to a highly
Szigeti út 12., II. em., H-7624 specialized ward, with a multidisciplinary team, strict
Pécs, Hungary Medical care for ac ute adherence to guidelines and easy access to special procedures
hegyi2009@gmail.com diseases requiring hospitalization (Fig. 1A). There are examples of established specialized
varies between countries and care models for the treatment of stroke and acute coronary
often within the same country. syndrome [1, 2].
Received: 15.02.2018 The same acute diseases are On the other pathway, patients are referred to general
Accepted: 30.04.2018 treated in hospitals with different medical wards (internal medicine or surgery), and, depending
profiles of expertise, different bed on the progression of the disease, some patients are transferred
bases for specialties and different to specialized wards. If there is further deterioration, transfer
guidelines. There are two major to an intensive care unit may be necessary. We define this as
pathways for admission with the general medical care model.
*equally contributed. List acute diseases. Outcomes for acute diseases can be significantly different
of clinical collaborators One of the pathways is depending on care, and there are examples of significantly
contributors on page 156. organized care in high-volume improved outcomes for acute diseases treated in specialized
specialized centers for specific centers. There is ample evidence that organized care for

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152 Gódi et al.

stroke [1] and acute myocardial infarction with ST elevation Our aim was to investigate whether specialized care
in specialized centers have saved lives and reduced the improves the outcomes for AP.
burden of these diseases [2]. Based on this evidence,
national and international stroke [3] and cardiology [4] METHODS
associations organized care in specialized centers, with specific
recommendations in their guidelines. The Hungarian Pancreatic Study Group was established
Acute pancreatitis (AP) is the most common acute in 2011 to improve care for pancreatic diseases. To date,
presentation in gastroenterology requiring hospital admission the Hungarian Pancreatic Study Group has built up an
in the USA [5]. According to data obtained from the international prospective registry for AP and organized five
Hungarian National Health Insurance Fund, there is an registered clinical trials to investigate AP under the acronyms
estimated 5500 AP hospital admissions/year for Hungary’s PREPAST [11], APPLE [12], PINEAPPLE [13], GOULASH
population of 10 million. There have been significant efforts [14] and EASY [15].
to improve outcomes and to reduce the disease burden in AP
as suboptimal care can result in progression to severe forms Study design
of the disease, higher morbidity and mortality. The Working In this observational cohort study, we analyzed and
Group of the International Association of Pancreatology and compared data from the prospectively collected AP Registry,
the American Pancreatic Association (IAP/APA) updated specifically, outcomes, quality of care and costs for AP in
and published evidence-based guidelines for the treatment two university hospitals with two different models for the
of AP [6] most recently in 2013, and the American College of management of AP.
Gastroenterology (ACG) also published their guidelines [7] the Treatment Center A fulfilled the criteria for a specialized
same year. The Hungarian Pancreatic Study Group translated center for AP. Patients were admitted directly to the specialized
both and synthesized them in the Hungarian guidelines [8] ward from regional emergency departments. Center A admits
in 2015. patients from nine high-volume emergency units in the region.
The IAP/APA guidelines suggest intensive care for patients The specialized center has an integrated care pathway for
with severe AP and referral to a specialized center [6]. In patients requiring care in the high dependency unit or intensive
defining a center specialized for AP, the guidelines specify the care unit (Fig. 1A).
need for intensive care facilities for organ replacement therapy, Treatment Center B admits patients with AP to general
continuous access to interventional radiology, endoscopic internal medicine wards from the emergency department, and
retrograde cholangiopancreatography (ERCP), endoscopic patients are transferred to the specialized pancreatic ward, if
ultrasonography and surgical expertise in the treatment of there is deterioration. Treatment Center B transfers patients
necrotizing AP [6]. from the emergency department to one of the five general
The ACG guidelines recommend risk stratification to internal medicine wards or to a surgical ward, or if indicated
identify patients who will need early transfer to an intensive by the patient’s status, either to the tertiary pancreatic center
care unit [7]. Referral to a specialized center in the case of or to the intensive care unit (Fig. 1B).
severe AP is also recommended in the Hungarian guidelines Both treatment centers (A and B) deal with high volumes,
[8]. However, there is no recommendation in these guidelines but their models of care for AP are different. Both institutions
regarding whether all AP (mild and moderate) should be care for populations with nearly identical demographics.
referred to centers with specialized care after diagnosis at the
emergency unit. There is convincing evidence on improved Limitation
outcomes for AP in high-volume centers (more than 118 The study design and the differences between the two
admissions/year for AP), according to Singla et al. [9]. cohorts are potential sources of bias and limitation; therefore,
It is difficult to predict the severity of AP at the time of both cohorts were carefully scrutinised through statistical
admission, and patients presenting with mild forms can analysis before comparing outcomes to ensure that they were
develop fulminant AP within a few days. Current stratification comparable.
systems for AP are unable to predict the course of the disease
at the early stage unless the disease is severe at the time of Ethical approval
admission. The revised Atlanta classification of AP severity The study was approved by the Scientific and Research
is determined by clinical parameters recorded throughout Ethics Committee of the Medical Research Council (22254-
the disease and provides disease severity in retrospect [10]. 1/2012/EKU) on 15 August 2012 and conforms to the 1975
Therefore, it is not suitable for predicting the outcome. Declaration of Helsinki ethical guidelines as reflected in a priori
The guidelines for the treatment of AP [7-9] recommend approval by the institution’s human research committee. The
that the risk factors, the clinical prognostic factors and the patients signed the relevant consent forms.
response to the treatment should be monitored to predict
the outcome. However, a reliable prediction system based on Statistical analyses
admission parameters is yet to be developed for the accurate The demographics and the etiology in both samples were
prediction of the clinical course of and outcome for AP. compared. To analyze the differences in the distribution of
Until now, no evidence has been published for or against severity, complications (local and systemic), mortality and
the treatment of AP of all severities in specialized pancreatic management (enteral feeding and antibiotic use) between the
centers. centers, we used Pearson’s chi-squared test or Fisher’s exact

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Centralized care for acute pancreatitis 153

Fig. 1. A: Patient pathways in the specialized high-volume center from different Emergency
Units (ER); B: Patient pathways in the step-up care pathway institution from Territorial Internal
Medical Departments (TIMD), Intensive Care Units (ICU), the Tertiary Pancreas Center (TPC)
and the Surgical Department (SD), number of cases (n).

test. We used the independent samples Student’s t-test for age The two university centers are located in the same region of
and the Mann–Whitney U test for comparison of hospital stay. Europe with an ethnically homogeneous population, and 98%
P values under 0.05 were considered statistically significant. of the patients approached gave their consent at both centers.
Where the p value was less than 0.1 but higher than 0.05, we
only regarded the result as a tendency. All statistical analyses Demographic characteristics
were performed by IBM SPSS Statistics v 24.0 (IBM, New Treatment Center A with specialized care for AP admitted
York, NY, USA). 195 patients, while treatment Center B treated 160 patients with
AP in 2016 (Fig. 1A, B). A demographic analysis of the two
RESULTS cohorts showed no significant difference. Mean age was 57.02
(±17.16) in Center A and 57.31 (±16.50) in Center B (p=0.872).
The best evidence in comparative medicine is always The proportion of males was 56% in Center A and 57% in Center
provided by the results from randomized clinical trials, as B (p=0.837). Age did not differ significantly in males or females
they ensure that there is no selection bias between cases and between the two cohorts (male mean age in center A: 54.16
controls. However, in this observational trial, it was impossible ±16.96; in Center B: 57.03±16.01, p=0.221; female mean age in
to perform randomization, since there was only one model of Center A: 60.71 ±16.80; in Center B: 57.68 ±17.26, p=0.276).
care for AP in the two centers. In addition, these large centers Although it was not intentional, the cohorts were matched
are far away from each other; therefore, transfer of patients for age and sex (Fig. 2 A, B ).
after randomization would not have been possible. Finally, and The etiology of AP was similar in both cohorts. The
most importantly, randomization would have been unethical. major causes were biliary stones, alcohol, and idiopathic

Fig. 2. A: The demographic characteristics and etiological factors of acute pancreatitis in the
specialized high-volume center; B: The demographic characteristics and etiological factors of
acute pancreatitis in the step-up care pathway institution.

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154 Gódi et al.

and hyperlipidemia, accounting for the vast majority in both 16.9%, p=0.177, respectively). The detailed results are shown
centers (Fig. 2). in Fig. 3C.
This similarity, along with the matched age and sex ratio,
allowed us to compare the outcomes for AP in both cohorts and Interventions and therapy
reduced the selection bias of this observational cohort study. There were no differences between Center A and B
in the number of ERCP (n=85, 43.59% vs. n=59, 36.88%,
Severity and mortality of AP p=0.143), necrosectomy (n=1, 0.5% vs. n=2, 1.25%, p=0.793)
The distribution of the worst severity of AP was different in and radiological or endoscopic ultrasound-guided drainage
Centers A and B (Fig. 3 A, B). Center B had 67% more severe procedures (n=8, 4.1% vs. n=2, 1.2%, p=0.118).
AP (n=19, 11.9%) than Center A (n=14, 7.1%); however, this We found no differences in the number of ERCPs for
was not statistically different (p=0.310), likely due to the small biliary pancreatitis, n=69, 83% ERCPs in n=83 patients in
sample sizes, 14 patients in Center A and 19 in Center B. Center A and n=45, 84.9% ERCPs in n=53 patients in Center
The mortality of all AP in Center B was six times higher B (p=0.817). The ERCPs in AP with biliary etiology were
(n=16, 6.25%) than in Center A (n=2, 1.03%), and this performed in n=60 mild, n=4 moderate, and n=5 severe AP
difference proved to be statistically significant, p=0.007. Severe cases in Center A and n=40, n=4 and n=1 in Center B. None
AP showed a threefold increase of mortality in Center B (n=8, of these were significantly different.
47.37% vs. n=2, 14.29%, p=0.067). There were no deaths from
mild AP in either cohort. Quality of care and management
The average hospital stay was significantly shorter in Center We investigated whether management of patients and
A (Me: 6 (IQR: 5–9) days vs. Me: 8 (IQR: 6–11) days, p=0.02) adherence to the guidelines differed in the two centers. The
(Fig. 3 A, B). The subgroup analysis found shorter means of best and most reliable management markers which we could
hospital stay for all grades of severity; however, it was only identify were enteral feeding and the use of antibiotics (Fig.
significant in mild AP, suggesting that mild cases of AP were 4 A, B).
discharged sooner from Center A. More patients had enteral feeding in Center A than in
Center B (n=179, 91.8% vs. n=36, 22.5%, p<0.001) (Fig. 4 A,B).
Complications of AP The use of antibiotics also differed; significantly fewer
Our analysis found no differences between the local and patients were treated with antibiotics in Center A in contrast
systemic complications of AP between Centers A and B (n=43, to Center B (n=85, 43.6% vs. n=123, 76.9%, p<0.001) (Fig.
23.1% vs. n=35, 21.8%, p=0.872, and n=21, 10.5% vs. n=27, 4 A, B). A detailed analysis of antibiotic use demonstrated a

Fig. 3. A: The distribution of disease severity, mortality and length of hospitalization (LOH) in
the specialized high-volume center; B: The distribution of disease severity, mortality and length of
hospitalization (LOH) in the step-up care pathway institution; C: Complications in the two centers.
*significant difference; severe (SEV); moderate (MOD); number of cases (n).

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Centralized care for acute pancreatitis 155

Fig. 4. A: Managing acute pancreatitis (with antibiotics and enteral nutrition) in the specialized
high-volume center; B: Managing acute pancreatitis (with antibiotics and enteral nutrition) in the
step-up care pathway institution; C: Antibiotic use in the two centers for different severities of acute
pancreatitis. Severe (SEV); moderate (MOD).

significant difference between the two centers with regard to

mild and moderate AP (n=54, 63.5%, vs. n=83, 67.5%, p<0.05
and n=18, 21.2%, vs. n=21, 17.1%, p=0.024). There was no
difference in antibiotic use between the two centers with regard
to severe AP (n=13, 15.3%, vs. n=19, 15.4%, p=0.424). Results
are shown on Fig. 4C.

Economic implications
To understand the economic implications of the two
different models of AP treatment, the average cost of
management for 10 patients was calculated in both groups. The
calculated average costs are based on the costs of medication,
disposables, procedures and investigations. However, our
calculation was limited by costs that could not be estimated,
such as the costs of staff and hospital stay (Fig. 5).
The average daily costs in both centers in subgroups of
mild, moderate and severe AP are indicated with or without
Fig. 5. A: Costs of managing acute pancreatitis (AP) in the specialized,
antibiotic treatment. Based on this estimate, the cost of
high-volume center; B: Costs of managing acute pancreatitis (AP) in
treatment for AP is 25% lower in the specialized care model the general medical center. This estimate does not include the costs
than in the general medical model. of staff and hospital bed.

DISCUSSION

We hypothesized that specialized care for AP in high- The only significant difference in terms of AP is their model
volume centers is beneficial and measurable in both outcomes of management of AP.
and costs. We analyzed comparable cohorts in both centers, We believe that these prospectively collected data from
without significant differences in their demographics. Both the two cohorts are nearly as comparable as data from two
centers are tertiary referral institutions and university branches of a randomized controlled trial, and we note
hospitals with the same level of medical expertise and skills. that the latter would have been impossible and unethical to
Funding for health care services in both centers is identical. organize.

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156 Gódi et al.

There are multiple reasons we were able to show CONCLUSION

significantly improved outcomes, management and hospital
stay in the specialized center. Managing AP in a high-volume center can potentially
In our analysis, we found that lower mortality and shorter decrease disease severity, reduce the need for medications,
hospital stay were associated with significant differences in the improve mortality, shorten hospital stay and reduce costs of
practices between the two centers. The specialized center with care. Therefore, further in-depth analysis would be warranted
better outcomes used significantly more often enteral feeding to establish whether AP should be managed in high-volume
and fewer antibiotics. However, there was no difference in the specialized centers.
number of endoscopic or radiological procedures.
Center B followed the guidelines of enteral tube feeding Conflicts of interest: No conflicts to declare.
more rigorously than Center A and limited the use of enteral
tube feeding to manage patients with severe pancreatitis and Authors, contributions: G.S. and H.P. formulated the research
predicted severe AP. We acknowledge that Center A used questions and designed the study. P.A., G.Z., S.A., G.S. and H.P.
more enteral feeding to treat AP than strict adherence to the interpreted the data. F.N. performed the statistical analysis. G.S., M.A.,
guidelines [8] would have suggested. There are many studies E.B. and H.P. wrote the manuscript. The other authors contributed to
with evidence for early feeding in AP, but they compared enteral the implementation of the study and the data acquisition. All authors
nutrition or enteral tube feeding vs. nil per os management. We read and approved the final manuscript.
note that there is a lack of clinical trials providing evidence and ORCHID numbers of the authors (See Supplementary Material)
information on early oral vs. enteral tube feeding.
Petrov et al. [16] reported the benefits of enteral tube Clinical collaborators:
feeding in a randomized control trial compared to the nil per os Dezső Kelemen, Róbert Papp (Department of Surgery, University of
approach and concluded that it leads to less oral food intolerance. Pécs School of Medicine, Pécs, Hungary), Nándor Faluhelyi, Krisztián
Furthermore, our recent meta-analysis by Marta et al. [17] Molnár, Péter Farkas (Department of Radiology, University of Pécs
confirmed this. In addition, as a leading pancreatic clinical School of Medicine, Pécs, Hungary), Tamás Takács (1st Department
research unit, Center A is conducting a long-term randomized of Medicine, University of Szeged, Szeged, Hungary), József Fenyő
clinical trial investigating the benefits of early high-energy enteral (Department of Emergency Medicine, St. Rókus Hospital, Baja,
tube nutrition in AP [14]. Prediction of severe AP is difficult Hungary), Előd Papp (Department of Internal Medicine, St. Lukács
in the early phase of the disease (24–48 hours). Enteral tube Hospital, Dombóvár, Hungary), István Késői (Department of Internal
feeding may have the potential to prevent severe AP, and this is Medicine, Komló General Hospital, Komló, Hungary), Balázs Marton
one of the foci of our research. Patients in Center A started oral (Department of Emergency Medicine, Mohács General Hospital,
feeding once their abdominal pain resolved, and enteral tube Mohács, Hungary), Csaba Csizmadia (Department of Internal
feeding often lasted less than one or two days in cases of mild Medicine, Mohács General Hospital, Mohács, Hungary), János Simon
and moderate AP. (Department of Emergency Medicine, Balassa János Tolna County
Moraes et al. [18] and Larino-Noia et al. [19] showed that Hospital, Szekszárd, Hungary), Ágnes Salamon (Department of
early oral re-feeding was safe and well tolerated, but neither Internal Medicine, Balassa János Tolna County Hospital, Szekszárd,
study compared it to enteral tube feeding. Hungary), Éva Szabó (Department of Internal Medicine, Szigetvár
Finally, yet importantly, none of the guidelines precludes General Hospital, Szigetvár, Hungary)
the option of enteral tube feeding in mild or moderate AP.
In Center A, with high-volume specialized care, patients are Acknowledgement: The study was supported by a Project Grant
reviewed within 24 hours by gastroenterologists with expertise in (KH125678 to PH), an Economic Development and Innovation
AP, and patients are looked after by that same team throughout Operative Program Grant (GINOP 2.3.2-15-2016-00048 to PH)
their hospital stay. Therefore, their continuity of care is optimal. and a Human Resources Development Operational Program Grant
In Center B, patients are admitted to a general internal (EFOP-3.6.2-16-2017-00006 to PH) from the National Research,
medicine unit, often without expertise in gastroenterology. Development and Innovation Office as well as by a Momentum Grant
We believe that this profound difference results in a significant from the Hungarian Academy of Sciences (LP2014-10/2014 to PH)
delay in decision making in the treatment of AP, translated and the ÚNKP-17-3-I. New National Excellence Program, Ministry
to poorer mortality. Patients transferred between medical of Human Capacities (PTE/46539/2017 to KM).
teams often receive more fragmented treatment, and this
approach increases the possibility of further delays and risks Supplementary material: To access the supplementary material visit
of complications as well. the online version of the J Gastrointestin Liver Dis at http://dx.doi.
Other possible factors are suboptimal knowledge and org/10.15403/jgld.2014.1121.272.pan
adherence to the AP guidelines among physicians without
expertise and low case numbersof AP.
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 Pancreatology 19 (2019) 488e499

Contents lists available at ScienceDirect

Pancreatology
journal homepage: www.elsevier.com/locate/pan

Antibiotic therapy in acute pancreatitis: From global overuse to

evidence based recommendations
Andrea Pa
rniczky a, b, 1, Tama
s Lantos c, 1, Eszter Margit To
th d, e, 1, Zsolt Szaka
cs a,
Szila
rd Go
di f, Roland Ha
gendorn g, Do
ra Ille
s e, Bala
zs Koncz e, Katalin Ma
rta a,
Alexandra Miko
a, h
, Do
ra Mosztbacher , Bala a, i
zs Csaba Ne
meth e, bk
niel Pe
, Da
csi a,
Aniko
Szabo a


, Akos Szücs , Pe j
ter Varjú , Andrea Szentesi , Erika Darvasi ,
a a, e e

} a
Balint Eross , Ferenc Izbeki , La
k
szlo

Gajda
n k, Adrienn Hala


sz k, Aron Vincze f,
Imre Szabo
f, Gabriella Pa
r f, Judit Bajor f, Patrícia Sarlo
s f, Jo

zsef Czimmer f,

zsef Hamvas , Tama
Jo l
s Taka
cs , Zolta
e
n Szepes , La e
szlo

Czako
e, Ma
rta Varga m,

nos Nova
Ja
k , Barnaba
d
s Bod , Attila Szepes , Ja
n o
nos Sümegi , Ma p
ria Papp q, Csaba Go
g r,
Imola To € ro
€ k , Wei Huang , Qing Xia , Ping Xue , Weiqin Li , Weiwei Chen ,
s t t u v w

Natalia V. Shirinskaya x, Vladimir L. Poluektov y, Anna V. Shirinskaya y,

Pe
ter Jeno} Hegyi a, z, Marian Ba
tovský z, Juan Armando Rodriguez-Oballe aa,
Isabel Miguel Salas , Javier Lopez-Diaz ab, J. Enrique Dominguez-Munoz ab,
aa

Xavier Molero ac, Elizabeth Pando ad, María Lourdes Ruiz-Rebollo ae,
Beatriz Burguen ~ o-Go
mez ae, Yu-Ting Chang af, Ming-Chu Chang af, Ajay Sud ag,
Danielle Moore ag, Robert Sutton ag, Amir Gougol ah, Georgios I. Papachristou ah,
Yaroslav Mykhailovych Susak ai, Illia Olehovych Tiuliukin ai, Anto
nio Pedro Gomes aj,
aj
Maria Jesus Oliveira , David Joa ~o Aparício , Marcel Tantau , Floreta Kurti al,
aj ak

Mila Kovacheva-Slavova , Stephanie-Susanne Stecher an, Julia Mayerle an,

am

Goran Poropat ao, Kshaunish Das ap, Marco Vito Marino aq, Gabriele Capurso ar,
Ewa Małecka-Panas as, Hubert Zatorski as, Anita Gasiorowska at, Natalia Fabisiak at,
Piotr Ceranowicz au, Beata Ku
snierz-Cabala au, Joana Rita Carvalho av,
Samuel Raimundo Fernandes av, Jae Hyuck Chang aw, Eun Kwang Choi ax, Jimin Han ay,
Sara Bertilsson az, ba, Hanaz Jumaa bb, Gabriel Sandblom bc, Sabite Kacar bd,
Minas Baltatzis be, Aliaksandr Vladimir Varabei bf, Vizhynis Yeshy bg, Serge Chooklin bh,
Andriy Kozachenko bi, Nikolay Veligotsky bj,
Pe
ter Hegyi a, e, h, bk, *, on behalf of the Hungarian Pancreatic Study Group
a
Institute for Translational Medicine, Szenta
gothai Research Centre, Medical School, University of P

ecs, P

ecs, Hungary
b
Heim Pa
l National Insititute of Pediatrics, Budapest, Hungary
c
Department of Medical Physics and Informatics, Faculty of Medicine, University of Szeged, Szeged, Hungary
d

lma
n Hospital of B

Pandy Ka ek
es County, Gyula, Hungary
e
First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
f
Division of Gastroenterology, First Department of Medicine, Medical School, University of P
ecs, P

ecs, Hungary
g
Intesive Care Unit, First Department of Medicine, Medical School, University of P
ecs, P

ecs, Hungary
h
Division of Translational Medicine, First Department of Medicine, Medical School, University of P
ecs, P

ecs, Hungary
i
First Department of Pediatrics, Semmelweis University, Budapest, Hungary
j
First Department of Surgery, Faculty of Medicine, Semmelweis University, Budapest, Hungary
k
Szent Gyo €rgy University Teaching Hospital of Fej
er County, Sz

ekesfeh

r, Hungary
erva

cs, Faculty of Medicine Centre for Translational Medicine, Institute for Translational Medicine & Department of Translational
* Corresponding author. University of Pe

cs, H-7624, Hungary.
Medicine/1st Department of Medicine, 12 Szigeti Street, Pe

URL: http://www.tm-centre.org

https://doi.org/10.1016/j.pan.2019.04.003
1424-3903/© 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.

rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa 489

l
Bajcsy-Zsilinszky Hospital, Budapest, Hungary
m
Dr. R

l Hospital, B

ethy Pa ek
escsaba, Hungary
n
n Hospital, Szentes, Hungary
Dr. Bugyi Istva
o

Bacs-Kiskun County Hospital, Kecskem
et, Hungary
p
Borsod-Abaúj-Zempl
en County Hospital and University Teaching Hospital, Miskolc, Hungary
q
Department of Internal Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary
r
Healthcare Center of County Csongra
d, Mako
, Hungary
s
County Emergency Clinical Hospital of Targu Mures Hospital, University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, Targu Mures,
Romania
t
Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical
Research Centre, West China Hospital of Sichuan University, Chengdu, China
u
Department of Integrated Traditional Chinese and Western Medicine, Shangjin Hospital, West China Medical School of Sichuan University, Chengdu, China
v
Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
w
Department of Gastroenterology, Subei People's Hospital of Jiangsu Province, Clinical Medical College of Yangzhou University, Yangzhou, China
x
Omsk State Medical Information-Analytical Centre, Omsk State Clinical Emergency Hospital #2, Omsk, Russia
y
Department of Surgery and Urology, Omsk State Medical University, Omsk, Russia
z
Departement of Gastroenterology Slovak Medical University in Bratislava, Bratislava, Slovakia
aa
Department of Gastroenterology, University Hospital Santa María - University Hospital Arnau de Vilanova, Lerida, Spain
ab
Department of Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
ac
Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron - Institut de Recerca, Autonomous University of Barcelona, CIBEREHD, Barcelona,
Spain
ad
Department of Hepato-pancreato-biliary and Transplat Surgery, Hospital Universitari Vall d'Hebron, Barcelona, Spain
ae
Digestive Diseases Department Clinical University Hospital of Valladolid, Valladolid, Spain
af
Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
ag
Liverpool Pancreatitis Research Group, University of Liverpool and the Royal Liverpool and Broadgreen University Hospital Trust, Liverpool, United
Kingdom
ah
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
ai
O.O.Bogomolets National Medical University, Kiev, Ukraine
aj
Department of Surgery, Hospital Prof. Dr. Fernando Fonseca, Amadora, Portugal
ak
Iuliu Hatieganu” University of Medicine and Pharmacy, Department of Internal Medicine, 3rd Medical Clinic and “Prof. Dr. Octavian Fodor” Regional
Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
al
Department of Gastroenterology and Hepatology, University Hospital Center “Mother Theresa”, Tirana, Albania
am
University Hospital “Tsaritsa Ioanna - ISUL”, Departement of Gastroenterology, Sofia, Bulgaria
an
Department of Medicine II, University Hospital, LMU Munich, Germany
ao
Department of Gastroenterology, Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, Croatia
ap
Division of Gastroenterology, School of Digestive and Liver Diseases, IPGME &R, Kolkata, India
aq
Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
ar
PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita Salute San
Raffaele University, Milan, Italy
as
Department of Digestive Tract Diseases, Medical University of Lodz, Poland
at
Department of Gastroenterology Medical University of Lodz, Poland
au
Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
av
Department of Gastroenterology and Hepatology, North Lisbon Hospital Center, Hospital Santa Maria, University of Lisbon, Lisbon, Portugal
aw
Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
ax
Department of Internal Medicine, Jeju National University College of Medicine, Jeju, South Korea
ay
Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu Catholic University School of Medicine, Daegu, South Korea
az
Department of Clinical Sciences, Lund University, Lund, Sweden
ba
Department of Health Sciences, Lund University, Lund, Sweden
bb
Eskilstuna Hospital, Ma€larsjukhuset, Eskilstuna, Sweden
bc
Department of Clinical Science and Education So €dersjukhuset, Karolinska Institutet, Department of Surgery, So
€dersjukhuset, Stockholm, Sweden
bd _
Department of Gastroenterology Türkiye Yüksek Ihtisas Hospital, Ankara, Turkey
be
Manchester Royal Infirmary Hospital, Manchester, United Kingdom
bf
Belarusian Medical Academy of Postgraduate Education, Minsk, Belarus
bg
Department of Surgery, Belarusian Medical Academy Postgraduate Education, Minsk, Belarus
bh
Regional Clinical Hospital, Lviv, Ukraine
bi
Kharkiv Emergency Hospital, Medical Faculty of V. N. Karazin Kharkiv National University, Kharkiv, Ukraine
bj
Department Thoraco-abdominal Surgery Kharkov Medical Academy Postgraduate Education, Kharkov, Ukraine
bk
Hungarian Academy of Sciences-University of Szeged, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary

a r t i c l e i n f o a b s t r a c t

Article history:
Received 31 March 2019 Background: Unwarranted administration of antibiotics in acute pancreatitis presents a global challenge.
Accepted 1 April 2019
The clinical reasoning behind the misuse is poorly understood. Our aim was to investigate current clinical
Available online 19 April 2019
practices and develop recommendations that guide clinicians in prescribing antibiotic treatment in acute
pancreatitis.
Keywords:
Methods: Four methods were used. 1) Systematic data collection was performed to summarize current
Acute pancreatitis
Antibiotic
evidence; 2) a retrospective questionnaire was developed to understand the current global clinical
Guideline practice; 3) five years of prospectively collected data were analysed to identify the clinical parameters
Recommendation used by medical teams in the decision making process, and finally; 4) the UpToDate Grading of Rec-
Infection ommendations, Assessment, Development and Evaluation (GRADE) system was applied to provide evi-
dence based recommendations for healthcare professionals.

1
The first three authors equally contributed.
490
rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa

Results: The systematic literature search revealed no consensus on the start of AB therapy in patients
with no bacterial culture test. Retrospective data collection on 9728 patients from 22 countries indicated
a wide range (31e82%) of antibiotic use frequency in AP. Analysis of 56 variables from 962 patients
showed that clinicians initiate antibiotic therapy based on increased WBC and/or elevated CRP, lipase and
amylase levels. The above mentioned four laboratory parameters showed no association with infection in
the early phase of acute pancreatitis. Instead, procalcitonin levels proved to be a better biomarker of early
infection. Patients with suspected infection because of fever had no benefit from antibiotic therapy.
Conclusions: The authors formulated four consensus statements to urge reduction of unjustified anti-
biotic treatment in acute pancreatitis and to use procalcitonin rather than WBC or CRP as biomarkers to
guide decision-making.
© 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Introduction agreement), failing to offer indication for proper AB treatment [18].

2) Misinterpretation of inflammatory biomarkers, such as C reac-
There is a general overuse of antibiotics (ABs) worldwide tive protein (CRP) during AP [26]. It has been suggested that
resulting in AB resistance, which is part of the most remarkable elevation of CRP can have major influence on prescribing prophy-
hazards to global health [1]. The misuse of AB has been associated lactic ABs in AP [26]. 3) Non-adherence to guidelines [13]. Several
with fungal infection, Clostridium difficile infection and increased studies reported moderate or non-compliance to the recommen-
costs [2,3]. In 2009, approximately $10.7 billion was spent on dations for the management of AP [23,27,29,32e36]. 4) Defensive
antibiotic therapy in the United States (US), including $6.5 billion in medical care in which healthcare providers try to protect them-
the outpatient, $3.6 billion in acute inpatient care, and $526.7 selves from malpractice claims [37e39].
million in long-term care settings [4]. According to the latest report These data clearly suggest the crucial importance of multicentre,
from Germany, the total amount of antimicrobials used in human multinational studies aiming to give proper recommendations for
medicine is estimated to range between 700 and 800 tonnes per AB utilization in AP.
year [5], 15% of its used by hospitals, while 85% in primary practice The specific aims of this study were to (1) summarize current
[6]. European Surveillance of Antimicrobial Consumption Networks evidence, (2) understand the current global practice, (3) under-
report that antibiotic-resistant bacteria claim lives of approxi- stand the clinical parameters used by medical teams in the decision
mately 700000 people each year globally [7]. The annual impact of making process, (4) verify the usefulness of these parameters, (5)
resistant infections is estimated to be $20 billion in excess health make more informed recommendations for healthcare
care costs and 8 million additional hospital days in the US [8e10] professionals.
and over 1.6V billion and 2.5 million additional hospital days in the
European Union (EU) [11]. Antimicrobials currently account for
over 30% of hospital pharmacy budgets in the US [12].
Methods
The administration of ABs in acute pancreatitis (AP) has been
widely and thoroughly investigated [13]. We must note that either
1. Systematic review
direct pathologic insult of the pancreas i.e., alcohol, bile or fatty
acids [14], or increased autoactivation of trypsinogen [15] without
The systematic review aimed to summarize the recent evidence
infection can activate inflammatory pathways, therefore AP itself is
(1) on the guidance of AB therapy and (2) on the strategies how
not an indication for AB therapy [16,17]. Notably, current guidelines
high-quality studies raised the suspicion of pancreatic infection in
do not recommend prophylactic AB therapy for the prevention of
AP. We observed the rules of Preferred Reporting Items for Sys-
infectious complications in AP (IAP/APA guideline, Grade 1B) [18],
tematic Reviews and Meta-Analyses (PRISMA) 2009 guideline
(American College of Gastroenterology, strong recommendation,
when reporting this work [40].
moderate quality of evidence) [19]. However, in cases of proven
source of infection empiric administration of ABs is justified [20].
Based on the above mentioned suggestions we can calculate the
rate of ABs should be used in AP: pancreatic infection is a rare event Eligibility
in AP (around 5%) [21], moreover there is only 14%e37.4% extra-
pancreatic indications (such as cholangitis or pneumonia) are re- Eligible randomized controlled trials (RCTs) discussed (1) pa-
ported [22e25], therefore, the justified rate of ABs use should be tients diagnosed with AP (2) who were given any ABs orally and/or
between 20 and 40% in AP. intravenously (3) with available full-text of any languages. Studies
However, the Hungarian Pancreatic Study Group (HPSG) found applying continuous regional arterial infusion or other drugs (e.g.,
that 77.1% of the total study population (n ¼ 600) received AB protease inhibitors) were excluded. We chose the inclusion of RCTs
therapy and two thirds of this group had no signs of infection, on the guidance of AB therapy or preventive AB therapy because
meaning AB treatment was administered on a preventive basis [25]. high-quality studies centered around the suspicion of pancreatic
In population-based studies, 14% of patients received unjustified (so infection are lacking. Our assumption that the best evidence on the
called prophylactic) AB in Portugal [26], 25.5% in Canada [27], topic might be present in these studies relies on two arguments. On
27e58% in the USA [28], 30.7% in the UK [23], 81.4% in India [29], one hand, definitive infection and infected pancreatic necrosis are
44.6e69.3% [30] and 74.3% in Japan [31]. high-priority hard outcomes of these studies focusing on infection
There could be several reasons behind AB overuse worldwide: control. On the other hand, suspicion of infection is a safety issue in
1) The guideline is insufficient regarding AP therapy. It only states these studies because of the required immediate intervention, such
that intravenous AB prophylaxis is not recommended for the pre- as a change in per protocol drug regime or a surgical/radiological
vention of infectious complications in AP (GRADE 1B, strong approach.

rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa 491

Search and selection the following alterations were confirmed in each patient: abdom-
inal pain (clinical symptom), pancreatic enzyme elevation at least
We searched cited and citing articles, including previous meta- three times above upper limit and morphological changes (imaging
analysis and systematic reviews, of relevant reports for eligible techniques).
studies. We did not contact the authors of original studies for Four quality control points were established in our registry. First,
information. the local clinical research assistant electronically uploads the data
We conducted a comprehensive systematic search in MEDLINE and confirms equivalency with the hard copy. Second, the local
(PubMed), EMBASE, and Cochrane Trials from inception up to 7 July institutional principal investigator (who holds a medical doctoral
2018 for articles reporting on the use of antibiotics in AP. We degree) double-checks the uploaded data and confirms the validity
applied the following query without any filters imposed on the and accuracy. Third, the central data administrator, who is based at
search: pancreatitis AND (antibiotic OR antibiotics OR carbapenem the headquarters of HPSG, controls the accuracy and finally (in
OR imipenem OR meropenem OR ertapenem OR doripenem OR house monitor), the registry leader reviews the presented data and
aminoglycoside OR amikacin OR gentamicin OR cephalosporin OR verifies them. Patients with inadequate or insufficient data are
cefepime OR ceftriaxone OR ceftazidime OR cefoperazone OR excluded.
cefixime OR cefuroxime OR cephalexin OR ceftobiprole OR cefa- To answer our post hoc defined research question, data from
zolin OR cefalotin OR glycopeptide OR vancomycin OR teicoplanin HPSG pancreatic registry were analysed. We selected 56 parame-
OR penicillin OR amoxicillin OR ampicillin OR oxacillin OR piper- ters relating to our research question (Supplementary Fig. 2.). Those
acillin OR mezlocillin OR ticarcillin OR sulbactam OR tazobactam patients’ data were used for further analysis where the following
OR clavulanate OR fluoroquinolone OR ciprofloxacin OR levo- information were available in its entirety: age, gender, length of
floxacin OR moxifloxacin OR ofloxacin OR pefloxacin OR metroni- hospitalization, severity, based on revised Atlanta classification,
dazole OR tigecycline OR linezolid OR daptomycin). mortality, complications and details about AB therapy (starting
Yield of search was combined in reference manager software date, type of antibiotics, etc.) [17]. Data of 962 patients met the
(EndNote X7.4, Clarivate Analytics, Philadelphia, PA, US) to remove criteria mentioned above, so this cohort was used for further
overlaps between databases and duplicates, then, two independent analysis.
investigators screened the records by title, abstract, and full-texts The following groups have been designated. Patients in Group1
against our eligibility criteria in duplicate. Discrepancies were and 2 did not receive AB therapy. Patients in Group 1 did not receive
resolved by third party arbitration. AB therapy and their no symptoms or evidence of infection. Pa-
tients in Group 2 did not receive AB treatment either, however,
Data collection there were symptoms which may associated with infection (ie.
fever) or the followings were declared: positive bacterial culture,
A pre-constructed data collection table was designed by our cholangitis, upper or lower respiratory tract infection, urogenital
research team. After this step, training was organized to increase infection, and infection of any other organ system.
the consistency of data collection. Data were extracted by two in- Members of Group 3, 4 and 5 all received AB treatment. In Group
dependent review authors in duplicate. Discrepancies were 3, patients had no features characteristic of infection, therefore
resolved by a consensus meeting of our research team. received AB as prevention. In these patients there were no signs of
The following data were extracted: publication data (authors, infection or negative bacterial culture. Patients in Group 4 received
year), setting (country, centres, setting), definition and etiology of empirical AB therapy since they had features characteristic of
AP, eligibility criteria of the study, the total number of patients (in infection (with no (a) or negative bacterial culture (b)). Group 5
intention to treat and per protocol analyses), and interventions patients took AB as a targeted therapy following positive bacterial
(drug regimens and/or guidance of therapy). In addition, definitions culture, specifying the exact cause of infection and/or gas in and/or
of suspected and definitive pancreatic and extrapancreatic in- around the pancreas on CECT or MRI.
fections, and the consequent clinical management were collected.
Statistical analysis
2. Retrospective data analysis
For descriptive statistics, the number of patients, mean, stan-
To assess the worldwide trends in administration of AB we sent dard deviation (SD), standard error of mean (SEM), minimum,
a letter of invitation and a questionnaire to the member of the In- median and maximum values were calculated for continuous var-
ternational Association of Pancreatology in November 2017. Col- iables, and the case number and percentage were computed for
leagues have provided data from their past-year inpatients’ practice categorical values.
accordingly to gender, etiology, mortality and severity of AP, and AB For inferential statistics, the following tests were applied to
therapy irrespectively from its indication. Percentage of AB treat- determine statistical significance of differences between groups. To
ments was calculated, and it has been illustrated on a colour scaled compare two groups of independent samples, the t-test was used
map. for normally distributed data and the Mann-Whitney U test for
non-normally distributed data. To compare more than two groups,
3. Prospectively collected data analysis one-way ANOVA followed by the Tukey post hoc test was employed
for normally distributed data with homogenous group-wise stan-
The Hungarian Pancreatic Study Group (HPSG) (https://tm- dard deviation; Brown-Forsythe Levene-type test was applied to
centre.org/en/study-groups/hungarian-pancreatic-study-group/) test of variance homogeneity; the Welch test followed by the
was established in 2011 with the aim to improve patients’ care in Games-Howell post hoc test for normally distributed data with
pancreatic disease. We have developed an international, uniform heterogeneous group-wise standard deviation; and the Kruskal-
and prospective electronic data registry to collect high quality data Wallis test followed by the Holm p-value adjustment method for
from patients suffering from AP. From January 1, 2013 to November non-normally distributed data.
30, 2016, 1070 episodes of AP have been enrolled. Centre distri- The association between categorical variables was inspected by
bution is indicated in Supplementary Fig. 1. Diagnosis of AP was the Chi-square test and Fisher's exact test. To compare proportions
based on the A1 recommendation of the IAP/APA guideline. Two of for more than two groups, the pairwise proportion test followed by
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rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa

the Holm p-value adjustment was used. The level of statistical Antibiotics are overused worldwide
differences were defined in all cases.
The relevant statistical tests are also described in the legends to 9869 patients’ data were collected from 23 countries and it
the figures. Statistical analyses were performed using SPSS (Version showed a global overuse of ABs. The highest rates of AB therapy
23, IBM, New York, NY, USA) and R Studio (Version 1.1.453, fmsb could be seen in Asia (China 81.4%, Taiwan 80.6%) and Eastern
package). Europe (Albania 78.6%, Bulgaria 78%), whereas the lowest rates are
The authors have read the Strengthening the Reporting of observed in Western Europe (Spain 31.8%, United Kingdom 31.2%)
Observational Studies in Epidemiology (STROBE) State- (Fig. 1). There is no association between the rate of AB therapy and
mentdchecklist of items, and the manuscript was prepared and the outcome (mortality, severity) of the disease between the
revised accordingly [41]. countries. The details of centres and countries can be found in
Supplementary Fig. 6.
4) Development of evidence based recommendations
There is a large detection bias in the initiation of AB therapy and
bacterial culture test
Grading
In these series of data analysis we aimed to understand the
Strength of recommendation and quality of evidence were decision making process of physicians concerning the initiation of
based on the guideline of the Grading of Recommendations AB therapy in AP. 962 of 1070 prospectively collected patients in the
Assessment, Development and Evaluation (GRADE) Working HPSG AP registry had details concerning AB therapy. Firstly, we
Group, an internationally accepted system established in 2011 confirmed that the registry represents a normal distribution of AP
(https://www.uptodate.com/home/grading-tutorial#). Strength of concerning age, gender, etiology, length of hospitalization (LOH),
any recommendation depends on the establishment between severity and mortality (Supplementary Fig. 7). Secondly, we per-
benefits and risks and burden. Three-category has been imitated for formed the analysis on the major outcome parameters (LOH,
quality of evidence regarding treatment effect. All authors deter- severity and mortality) and found that (i) worse LOH, severity and
mined the strength of the consensus by voting yes or no: 95% or mortality parameters are associated with AB treatment, (ii) holding
more ‘yes’ votes ¼ ‘full agreement’; at least 70% ‘yes’ votes ¼ ‘strong off the AB therapy among patients with suspected infection (Group
agreement’, and more than 50% ‘yes’ votes ¼ ‘weak agreement’. 2) is not associated with poor outcome, (iii) patients having bac-
terial culture (Group 4b) test had significantly worse outcome than
5) Ethics patients having no bacterial test (Group 4a) among AB treated
groups, (iv) confirmed infection had the worst outcome in AP
The study was approved by the Scientific and Research Ethics (Group 5) (Fig. 2A and B) (v) the willingness of the initiation of AB
Committee of the Medical Research Council (22254e1/2012/EKU). therapy elevates parallel with the severity and finally (vi) the
All participants provided written consent of participation to this highest level of AB therapy is in biliary AP (Fig. 2C).
study. The ethics committee carefully checked and approved the
consent procedure. 90% of AB therapy started in the first 3 days of AP

Results 74% of AB are started on Day 1, 10.5% on Day 2, whereas 6.0% on

Day 3 (Supplementary Fig. 8A). Early AB treatment had no associ-
There is no consensus on the start of AB therapy in patients with no ation either with shorter AB administration (Supplementary
bacterial culture test Fig. 8D), or with the outcome of AP (Supplementary Figs. 8E and
J). Administration of three different ABs (Supplementary Figs. 8B,
Supplementary Figure 3 shows the flowchart of this systematic F, G, K) or higher number of changes in the AB regime
review. After careful selection, only 1 RCT reporting on the guidance (Supplementary Figs. 8C, H, I, L) are associated with longer AB
of AB therapy was eligible for inclusion [42]. In this study, pro- therapy and worse outcome of the disease suggesting that if pa-
calcitonin (PCT)-guided (>0.5 ng/ml) AB regime proved to be su- tients’ condition do not improve during AB therapy or bacterial
perior over 2-week prophylactic AB treatment in severe AP resistance occurs doctors initiate AB therapy changes. Detailed
(Supplementary Fig. 4). We identified 22 studies [42e63] reporting statistics can be found in Supplementary Fig. 9. In 52% of the cases
on prophylactic antibiotic treatment in AP. Severe AP/acute necro- single AB, in 43.7% double AB, whereas in 4.3% three or more AB
tizing pancreatitis were analysed in 18 of 22 studies, however, these were administered. In the single AB group cephalosporin 29.5%,
entities were defined in many forms: 9 and 11 studies incorporated whereas in the double AB group ciprofloxacin and metronidazole
CRP (ranging from >100 to >200 mg/l) and pancreatic necrosis were the most commonly chosen therapies (Supplementary
(confirmed by CT or FNA) into the definitions Supplementary Fig. 5. Fig. 10). Of course a cohort analysis is not enable to differentiate
Despite the inclusion of RCTs, the way how the studies defined the between the drugs, but not surprisingly imipenem or not conven-
suspicion of an infection was vague. Factors taken into consider- tional AB therapies were associated with more severe pancreatitis
ation were, as follows: CRP (5 studies), fever (generally in 5 studies, and higher mortality (Supplementary Fig. 10). Detailed statistics
2 of them considered persistent fever only), criteria of SIRS/organ can be found in Supplementary Fig. 11.
failure/sepsis (3 studies), air bubbles in necrosis on CT (2 studies),
and leukocytosis (2 studies). Only 2 studies suspected an infection Elevated CRP level, white blood cell (WBC) count, lipase and amylase
when a rise in inflammatory markers occurred following an initial levels are the biomarkers used for the initiation of AB therapy
decrease. Interestingly, neither of the studies testing prophylactic
ABs mentioned PCT, as a marker of infection in the included studies. We investigated the four most commonly monitored laboratory
The general approach proved a suspected infection was FNA and markers (amylase, lipase, C-reactive protein, WBC count) during
culturing in most cases followed by surgery as a treatment. A the course of AP. Mean levels of these parameters on the starting
change in drug regime was managed either empirically and/or by day of AB therapy were compared. The amylase and lipase levels
culturing. showed association with the AB treatment, but as we expected, not

rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa 493

Fig. 1. Map of antibiotic use worldwide. There is a general overuse of AB worldwide (57.2%). The highest rates of AB therapy are in Asia (China 81.4%, Taiwan 80.6%) and Eastern
Europe (Albania 78.6%, Bulgaria 78%), whereas the lowest rates are observed in Western Europe (Spain 31.8%, United Kingdom 31.2%).

Fig. 2. Grouping of patients based on sign of infection, antibiotic (AB) treatments and microbiology examination. General characterisation of AB administration, length of
hospitalization (LOH) and mortality. Based on the AB treatment patients were divided into two main groups (non-AB and AB) and six subgroups. Group 1: Patients had no sign of
inflammation and did not received ABs. Group 2: Patients had sign of inflammation (fever, imaging alterations, etc.) but did not received ABs. Group 3: Patients had no sign of
inflammation but received preventive ABs. Group 4a: Patients had sign of inflammation (fever, imaging alterations, etc.) and received antibiotics, however no microbiology culture
was requested. Group 4b: Patients had sign of inflammation (fever, imaging alterations, etc.) and received antibiotics. Microbiology culture was done but no pathogen bacteria were
found. Group 5: Patients had sign of inflammation (fever, imaging alterations, etc.), microbiology culture was performed with positive results and received AB treatment. A. LOH was
significantly longer in AB therapy groups then in non-AB groups. (13.4 ± 0.5 days vs 8.3 ± 0.3 days, p < 0.001) In presence of suspected infection (Group 2) LOH (8.3 ± 0.4 days vs
8.2 ± 0.4 days), severity and mortality were the same as in Group 1. Preventive AB therapy (Group 3) resulted significantly longer hospitalization compare to Group 1 (12.3 ± 1.1 days
vs 8.3 ± 0.4 days, p < 0.001). Significantly more patients with moderate (220/718 vs 46/244, p < 0.001) and severe disease (50/718 vs 3/244, p < 0.001) course received AB therapy.
There was no significant difference in mortality between the groups. B. If we retracted Group 5 (patients with proven infection), the rate of AB therapy still remained significantly
high in moderate and severe AP (p < 0.001, p ¼ 0.023). C. AB treatment in context of etiology of AP.
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rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa

with the severity of the disease (Fig. 3AeB, E-F). In addition, (AUC:0.73). Fig. 5 shows the changes of amylase and lipase during
significantly higher inflammatory markers (CRP and WBC) were AP. It is very clear that neither infection (Group 2) nor AB treatment
associated with the AB treatment and more severe AP (Fig. 3CeD, (Group 3, 4 and 5) change the pattern of enzyme levels during AP.
G-H).

Elevation of PCT level but not CRP, WBC, lipase or amylase levels are Pancreatic infection causes the worst outcome in AP
associated with infection in the early phase of AP
Here we correlated the disease outcome with the infected or-
CRP levels progressively increase, whereas WBC values decrease gans. Biliary, respiratory, urogenital infection or elevated PCT or
during the first 3 days of AP irrespectively of AB therapy in either fever alone with no identified organ infection resulted in a mod-
suspected (Group 4a and b) or in confirmed (Group 5) infection (Fig erate severity range (8.3%e14.3%) without mortality, however
4A, F). Suspected infection (Group 2) did not show difference in CRP pancreatic infection caused 25% severe AP with extremely high
and WBC levels compared to Group 1 among the non-AB groups mortality rate (25%), (Fig. 6). Detailed statistics can be found in
(Fig. 4B, G). Preventive AB therapy (Group 3) was administered in Supplementary Fig. 12.
patients with significantly higher CRP and WBC levels (p < 0.001,
p ¼ 0.046), however, both CRP and WBC level decreased nearly the
same level as Group 1 by day 5 (Fig. 4C, H). Bacterial culture test Increase in the pathogen numbers is associated with the worse
(Group 4b) was performed in patients with significantly higher CRP outcome of AP
(p ¼ 0.008) (Fig. 4D). These data are in accordance with the results
at the start of AB therapy in AP (Fig. 3.). Very importantly, neither The most common pathogens were Staphylococci (34.2%),
CRP nor WBC showed differences between patients having positive Enterococci (27.4%), Clostridium difficile (22.4%), Escherichia coli
blood culture (Group 5) vs. patients having negative blood culture (18.4%) and Pseudomonas (13.2%). Due to the relatively low event
tests (group 4b), suggesting that CRP and WBC have no association rates, we could not analyse the differences among pathogens,
with infection at the early phase of AP (Fig. 4E, J, L, M). However, however, it was obvious that increased numbers of detected
PCT level, as confirmed in earlier studies showed correlation with pathogens strongly correlates with worse outcomes in AP
infection (Fig. 4K, N) with acceptable sensitivity and specificity (Supplementary Fig. 13).

Fig. 3. Most commonly monitored laboratory markers on starting day of AB therapy. Average amylase, lipase, C-reactive protein (CRP) and white blood cells (WBC) were
calculated on starting day of AB therapy. In non-AB groups day-matched controls were selected. A. Average amylase in non-AB group (510.01 ± 57.91 U/L) compare to AB group
(1004.15 ± 50.22 U/L) has been significantly differed (p < 0.001). B. There has been a significant difference (p < 0.001) between average lipase in non-AB (815.83 ± 96.73 U/L) and AB
(2298.72 ± 207.82 U/L) groups. C. CRP showed a significant difference between non-AB and AB groups (52.16 ± 4.91 mg/L vs 86.4 ± 4.2 mg/L, p < 0.001) similar trends have been
detected with regards to WBC levels (10.32 ± 0.28 G/L vs 13.8 ± 0.2 G/L, p < 0.001 (D). E. Average amylase (1015.25 ± 55.10 U/L, 957.41 ± 83.33 U/L, 1077.48 ± 397.02 U/l and lipase (F)
(2303.05 ± 219.19 U/L, 2286.82 ± 378.21 U/L, 2131.42 ± 1377.75 U/L) did not differ between severity groups (mild-moderate: p ¼ 0.26, p ¼ 0.16; moderate-severe: p ¼ 0.16, p ¼ 0.15).
G. Average CRP (68.77 ± 4.32 mg/L, 104.56 ± 8.71 mg/L, 181.7 ± 27.26 mg/L) and WBC (H) (12.83 ± 0.21 G/L, 15.11 ± 0.49 G/L, 16.5 ± 0.98 G/L) levels showed correlation with severity of
AP (mild-moderate: p ¼ 0.007 and p < 0.001, moderate-severe: p ¼ 0.012 and p ¼ 0.22).

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A. Pa 495

Fig. 4. Trends in the changes of CRP and WBC during the early phase of AP. A. Due to the inflammation of the pancreas, irrespectively from the infection CRP levels rose during
the first 3 days. F. Non-similar trend can be seen in WBC levels. B and G. Suspected infection (Group 2) in AP did not show difference (p ¼ 0.431, p ¼ 0.923) in cumulative average
(cAVE) of CRP (70.33 ± 6.31 mg/L) and cAVE of WBC levels (10.82 ± 0.47 G/L) compare to Group 1 (57.12 ± 5.50 U/L, 10.14 ± 0.29 G/L). C and H. Preventive AB therapy (Group 3) was
administered in patients with significantly higher CRP (104.69 ± 8.05 mg/L) and WBC levels (11.71 ± 0.40 G/L) (p¼<0.001 and p ¼ 0.046, respectively), however we observed the CRP
increase, then drop at day 3 and decreased nearly the same level as Group 1 by the day 5. D and I. Bacterial culture (Group 4b) was performed in patients with significantly higher
CRP (102.90 ± 3.88 mg/L vs 141.05 ± 8.66, p < 0.001). E. and J. Proven infection (Group 5) did not result in significant difference in CRP and WBC levels in the first five days. K: cAVE of
PCT differ significantly between Group 4b and Group 5 (p¼0.026). L, M and N. CRP (AUC: 0.51) and WBC (AUC: 0.45) failed, however PCT (AUC: 0.73) fairly can predict infection in
AP.

Consensus statements Statement 1: There is a general overuse of ABs in AP, therefore,

centres should make a strong effort to reduce it to a justifiable
Based on the systematic review and retrospective and pro- level (GRADE 1C: strong suggestion, low quality evidence, full
spective data analysis, the authors from 62 centres/23 countries agreement)
accepted the following statements and recommendations as Statement 2: CRP and WBC values are not associated with
amendments to the current guidelines (Table 1.) infection in the early phase of AP, therefore CRP and WBC should
not be used as biomarkers for decision making concerning AB
496
rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa

Fig. 5. Trends in the changes of amylase and lipase during the early phase of AP. There are no significant differences between the groups.

therapy in the early phase of AP (GRADE 1C: strong suggestion, Generally, in Western European countries less AB is adminis-
low quality evidence, full agreement). tered, whereas Eastern European and Asian countries are the most
Statement 3: Progressive elevation of CRP is part of the in- frequent users of AB. Our data are in accordance with several na-
flammatory response in AP, therefore, an upward trend of CRP tional surveys performed in the past two decades. In Germany, 47%
levels should not be an indicator for AB treatment in the early of respondents use AB prophylaxis [32] and 44% of the doctors al-
phase of AP (GRADE 1C: strong suggestion, low quality evidence, ways administer AB in cases of severe AP [33]. In the UK and
full agreement). Ireland, 24% use prophylaxis in AP regardless of the severity [64].
Statement 4: Elevation of PCT levels during the early phase of Prophylactic AB treatment is utilized by 73% of the European
AP is associated with infection, therefore, it can guide the choice members of the International Hepato-Pancreato-Biliary Association
to start AB treatment in the absence of proven infection (GRADE [65]. 40.9% of the interviewed American clinicians give AB in more
2C: weak suggestion, low quality evidence, full agreement). than 75% of patients with severe AP [35]. In Japan, before the
publication of the Japanese evidence-based guidelines in 2003,
82.5% of the physicians used AB prophylaxis after the publication
Discussion 76.1% [34], which is still a frequent practice pattern, considering
that the Japanese guidelines also endorse routine use of AB pro-
At the beginning of our study, we performed a systematic re- phylaxis in mild to moderate AP [66,67]. These data show without
view in which we showed that (i) PCT can be a good marker for proper guideline, the physicians’ willingness of AB therapy is very
suspected infection (ii), there is no consensus concerning the high. The high rate of AB treatment can also be explicable with the
compulsory start of AB therapy in patients with no positive bac- fact that the death rate can increase from 2 to 35% due to bacterial
terial culture test, (iii) patients having necrosis have no benefits infection of the necrotic pancreatic tissue [25,68] Organ failure
from AB therapy. These data have predicted the results of our in- alone was associated with a mortality of 19.8% [68,69], whereas,
ternational retrospective data analysis, which showed that infected necrosis without organ failure has low mortality [70].
administration of ABs widely differs between countries. Based on these observations, it is not surprising that several trials

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A. Pa 497

Fig. 6. Source of infection in AP. Infection of the pancreas extended the length of hospitalization (LOH) to 25.55 ± 4.76 days, deteriorated the course of the disease (moderate 25%,
severe 75%) and elevated the mortality to 25%. PIe charts represent the distribution of mild (green), moderate (yellow) and severe (red) cases in each group of AP patients.

Table 1
Summary of the consensus statements.

Statements Grade of Level of

evidence agreement

1 There is a general overuse of antibiotics in AP, therefore, centres should make a strong effort to reduce it to a justifiable level. 1C full (99%)
2 CRP and WBC values are not associated with infection in the early phase of AP, therefore CRP and WBC should not be used as biomarkers 1C full (97%)
for decision making concerning AB therapy in the early phase of AP.
3 Progressive elevation of CRP is part of the inflammatory response in AP, therefore, an upward trend of CRP levels should not be an 1C full (97%)
indicator for AB treatment in the early phase of AP.
4 Elevation of PCT levels during the early phase of AP is associated with infection, therefore, it can guide the choice to start antibiotic 2C full (96%)
treatment in the absence of proven infection.

and meta-analysis were performed to understand the usefulness of parameters mislead physicians during the initiation of AB therapy
preventive AB in AP [44,49,53,54,56,57,59,61,71]. A recently pub- (ii) to find a biomarker(s), which can predict infection without
lished Cochrane review showed that neither of the preventive AB bacterial culture test. In this investigation we showed with several
treatments decreased short-term mortality in AP [72]. analysis that elevation of amylase, lipase levels, CRP and WBC
The most important goals of our study were (i) to find out what mislead the doctors decision making on the initiation of AB therapy.
498
rniczky et al. / Pancreatology 19 (2019) 488e499
A. Pa

CRP and WBC have been confirmed to be strongly associated with support from the NIHR Biomedical Research Unit funding scheme.
the severity of AP [73e75] however, data on lipase and amylase are
contradictory [76e79]. In our study, the initiation of AB therapy Appendix A. Supplementary data
was based on the severity and most probably on a predicted
infection diagnosed by the elevation of inflammatory biomarkers Supplementary data to this article can be found online at
namely the CRP and WBC. Here we confirmed that these laboratory https://doi.org/10.1016/j.pan.2019.04.003.
parameters have no association with infection, but PCT, which
showed correlation with infection with acceptable sensitivity and Financial or ethical conflict of interest
specificity.
Finally, based on the systematic review and the retrospective Authors disclose any financial or ethical conflict of interest.
and prospective cohort analyses, the participants of this trial
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A double-blind, placebo-controlled trial of ciprofloxacin prophylaxis in pa- different degrees of severity of acute alcoholic pancreatitis. Pol Przegl Chir
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acute pancreatitis. J Surg Res 1975;18:197e200. centre retrospective cohort study. Pancreatology 2016;16:529e34.
[51] Isenmann R, Runzi M, Kron M, Kahl S, Kraus D, Jung N, et al. Prophylactic [77] Kumaravel A, Stevens T, Papachristou GI, Muddana V, Bhatt A, Lee PJ, et al.
antibiotic treatment in patients with predicted severe acute pancreatitis: a A model to predict the severity of acute pancreatitis based on serum level of
placebo-controlled, double-blind trial. Gastroenterology 2004;126:997e1004. amylase and body mass index. Clin Gastroenterol Hepatol 2015;13:1496e501.
[52] Luiten EJ, Hop WC, Lange JF, Bruining HA. Controlled clinical trial of selective [78] Fabre A, Boulogne O, Gaudart J, Mas E, Olives JP, Sarles J. Evaluation of serum
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[53] Manes G, Rabitti PG, Menchise A, Riccio E, Balzano A, Uomo G. Prophylaxis [79] Devanath A, Kumari J, Joe J, Peter S, Rajan S, Sabu L, et al. Usefulness of lipase/
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[54] Manes G, Uomo I, Menchise A, Rabitti PG, Ferrara EC, Uomo G. Timing of
 ORIGINAL RESEARCH
published: 20 September 2019
doi: 10.3389/fphys.2019.01202

Multiple Hits in Acute Pancreatitis:

Components of Metabolic Syndrome
Synergize Each Other’s Deteriorating
Effects
Andrea Szentesi 1,2,3 , Andrea Párniczky 1,4 , Áron Vincze 5 , Judit Bajor 5 , Szilárd Gódi 6 ,
Patricia Sarlós 5 , Noémi Gede 1 , Ferenc Izbéki 7 , Adrienn Halász 7 , Katalin Márta 1 ,
Dalma Dobszai 1,3 , Imola Török 8 , Hunor Farkas 8 , Mária Papp 9 , Márta Varga 10 ,
József Hamvas 11 , János Novák 12 , Artautas Mickevicius 13,14 , Elena Ramirez Maldonado 15 ,
Ville Sallinen 16 , Dóra Illés 2 , Balázs Kui 2 , Bálint Erőss 1 , László Czakó 2
Tamás Takács2 and Péter Hegyi1,2,6,17* on behalf of the Hungarian Pancreatic Study Group
1
Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary,
2
First Department of Medicine, University of Szeged, Szeged, Hungary, 3 Doctoral School of Clinical Medicine, University
of Szeged, Szeged, Hungary, 4 Heim Pál National Institute of Pediatrics, Budapest, Hungary, 5 Division of Gastroenterology,
First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary, 6 Division of Translational Medicine, First
Edited by:
Department of Medicine, Medical School, University of Pécs, Pécs, Hungary, 7 Szent György Teaching Hospital of Fejér
Richard T. Waldron,
County, Székesfehérvár, Hungary, 8 County Emergency Clinical Hospital – Gastroenterology and University of Medicine,
Cedars-Sinai Medical Center,
Pharmacy, Sciences and Technology, Târgu Mureş, Romania, 9 Division of Gastroenterology, Department of Internal
United States
Medicine, University of Debrecen, Debrecen, Hungary, 10 Dr. Réthy Pál Hospital of Békés County, Békéscsaba, Hungary,
Reviewed by: 11
Bajcsy-Zsilinszky Hospital, Budapest, Hungary, 12 Department of Gastroenterology, Pándy Kálmán Hospital of Békés
Juan Sastre, County, Gyula, Hungary, 13 Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania, 14 Clinics of Abdominal Surgery,
University of Valencia, Spain Nephrourology and Gastroenterology, Faculty of Medicine, Vilnius University, Vilnius, Lithuania, 15 Consorci Sanitari del
Savio George Barreto, Garraf, Sant Pere de Ribes, Barcelona, Spain, 16 Department of Transplantation and Liver Surgery, Helsinki University
Medanta – The Medicity, India Hospital and University of Helsinki, Helsinki, Finland, 17 Hungarian Academy of Sciences – University of Szeged, Momentum
*Correspondence: Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
Péter Hegyi
hegyi2009@gmail.com
Introduction: The incidence of acute pancreatitis (AP) and the prevalence of metabolic
Specialty section: syndrome (MetS) are growing worldwide. Several studies have confirmed that obesity
This article was submitted to (OB), hyperlipidemia (HL), or diabetes mellitus (DM) can increase severity, mortality,
Gastrointestinal Sciences,
a section of the journal
and complications in AP. However, there is no comprehensive information on the
Frontiers in Physiology independent or joint effect of MetS components on the outcome of AP. Our aims were
Received: 04 May 2019 (1) to understand whether the components of MetS have an independent effect on the
Accepted: 03 September 2019
outcome of AP and (2) to examine the joint effect of their combinations.
Published: 20 September 2019
Citation: Methods: From 2012 to 2017, 1435 AP cases from 28 centers were included in
Szentesi A, Párniczky A, Vincze Á, the prospective AP Registry. Patient groups were formed retrospectively based on the
Bajor J, Gódi S, Sarlós P, Gede N,
Izbéki F, Halász A, Márta K, presence of OB, HL, DM, and hypertension (HT). The primary endpoints were mortality,
Dobszai D, Török I, Farkas H, Papp M, severity, complications of AP, and length of hospital stay. Odds ratio (OR) with 95%
Varga M, Hamvas J, Novák J,
Mickevicius A, Maldonado ER,
confidence intervals (CIs) were calculated.
Sallinen V, Illés D, Kui B, Erőss B,
Results: 1257 patients (55.7 ± 17.0 years) were included in the analysis. The presence
Czakó L, Takács T and Hegyi P (2019)
Multiple Hits in Acute Pancreatitis: of OB was an independent predictive factor for renal failure [OR: 2.98 (CI: 1.33–6.66)]
Components of Metabolic Syndrome and obese patients spent a longer time in hospital compared to non-obese patients
Synergize Each Other’s Deteriorating
Effects. Front. Physiol. 10:1202.
(12.1 vs. 10.4 days, p = 0.008). HT increased the risk of severe AP [OR: 3.41 (CI:
doi: 10.3389/fphys.2019.01202 1.39–8.37)], renal failure [OR: 7.46 (CI: 1.61–34.49)], and the length of hospitalization

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

(11.8 vs. 10.5 days, p = 0.020). HL increased the risk of local complications [OR: 1.51
(CI: 1.10–2.07)], renal failure [OR: 6.4 (CI: 1.93–21.17)], and the incidence of newly
diagnosed DM [OR: 2.55 (CI: 1.26–5.19)]. No relation was found between the presence
of DM and the outcome of AP. 906 cases (mean age ± SD: 56.9 ± 16.7 years) had
data on all four components of MetS available. The presence of two, three, or four MetS
factors increased the incidence of an unfavorable outcome compared to patients with
no MetS factors.
Conclusion: OB, HT, and HL are independent risk factors for a number of
complications. HT is an independent risk factor for severity as well. Components of
MetS strongly synergize each other’s detrimental effect. It is important to search for and
follow up on the components of MetS in AP.
Keywords: acute pancreatitis, metabolic syndrome, obesity, diabetes mellitus, hypertension, hyperlipidemia,
severity, mortality

INTRODUCTION However, there is no data regarding a link between the

outcome of AP and the presence of arterial HT. Furthermore,
Acute pancreatitis is a severe inflammatory condition with there is a lack of data on how the components of MetS, namely,
increasing incidence and hospitalization worldwide (Forsmark OB, DM, HT, and HL, influence the outcome of AP individually
et al., 2016; Garg et al., 2019). AP has a variable severity or in combination. Therefore, in this study, we aimed to analyze
ranging from mild and self-limited to severe and fatal. The how the components of MetS influence the outcome of AP (1)
mortality of the disease ranges approximately from 2 to 5% individually and (2) in combination.
and depends on the development of organ failure and local
complications, which are summarized in the revised Atlanta
classification (Banks et al., 2013). The major etiological factors are MATERIALS AND METHODS
gallstones and alcohol consumption (Forsmark et al., 2016), but
hypertriglyceridemia (HTG) and intake of certain medications Patient Population and Study Design
may also be in the background. The APR launched in 2011 by the Hungarian Pancreatic
The severity and outcome of AP are influenced by the Study Group is an international prospective registry for
metabolic comorbidities of the host (Working Group Iap/Apa patients suffering from AP. Besides pancreatic registries,
Acute Pancreatitis Guidelines, 2013; Goodger et al., 2016). HPSG has already organized five registered clinical trials to
Metabolic syndrome is characterized by the clustering of investigate AP with the acronyms PREPAST (Dubravcsik
abdominal OB, HTG, low levels of high-density lipoprotein et al., 2015), APPLE (Parniczky et al., 2016), PINEAPPLE
(HDL), elevations in blood pressure and fasting glucose, or (Zsoldos et al., 2016), GOULASH (Marta et al., 2017),
diabetes (Alberti et al., 2009). MetS is associated with an increased and EASY (Hritz and Hegyi, 2015) and has submitted
risk of development of and death from cardiovascular disease three further pre-study protocols: GOULASH PLUS
and chronic kidney disease (Isomaa et al., 2001). The presence of (follow-up to the GOULASH study), EMILY (endoscopic
MetS was previously shown to be associated with a higher risk of sphincterotomy for delaying cholecystectomy in mild acute
severe AP, higher mortality rate, and longer duration of stay in the biliary pancreatitis), and LIFESPAN (lifestyle, prevention,
intensive care unit (Mikolasevic et al., 2016). However, in another and risk of AP).
study, MetS did not affect the severity of AP (Sawalhi et al., 2014). From June 2012 to September 2017, 1435 adult patients
OB was previously shown to be independently associated with with AP from 28 community and university hospitals were
the severity of AP (Sawalhi et al., 2014) and the development prospectively enrolled (Supplementary Appendix S1).
of organ failure but not with mortality in AP (Smeets et al., Demographic and anthropometric data; history of HL, HT,
2019). DM was associated with a higher risk of AP (Yang et al., and DM; previous medical therapy and etiology; severity; local
2013) and negatively influenced the outcome of AP by raising and systemic complications; and mortality of AP were collected.
the incidence of renal failure, intensive care unit admission, and In this study, we aimed to maximize the number of
length of hospital stay (LOS) (Miko et al., 2018). The presence of cases for each individual effect analysis. We had information
HTG increased severity, complication rate, and mortality in AP concerning OB from 1257 cases, HT from 1127 cases,
(Kiss et al., 2018). DM from 1257 cases, and HL from 1036 cases. Patients
were grouped based on the World Health Organization
Abbreviations: AP, acute pancreatitis; APR, Acute Pancreatitis Registry; BMI, (WHO) classification of BMI (≥30 or <30 kg/m2 ) and the
body mass index; CI, 95% confidence interval; DM, diabetes mellitus; HL,
presence or absence of three other components, HT, HL,
hyperlipidemia; HPSG, Hungarian Pancreatic Study Group; HT, hypertension;
LOS, length of hospital stay; MetS, metabolic syndrome; OB, obesity; OR, odds and DM. However, in the “joint effect analysis,” we only
ratio; SD, standard deviation. included cases where data from all four components of

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

MetS, OB, HL, HT, and DM were available (906 cases). RESULTS
We conducted an additional analysis to confirm that the
cohorts noted above represent the total cohort of 1435 Individual Effect Analysis
cases. Importantly, there were no significant differences in A total of 1257 patients (mean age ± SD: 55.7 ± 17.0 years, males
demographics or the main outcome parameters between the vs. females: 57.1 vs. 42.9%) were recruited for the “individual
cohorts (Supplementary Appendix S2). effect analysis.” 371 patients (29.5%) had OB, 676 (60.0%) had
Data were collected by treating physicians with the help of HT, 349 (33.7%) had HL, and 206 (16.4%) had DM (Table 1).
trained and experienced study administrators on the basis of a The major etiologies of AP were biliary stones in 37.8% of the
standardized case report form and protocol in the prospective cases of the total cohort, alcohol in 18.5%, and HL in 3.7%. OB
APR. Accuracy of data recorded is secured by a four-level increased the risk of biliary etiology [OR: 2.06 (CI: 1.61–2.64)].
quality check system involving both medical administrative Meanwhile, HTG-induced AP was more frequent in the presence
personnel and gastroenterologists. Data quality is presented of HL (12.9 vs. 0.1%, p < 0.001) compared to the non-HL group
in Supplementary Appendix S3. The study protocol was and in the presence of DM compared to the non-DM patient
approved by the Scientific and Research Ethics Committee group [OR: 2.34 (CI: 1.39–4.00)], respectively (Table 1).
of the Medical Research Council (22254-1/2012/EKU). All
patients provided written informed consent to participate Obesity (Figure 1)
in the registry. Obesity was less common in males [OR: 0.75 (CI: 0.58–0.95)].
There was no difference between the ages of the OB and non-OB
Definitions groups (56.3 ± 15.2 vs. 55.4 ± 17.7, p = 0.398), although the age
Diagnosis of AP was made according to the recommendations distribution showed a larger proportion of obese patients in the
in the IAP/APA guidelines. At least two criteria of the following older age groups.
three were present: upper abdominal pain, pancreatic enzyme Obesity increased the risk of severe AP [OR: 2.15 (CI: 1.31–
levels exceeding more than three times the upper normal level, 3.54)] but showed no relation to the mortality rate [OR: 1.39
and features of pancreatitis on imaging (Working Group Iap/Apa (CI: 0.66–2.96)]. OB did not influence the incidence of local
Acute Pancreatitis Guidelines, 2013). Severity and complications complications (Figure 2F) but increased the risk of systemic
of AP were determined according to the revised Atlanta complications [OR: 1.99 (CI: 1.30–3.05)], and respiratory [OR:
classification (Banks et al., 2013). OB was determined if BMI 2.15 (CI: 1.26–3.65)] and renal [OR: 4.56 (CI: 2.23–9.32)] failure
was ≥30 kg/m2 (Jensen et al., 2014). HT was determined if in AP. Obese patients spent a longer time in the hospital (12.1 vs.
blood pressure was ≥140/90 mmHg or if the patient was on 10.4 days, p = 0.008) (Figure 2G).
anti-hypertensive medication. HL was defined by the presence
of either hypercholesterolemia or a low level of HDL or HTG. Independent effect
The condition was regarded as HL when fasting cholesterol level Logistic regression revealed that OB was an independent
>200 mg/dL (5.2 mmol/L), HDL < 44 mg/dL (1.15 mmol/L; predictive factor for renal failure [OR: 2.98 (CI: 1.33–
female) or <35 mg/dL (0.9 mmol/L; male), triglyceride level 6.66)] (Table 2).
exceeded 150 mg/dL (1.7 mmol/L), or the patient was receiving
Hypertension (Figure 2)
drug therapy for HL. The diagnosis of DM was made in
Patients with HT were 17.6 years older on average (63.8 ± 14.1 vs.
accordance with the American Diabetes Association Criteria
46.2 ± 15.2, p < 0.001). Male gender was associated with a lower
(American Diabetes Association, 2010) or if the patient was
risk of HT [OR: 0.66 (CI: 0.52–0.84)].
receiving drug therapy for hyperglycemia.
Hypertension increased the risks of severe AP [OR: 2.39 (CI:
The primary endpoints were mortality, severity, and
1.30–4.38)], systemic complications [OR: 2.83 (CI: 1.64–4.88)],
complications of AP and LOS.
and respiratory [OR: 3.14 (CI: 1.51–6.52)], heart [OR: 3.82 (CI:
Statistical Analyses 1.11–13.11)], and renal failure [OR: 6.40 (CI: 1.93–21.17)]. HT
was also associated with longer hospitalization (11.8 vs. 10.5 days,
Case numbers and percentages were calculated for categorical
p = 0.020) (Figure 3E).
variables, mean with SD, and medians with 25 and 75% quartiles
(Q1 and Q3, respectively) and ranges were computed for Independent effect
numerical variables in descriptive analysis. Logistic regression revealed that HT was a predictive factor for
The t-test was used for normally distributed data and the severity [OR: 3.41 (CI: 1.39–8.37)], systemic complications [OR:
Mann–Whitney U-test for non-normally distributed data to 2.64 (CI: 1.27–5.51)], and renal failure [OR: 7.46 (CI: 1.61–34.49)]
compare two groups of independent samples. The relation as well (Table 2).
between categorical variables was inspected by the Chi-square test
and Z-test with the Bonferroni correction and ORs with 95% CIs. Hyperlipidemia (Figure 3)
Logistic regression was used to define the independent effect Contrary to OB and HT, HL was associated with younger age
of the MetS factors and age. A two-sided p-value of <0.05 was (54.0 ± 14.5 vs. 56.4 ± 17.8, p = 0.032) and a higher rate among
regarded as statistically significant. The available-case analysis male patients [OR: 1.47 (CI: 1.12–1.92)].
was used for missing data. Statistical analyses were performed For patients with HL, the chance of having mild AP was
with SPSS 25.0 software (IBM Corporation). lower [OR: 0.64 (CI: 0.49–0.85)], but HL had no significant effect

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

TABLE 1 | Individual effect analysis.

Total cohort Obesity (n = 1257) Hypertension (n = 1127) Hyperlipidemia (n = 1036) Diabetes mellitus (n = 1257)

Non-OB OB Non-HT HT Non-HL HL Non-DM DM

n 1257 886 371 451 676 687 349 1051 206

% within groups 70.5 29.5 40.0 60.0 66.3 33.7 83.6 16.4
Age, sex, CCI
Average age 55.7 55.4 56.3 46.2 63.8∗ 56.4 54.0∗ 54.5 61.7∗
SD (average age) 17.0 17.7 15.2 15.2 14.1 17.8 14.5 17.3 13.9
Male (%) 57.1 59.3 52.0 61.9 51.8 55.6 64.8∗ 56.4 60.7
Female (%) 42.9 40.7 48.0∗ 38.1 48.2∗ 44.4 35.2 43.6 39.3
Average CCI 1.4 1.3 1.6 0.9 1.7 1.3 1.7 1.0 2.9
SD (CCI) 1.6 1.6 1.7 1.4 1.7 1.6 1.8 1.4 1.7
Etiology (%)
Biliary 37.8 33.6 47.7∗ 31.3 44.1 41.3 26.4 38.2 35.9
Alcoholic 18.5 21.1 12.1 20.2 12.4 21.4 17.2 19.0 15.5
HTG-induced 3.7 3.0 5.4 3.3 3.7 0.1 12.9∗ 2.8 8.7∗
Alcoholic + HTG-induced 1.8 1.9 1.6 1.6 1.9 0.0 6.6 1.8 1.9
Post-ERCP 2.6 3.0 1.6 3.1 2.8 2.9 0.9 2.6 2.9
Combined 8.0 7.1 10.0 11.1 7.0 7.7 7.2 7.9 8.3
Idiopathic 20.5 22.0 17.0 21.5 20.7 18.8 23.8 20.6 20.4
Other 7.1 8.1 4.6 8.0 7.4 7.7 5.2 7.2 6.3
Severity, mortality, LOS
Mild (%) 69.6 69.9 69.0 70.1 69.5 73.5 64.2∗ 69.7 68.9
Moderate (%) 25.1 26.1 22.6 26.8 23.4 22.1 29.5 24.9 25.7
Severe (%) 5.3 4.1 8.4∗ 3.1 7.1∗ 4.4 6.3 5.3 5.3
Mortality (%) 2.4 2.1 3.0 1.3 3.1 2.3 1.4 2.5 1.9
Average LOS 10.9 10.4 12.1∗ 10.5 11.8∗ 10.5 11.4 10.7 11.8
SD (LOS) 9.3 8.6 10.6 7.9 10.1 9.0 10.3 9.0 10.6
Complications (%)
Local complications 29.0 28.6 30.2 29.5 28.3 25.3 34.7∗ 29.1 28.6
Fluid collection 25.0 24.7 26.7 23.9 25.3 22.1 29.8∗ 24.9 27.2
Pseudocyst 7.6 7.8 7.3 6.9 9.3 6.0 10.6∗ 7.6 7.8
Necrosis 8.0 7.1 10.2 7.8 8.0 8.2 8.9 8.3 6.8
New onset diabetes 3.8 3.5 4.6 2.7 4.1 3.6 5.2 4.6 N/A
Systemic complications 7.6 6.0 11.3∗ 3.8 10.1∗ 6.6 9.5 7.0 10.2
Respiratory failure 4.6 3.5 7.3∗ 2.0 6.1∗ 4.5 4.9 4.1 7.3
Heart failure 1.8 1.4 3.0 0.7 2.5∗ 1.9 2.0 1.9 1.5
Renal failure 2.7 1.4 5.9∗ 0.7 4.1∗ 2.2 4.6∗ 2.8 2.4

Description of the study population. Demography, etiology, and outcome of AP. Significantly different values are marked in bold digits with an asterisk. Statistical analysis
is summarized in Supplementary Appendix S4.

on mortality. HL increased the risk of local complications [OR: ratio between the DM and non-DM groups [OR: 1.19 (CI:
1.55 (CI: 1.17–2.05)], and, within local complications, acute fluid 0.88–1.62)] (Supplementary Appendix S4). Statistical analyses
collections and pseudocyst formation were more frequent [OR: demonstrated no significant relation between DM and the
1.48 (CI: 1.11–1.99); OR: 1.81 (CI: 1.14–2.88), respectively]. HL severity, mortality, and complications of AP.
also increased the risk of renal failure [OR: 2.17 (CI: 1.06–4.43)].
Independent effect Joint Effect Analysis
Logistic regression revealed that HL was an independent A total of 906 patients in our cohort (mean age ± SD:
predictive factor for local complications [OR: 1.51 (CI: 1.10– 56.9 ± 16.7 years, males vs. females: 57.3 vs. 42.7%) were
2.07)] and for a new diagnosis of DM [OR: 2.55 (CI: 1.26– eligible for the “joint effect analysis.” 189 patients (20.9%) had
5.19)] (Table 2). no components of MetS, 294 (32.5%) had OB, 560 (61.8%)
had HT, 316 (34.9%) had HL, and 162 (17.9%) had DM. We
Diabetes Mellitus (Figure 4) formed groups of patients according to the factor combinations
Patients with DM were older (61.7 ± 13.9 vs. 54.5 ± 17.3, they had and compared the outcome parameters between the
p < 0.001), while there was no difference in the gender different factor combinations and the group of no MetS factors

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

FIGURE 1 | Individual effect analysis. OB and the outcome of AP. (A) The share of male patients was lower in the OB group [∗ OR: 0.75 (CI: 0.58–0.95)]. (B) There is
no difference in the average age between the OB and non-OB groups (p = 0.398). (C) Obese patients have more than double the risk of severe AP [∗ OR: 2.15 (CI:
1.31–3.54)]. (D) Obese patients did not have a higher risk of mortality. (E) Obese patients spent more time in the hospital (∗ p = 0.008). (F) More local complications
were observed in the OB group, although the difference was not significant. (G) Obese patients had a higher risk of systemic complications [∗ OR: 1.99 (CI:
1.30–3.05)], respiratory failure [∗ OR: 2.15 (CI: 1.26–3.65)], and renal failure [∗ OR: 4.56 (CI: 2.23–9.32)].

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

FIGURE 2 | Individual effect analysis. HT and the outcome of AP. (A) There are fewer male patients with HT [∗ OR: 0.66 (CI: 0.52–0.84)]. (B) Patients with HT are
older than patients without it (∗ p < 0.001). (C) Hypertensive patients have more than double the risk of the severe form of AP [∗ OR: 2.39 (CI: 1.30–4.38)]. (D) The
risk of mortality was not higher in the HT group. (E) Patients with HT spent more time in the hospital (∗ p = 0.020). (F) There was a higher incidence of fluid collection,
pseudocysts, and new onset diabetes, although the difference was not significant. (G) Hypertensive patients have a higher risk of systemic complications [∗ OR: 2.83
(CI: 1.64–4.88)], respiratory failure [∗ OR: 3.14 (CI: 1.51–6.52)], heart failure [∗ OR: 3.82 CI: (1.11–13.11)], and renal failure [∗ OR: 6.40 (CI: 1.93–21.17)].

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

TABLE 2A | Independent effect of components of MetS, including age, in the TABLE 2B | Logistic regression.
logistic regression.
Severity 1.01 0.99–1.03
MetS component Outcome parameter OR 95% CI Mortality 1.02 0.98–1.05

Severity 1.38 0.73–2.58 Local complications 0.99 0.98–1.00

Mortality 1.06 0.38–2.96 Fluid collection 0.99 0.98–1.00
Local complications 0.99 0.72–1.37 Pseudocyst 1.00 0.98–1.01
Fluid collection 1.05 0.75–1.48 Age Necrosis 0.99 0.97–1.00
Pseudocyst 0.85 0.50–1.44 New onset of diabetes 1.01 0.99–1.04
OB Necrosis 1.48 0.89–2.45 Systemic complication 1.01 0.99–1.03
New onset of diabetes 1.52 0.73–3.14 Respiratory failure 1.03 1.01–1.06
Systemic complication 1.35 0.79–2.30 Heart failure 1.05 1.01–1.09
Respiratory failure 1.52 0.77–3.02 Renal failure 1.00 0.97–1.03
Heart failure 2.45 0.88–6.78 Older age was demonstrated to be independently associated with respiratory and
Renal failure 2.98 1.33–6.66 heart failure in our study. Statistically significant values (ORs with CIs) are marked
in bold digits.
Severity 3.41 1.39–8.37
Mortality 4.50 0.91–22.20
Local complications 1.22 0.85–1.75 DISCUSSION
Fluid collection 1.42 0.97–2.08
Pseudocyst 1.55 0.85–2.81 Summary of Findings
HT Necrosis 1.36 0.76–2.43 Our results demonstrated in a large database of prospectively
New onset of diabetes 1.56 0.66–3.65 collected cases that the components of MetS deteriorate
Systemic complication 2.64 1.27–5.51 the outcome of AP. OB was shown to be an independent
Respiratory failure 1.59 0.63–4.00
risk factor for renal failure and was associated with a
Heart failure 1.41 0.36–5.54
longer hospital stay. HT was proved to be an independent
Renal failure 7.46 1.61–34.49
risk factor for severity of AP and increased the risk of
Severity 1.40 0.73–2.67 renal failure, while patients with HT spent a longer time
Mortality 0.61 0.19–2.00 in hospital. HL increased the risk of local complications,
Local complications 1.51 1.10–2.07 renal failure, and the new diagnosis of DM. Preexisting
Fluid collection 1.32 0.94–1.84 DM did not change the outcome of AP. Our study
Pseudocyst 1.58 0.95–2.61 demonstrated that the more components of MetS the
HL Necrosis 1.06 0.63–1.78 patients had, the higher the rate of worse outcome
New onset of diabetes 2.55 1.26–5.19 parameters was observed.
Systemic complication 1.34 0.77–2.32 The incidence of AP is increasing, and this is partly due to
Respiratory failure 0.90 0.43–1.90 the rising prevalence of OB, which stimulates gallstone formation
Heart failure 1.59 0.54–4.67 and increases HL, both causing AP (Yadav and Lowenfels, 2013;
Renal failure 1.93 0.85–4.38 Bonfrate et al., 2014). Indeed, biliary AP was more frequent in
Severity 0.48 0.20–1.16 obese patients compared to the total cohort in our study.
Mortality 0.46 0.10–2.14 To date, several cohort studies and a systematic review
Local complications 0.84 0.56–1.28 have reported that OB increases the severity, mortality, and
Fluid collection 1.02 0.67–1.56 occurrence of local and systemic complications in AP. However,
Pseudocyst 1.01 0.53–1.91 these results are conflicting on the link between OB and
DM Necrosis 0.53 0.24–1.14 outcomes in AP (Dobszai et al., 2019). The reason behind this
New onset of diabetes N/A N/A conflict may be that most of the included studies reported
Systemic complication 0.92 0.48–1.74 unadjusted analysis; therefore, it cannot be clarified whether
Respiratory failure 1.48 0.68–3.20 OB is an independent prognostic factor in AP or not (Dobszai
Heart failure 0.32 0.07–1.53 et al., 2019). In a recent individual patient data meta-analysis,
Renal failure 0.43 0.15–1.22 where confounders were adjusted, OB was independently
OB is an independent predictive factor for renal failure; HT for severity; and systemic associated with the development of organ failure and multiple
complications, renal failure, and hyperlipidemia for local complications and for organ failure in AP; however, there was no relation between
a new diagnosis of diabetes mellitus. OR, odds ratio; CI, confidence interval. OB and mortality, necrosis, and intervention (Premkumar
Statistically significant values (ORs with CIs) are marked in bold digits.
et al., 2015). These data are in agreement with our results,
where OB was demonstrated to be an independent predictive
one by one (Supplementary Appendix S5). The presence of factor for renal failure but did not modify the mortality
two, three, or four MetS factors significantly increased the rate (Table 2).
rate of worse outcome parameters by 9.5, 24.1, and 66.7%, A possible mechanism by which OB is associated with a higher
respectively (Figure 5). risk of renal failure is lipotoxicity.

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

FIGURE 3 | Individual effect analysis. HL and the outcome of AP. (A) There are more male patients with HL [∗ OR: 1.47 (CI: 1.12–1.92)]. (B) Patients with HL are
younger than patients without it (∗ p < 0.001). (C) Hyperlipidemic patients have a lower chance of having mild AP [∗ OR: 0.65 (CI: 0.49–0.85)]. (D) Patients with HL
did not have a higher risk of mortality. (E) Patients with HL spent more time in the hospital (∗ p = 0.053). (F) HL increases the risk of local complications [∗ OR: 1.55
(CI: 1.17–2.05)], acute fluid collection [∗ OR 1.48 (CI: 1.11–1.99)], and pseudocysts [∗ OR 1.81 (CI: 1.14–2.88)]. (G) Hyperlipidemic patients have a higher risk of renal
failure [∗ OR 2.17 (CI: 1.51–4.43)].

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

FIGURE 4 | Individual effect analysis. DM and the outcome of AP. (A) There is no significant difference in sex between the two groups. (B) Patients with diabetes are
older than patients without it (∗ p < 0.001). (C,D) Diabetic patients did not have a higher risk of moderately severe or severe AP or mortality in our cohort. (E) There is
no difference in LOS between the two groups (p = 0.139). (F,G) As regards local or systemic complications, there are no differences between diabetic and
non-diabetic patients in our cohort.

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

FIGURE 5 | Joint effect analysis. The effect of MetS factor combinations on the outcome of AP. The more MetS factors are present, the more significantly higher
incidence of the different outcome parameters can be observed. Statistical analysis is summarized in Supplementary Appendix S5.

Obesity is associated with elevated levels of intrapancreatic fat and microvascular and macrovascular structural changes in the
and with elevated visceral fat surrounding the pancreas (Smeets arteries may be responsible for the deteriorative effects of HT
et al., 2019). This hypothesis is also supported by experimental (Smits and van Geenen, 2011).
data. A long-term high-fat diet caused acinar cell injury and Preexisting HL was shown to be independently associated
pancreatic fibrosis via fat accumulation in pancreatic acinar with local complications and renal failure in our study. Our
cells (Matsuda et al., 2014). It has also been suggested that results are in line with those of a recent meta-analysis, which
intrapancreatic fat, which may cause metabolic and inflammatory reported that the presence of HTG significantly elevated the
processes, is associated with OB (Majumder et al., 2017). In risk of renal failure but did not increase the risk of mortality
addition, in the presence of intrapancreatic fat, pancreatic lipases in AP (Kiss et al., 2018). However, HTG also significantly
are released in AP digest adipocytes, resulting in an outflow elevated the risk of severe AP in this meta-analysis (Kiss et al.,
of unsaturated fatty acids into the circulation; they are toxic 2018), while HL did not increase the risk of severe AP in our
and can act as proinflammatory mediators and are implicated study. This discrepancy can be explained by the fact that (1)
in the development of systemic inflammation and organ failure most of the studies included in the meta-analysis reported an
(Navina et al., 2011). unadjusted analysis, and, therefore, the independent effect of
Hypertension was independently associated with the severity HTG in AP cannot be elucidated; and (2) the HL group in
of AP and the rate of renal failure in our study. To the best our study included patients with either hypercholesterinemia
of our knowledge, no study has ever analyzed the effect of and/or HTG, while patients with HTG only were included in the
arterial HT on the outcome of AP. The underlying mechanisms meta-analysis. One possible mechanism by which HL increases
by which HT deteriorates the outcome of AP is unclear. It local and systemic complications in AP is the formation and
has been suggested that the sympathetic nervous system may toxic effect of unsaturated fatty acid by pancreatic lipases. In
act as an amplifier of the blood pressure elevation and may addition, in the case of HTG, the chylomicron concentration is
be involved in the development of HT-related complications. elevated. As a result, blood viscosity increases, thus impairing
Sympathetic activation favors the development and progression blood flow and causing pancreatic ischemia and acidosis
of vascular hypertrophy and remodeling and contributes (Pedersen et al., 2016).
to impairing arterial distensibility and vascular compliance There is a special relationship between the exocrine and
(Seravalle et al., 2014). The presence of a hyperadrenergic state endocrine pancreas. Experimental data suggest that insulin has

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

a local protective effect on acinar cells during pancreatitis. Strengths and Limitations
Pancreatitis evoked by L-arginine causes severe acinar cell The main strength of the present study is that it has a large
necrosis in most of the territory of the exocrine pancreas. sample size of prospectively collected cases from hospitals in
However, acinar cells located around the islets of Langerhans multiple countries, including tertiary and non-tertiary centers.
remain totally intact (Hegyi et al., 1997). In addition, we also Furthermore, a logistic regression analysis was applied to control
confirmed that if the beta cells are destroyed by streptozotocin confounding variables, and the independent prognostic factors
treatment prior to the induction of AP, this locally visible of the components of MetS were analyzed for AP. Finally, our
protective effect disappears irrespectively of exogenous insulin study is the first to report the relation between the outcome
administration (Takacs et al., 2001). Unfortunately, in our of AP and the presence of arterial HT and to analyze the
registry analysis, we could not investigate the local effects influence of the combined presence of the components of MetS
of insulin. Here we showed that preexisting DM does not on the outcome of AP.
significantly influence severity, mortality, or rate of complications The present study has limitations. First, since APR is a
in AP in our cohort. We hypothesized that our cohort was multicenter prospective registry and not an observational trial,
not sufficiently large to determine a significant difference. our findings are affected by confounding factors or selection
We have recently published a meta-analysis in which DM bias. Second, our study design is cross-sectional, thus precluding
significantly elevated both local and systemic complications any causal interferences about the directionality of the relations
when an analysis was conducted of 354,880 cases (Miko observed in our study; therefore, long-term clinical outcomes
et al., 2018). However, it is clearly impossible to collect this could not be evaluated. Accordingly, long-term prospective
number of patients in a single cohort. Furthermore, intensive trials are needed in the future. Third, our study assessed the
care unit mortality only grew significantly with higher mean effect of HL, not HTG, thus not fully suiting the definition
blood glucose concentration in non-DM patients but not in of MetS. Fourth, peripancreatic fluid accumulations could not
DM patients (Egi et al., 2008; Pedersen et al., 2016). In always be adequately defined according to the modified Atlanta
agreement with our results, critically ill patients with DM classification. Acute fluid collection and acute necrotic fluid
did not have higher mortality compared to non-DM patients collection, pseudocysts, and walled-off pancreatic necrosis could
(Whitcomb et al., 2005). not always be differentiated because abdominal CT was not
Older age was demonstrated to be independently associated performed in all cases. Therefore, peripancreatic fluid collections
with pulmonary and heart failure in our study (Table 2B). Older without a definitive wall were named as acute fluid collections and
age has been investigated extensively as a marker of severity with a wall as pseudocysts.
and mortality in AP and is included in the APACHE II score,
Ranson score, Bedside Index of Severity in AP (BISAP) score,
and Japanese Severity Score (JSS) as a marker of severity (Graham CONCLUSION
et al., 2010). However, after adjusting for comorbid disease, only
the very extreme age (>85 years old) was associated with 30- In conclusion, the components of MetS deteriorate the outcome
day in-patient mortality and persistent organ failure in a recent of AP. OB, HT, and HL are independent risk factors for a number
prospective, multicenter study (Mounzer et al., 2012). Our results of complications. HT is an independent risk factor for severity as
are in line with a recent cohort analysis that found that elderly well. The more elements of MetS are present, the higher the risk
patients had a significantly higher risk of developing systemic for complications. It is important to search for and follow up on
complications, while high mortality in this group is due to the the components of MetS in AP.
effect of severe comorbidities (Szakacs et al., 2018).
Patients with AP often develop diabetes during and after the
attack of AP (Moran et al., 2018); however, the risk of DM DATA AVAILABILITY
was not fully evaluated. The severity of AP, its etiology, and
individuals’ age and sex had a minimal effect on the development All datasets generated for this study are included in the
of newly diagnosed diabetes in AP (Moran et al., 2018). We manuscript and/or the Supplementary Files.
showed that HL is an independent risk factor for the development
of newly diagnosed DM in AP. High cholesterol and triglyceride
ETHICS STATEMENT
levels increase the risk of DM, a finding supported by earlier
studies (von Eckardstein and Sibler, 2011; Das et al., 2014). The study protocol was approved by the Scientific and Research
We can hypothesize that the predisposition to DM caused by Ethics Committee of the Medical Research Council (22254-
dyslipidemia was manifested during AP. This finding emphasizes 1/2012/EKU). All patients provided written informed consent to
the need for a thorough screening for DM in AP patients with HL. participate in the study.
Moreover, all AP patients should be followed and screened for
DM as hyperglycemia stimulates the proliferation of pancreatic
stellate cells and collagen secretion, while hypoinsulinemia AUTHOR CONTRIBUTIONS
inhibits acinar cell growth and synthesis of pancreatic enzymes
and therefore facilitates fibrosis of the pancreas and might cause AS, AP, and PH contributed to the design of the research. AP, ÁV,
chronic pancreatitis (Czako et al., 2009). JB, SG, PS, FI, AH, IT, HF, MP, MV, JH, JN, AM, EM, VS, LC,

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Szentesi et al. Metabolic Syndrome and Acute Pancreatitis

and TT collected the data. AP, KM, DD, DI, and BK assessed the of Szeged (Szeged), the Department of Emergency,
data quality. NG and AS processed the data and conducted the University of Szeged (Szeged, Hungary), the Department
analysis. AS and PH designed the figures. AS, LC, and BE drafted of Surgery, University of Szeged (Szeged, Hungary),
the manuscript. PH supervised and coordinated the work. All the the Department of Gastroenterology, Dr. Bugyi István
authors discussed the results and commented on the manuscript. Hospital (Szentes, Hungary), the Markusovszky University
Teaching Hospital (Szombathely, Hungary), the Hospital of
Bezmialem Vakif University, School of Medicine (Istanbul,
FUNDING Turkey), the Saint Luke Clinical Hospital (St. Petersburg,
Russia), the Department of Gastroenterology, Vítkovická
The study was funded by the Project Grants (KH125678 Nemocnice (Ostrava-Vítkovice, Czechia), the Gomel Regional
and K116634 to PH, K120335 to TT, and K128222 to LC); Clinical Hospital (Gomel, Belarus), the Pauls Stradins
the Economic Development and Innovation Operational Clinical University Hospital (Riga, Latvia), the Bogomolets
Programme Grant (GINOP 2.3.2-15-2016-00048 to PH); the National Medical University (Kiev, Ukraine), and the Keio
Human Resources Development Operational Programme University (Tokyo, Japan).
Grant (EFOP-3.6.2-16-2017-00006 to PH) from the National
Research, Development and Innovation Office; and a Momentum
Grant from the Hungarian Academy of Sciences (LP2014-
SUPPLEMENTARY MATERIAL
10/2014 to PH).
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fphys.
ACKNOWLEDGMENTS
2019.01202/full#supplementary-material
We would like to thank the contributing investigators
APPENDIX S1 | Center distribution.
not meeting the authorship policy. These centers are the
Joint Saint Istvan and Saint Laszlo Hospitals (Budapest, APPENDIX S2 | Demography and representativeness of study populations.
Hungary), the Institute of Surgery, University of Debrecen APPENDIX S3 | Data quality.
(Debrecen, Hungary), the Bács-Kiskun County Hospital
APPENDIX S4 | Statistics of individual effect analysis.
(Kecskemét, Hungary), the Healthcare Center of County
Csongrád (Makó, Hungary), the Borsod-Abaúj-Zemplén APPENDIX S5 | Joint effect analysis. (A) Description of demography and
incidences of the different outcomes. (B) Statistics.
County Hospital and University Teaching Hospital (Miskolc,
Hungary), the Second Department of Medicine, University APPENDIX S6 | Database of the analysis.

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Parniczky, A., Mosztbacher, D., Zsoldos, F., Toth, A., Lasztity, N., Hegyi, P., et al.
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clinical relevance of obesity in acute pancreatitis: targeted systematic reviews. practice. No use, distribution or reproduction is permitted which does not comply
Pancreatology 15, 25–33. doi: 10.1016/j.pan.2014.10.007 with these terms.

Frontiers in Physiology | www.frontiersin.org 13 September 2019 | Volume 10 | Article 1202