Appendicitis Clinical Trial
Official title:
Explanations for Negative Laparoscopic Appendectomies and Normal Laparoscopies. What Does the Patient Suffer From When the Appendix Proves to be Healthy?
Trial The aim of the study is to investigate which infectious diseases might mimic the
symptoms of acute appendicitis to a degree to cause a diagnostic laparoscopy or laparoscopic
appendectomy. The primary outcome is to compare the incidence of Yersinia spp. infection in
patients, who undergo surgery due to suspected appendicitis, between those with and without
appendicitis detected by polymerase chain reaction on rectal swabs. The secondary outcomes
are comparison of the incidence of bacterial pathogens (Campylobacter spp., Salmonella spp.,
Shigella spp., Aeromonas spp.) and Enterobius vermicularis in the two groups. Rectal swabs,
appendix swabs, and blood samples are collected prospectively and research biobanks will be
established. Initially, the rectal samples and serology samples will be investigated, and
possible biomarkers and results of the appendix swabs will be evaluated at a later time
point.
Ethics The trial will be conducted according to the Helsinki II Declaration after approval
from both the local Health Research Ethics Committee and the Danish Data Protection Agency.
An informed written consent will be collected from the participants prior to inclusion in the
study. Data will be stored according to the approval from the Danish Data Protection Agency.
This study is conducted in patients with suspected appendicitis. These patients are fully
awake and conscious at time of inclusion. The patients included in this study will not
experience any adverse effects due to their participation.
Aim The aim of the study is to investigate which infectious diseases might mimic the symptoms
of acute appendicitis to a degree that cause a diagnostic laparoscopy or laparoscopic
appendectomy.
Primary outcome A comparison of the incidence of Yersinia spp. (enterocolitica and/or
pseudotuberculosis) infection diagnosed by PCR on rectal swabs in the two groups: patients
with histopathological confirmed inflammation (appendicitis group) and patients with one of
the following: a histopathological normal appendix without inflammation, mesenteric
lymphadenitis, or a normal diagnostic laparoscopy (normal appendix group).
Secondary outcomes A comparison of the incidence of other microbes: Campylobacter spp.,
Salmonella spp., Shigella spp., and Aeromonas spp. found by PCR of rectal swabs in the two
groups: normal appendix versus appendicitis group.
Patients positive for Yersinia spp. will be evaluated individually in subgroups of the two
groups: appendicitis group and normal appendix group. Serological investigation for Yersinia
will be conducted if funding is achieved.
A comparison of the incidence of Enterobius vermicularis found in the histopathological
examination in the two groups.
Design A prospective, observational cohort study. Trial participants Inclusion criteria
- ≥18 years old
- Suspicion of acute appendicitis and planned for diagnostic laparoscopy
- Written informed consent after written and verbal information Exclusion criteria
- Cannot understand, read or speak Danish
- Known with inflammatory bowel disease
- Other intra-abdominal pathology than appendicitis requiring other surgical intervention
or treatment (diagnosed either perioperatively, at a preoperative CT-scan, or shortly
after the surgery in the histopathological examination)
- Not undergoing diagnostic laparoscopy, laparoscopic appendectomy, or open appendectomy
- Use of antimicrobial agents within two weeks prior to inclusion until actual admission
for acute abdominal pain
Trial course Patients are admitted to the Department of Surgery, Herlev Hospital, with
suspected acute appendicitis. A surgeon from the department will either plan for an acute
surgery or keep patients for further observation. The investigators of the trial or research
assistants will approach these patients to give information about the study. Thereby, the
investigators ensure the patient has as much time as possible for consideration in this acute
setting. Patients, who fulfill the inclusion criteria and none of the exclusion criteria
(apart from those criteria that can only be clarified at or after surgery), are included in
the trial after informed consent. Baseline characteristics of the enrolled patients including
their medical history, travel history and gastrointestinal symptoms will be registered in the
electronic case report forms (eCRF) in RedCAP. Blood samples and a rectal swab are collected
before surgery. A note of the patient's inclusion in the trial will be added to the patient's
medical record. Included patients will undergo a diagnostic laparoscopy performed according
to standard clinical practice. If the appendix is removed during surgery, a swab from the
removed appendix will be collected postoperatively. The appendix swab will only be collected
if the appearance of the removed appendix is not suspicious for malignant disease
(SOP_Appendixpodning). This is in agreement with the Department of Pathology, Herlev
Hospital, not to compromise the histopathological examination and to prevent spread of
malignant cells in the rare case of an appendix tumor. If there is any doubt regarding the
appearance of the appendix no swab will be collected. A follow-up of the patient's medical
record with regard to the pathology report will be conducted ten days after surgery. These
results are noted in the patient's eCRF.
Withdrawal and drop-out criteria The participants can withdraw their consent at any point
during the trial. The collected blood samples, rectal swab and possible appendix swab will be
destroyed if a participant withdraws consent. A participant has concluded the trial ten days
after surgery when both the final record of the surgery and pathology report is available.
Patients, who during or shortly after surgery fulfill any exclusion criterion regarding other
intra-abdominal pathology, conditions requiring other treatment, or do not undergo the
planned surgery, will drop out of the study and will thus be excluded from the study and the
collected blood sample, rectal swab, and possible appendix swab will be destroyed. A
participant has concluded the study when the 10-day postoperative follow-up has been
conducted.
Primary outcome
The primary outcome will be based on the cumulative results from both methods:
• Detection of infection with Yersinia spp. (enterocolitica and/or pseudotuberculosis) by
microbiological investigation of rectal swab: Specimens (rectal swab) collected prior to
surgery are immediately frozen at -80°C and stored at Herlev Hospital in a research biobank.
When the last patient has concluded the trial, a fraction of the collected specimens from
each patient is sent to the Department of Clinical Microbiology, Hvidovre Hospital and
thereafter investigated with a real time PCR for Yersinia spp. These results are noted in the
patient's eCRF, but not in the patient's medical record. Samples with a positive PCR result
will be cultured for Yersinia spp. and in case of positive culture results, susceptibility
testing will be performed (secondary outcome). Hereafter, the collected human material and
the cultured Yersinia enterocolitica will be frozen at -80°C and stored for ten years at
Hvidovre Hospital as a biobank for future research.
Secondary outcomes
- Serology of Yersinia enterocolitica: This outcome will be reported on in the planned
publication if sufficient funding is achieved, otherwise, it will be presented in a
later publication. Six ml of blood collected prior to surgery are immediately frozen at
-80°C and stored at Herlev Hospital in a research biobank. When the last patient has
concluded the trial, the blood sample for serology from each patient is sent to Statens
Serum Institut. Here, the blood samples are investigated a soon as possible after
arrival with an in-house ELISA test for Yersinia enterocolitica IgM, IgA, and IgG. After
the analysis, the serum samples will be frozen at -80°C and stored for ten years at
Statens Serum Institut as a biobank for future research. Thereafter, the samples will be
anonymized and transferred to the biobank for future research belonging to Statens Serum
Institut.
- Detection of other bacterial pathogens: The specimens (rectal swab) collected prior to
surgery are immediately frozen at -80°C and stored at Herlev Hospital in a research
biobank. When the last patient has concluded the trial, a fraction of the collected
specimens from each patient is sent to the Department of Clinical Microbiology, Hvidovre
Hospital and thereafter investigated with a multiplex real time PCR for:
- Campylobacter spp.
- Salmonella spp.
- Shigella spp.
- Aeromonas spp. Samples with positive PCR results for bacterial pathogens will be
cultured (including Yersinia spp.) and in case of positive culture, susceptibility
testing will be performed. Hereafter, the collected human material and the cultured
bacteria will be frozen at -80°C and stored for ten years at that site as a
research biobank, hereafter samples are anonymized.
- Combined outcome of serology and PCR for Yersinia spp.: See description above. This
outcome will only be reported if funding is achieved.
- Plasma and full blood are kept for later analysis. 12 ml of blood will be collected per
patient: 6 ml will be used to make EDTA-plasma samples and buffycoat and 6 ml will be
stored as serum samples. A research biobank will be established for the collected
samples, which will be frozen and stored at -80°C for ten years. Thereafter the plasma
and full blood samples are destroyed. The local Health Research Ethics Committee
(Capital region of Denmark) will be contacted regarding the use of this research biobank
before further investigations are initiated. The participants will be asked for consent
specifically regarding the biological material for the biobank for future research.
- The remaining fractions of specimens from the rectal swabs and specimens from the
appendix swabs are stored for later analysis. A research biobank will be established for
the collected samples at Herlev Hospital, which will be frozen and stored at -80°C for
ten years. Thereafter the specimens are destroyed. The local Health Research Ethics
Committee (Capital region of Denmark) will be contacted regarding the use of the
research biobank before further investigations are initiated. The participants will be
asked for consent specifically regarding the biological material for the biobank for
future research.
Statistics Continuous numerical data will be reported as mean and standard deviation if
normally distributed. If not normally distributed, continuous numerical data will be reported
as median and percentiles. The investigators will analyze data with both parametric and
non-parametric statistics depending on the distribution of the data. A p-value <0.05 is
considered significant.
The power calculation is as follows. The rate of Yersinia spp. in the appendicitis group is
expected to be 13%. The sizes of the groups are expected to be unequal. Approximately 80% of
the included patients will be in the appendicitis group and 20% will be in the normal
appendix group.
When alfa is set at 0.05, beta is set at 0.80, and the least interesting difference between
the groups is set at 20%, a total of 225 patients are required: 45 patients in the normal
appendix group and 180 patients in the appendicitis group.
;
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