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Tobias Breidthardt, et al. Inflammatory Biomarkers and Clinical Judgment in the Emergency Diagnosis of Urgent Abdominal Pain. Clin Chem 2019;65:302-312.
Dr. Tobias Breidthardt is a senior consultant and clinical researcher at the Division of Internal Medicine at the University Hospital Basel in Switzerland.
This is a podcast from Clinical Chemistry, sponsored by the Department of Laboratory Medicine at Boston Children’s Hospital. I am Bob Barrett.
Acute abdominal pain is one of the most common presenting symptoms in emergency department patients and its differential diagnosis can be extensive and challenging. Rapid and accurate diagnosis of urgent causes of abdominal pain is essential for the early initiation of effective therapy and efficient patient flow.
To see how the clinical laboratory can help in this process, a recent study that appeared in the February 2019 issue of Clinical Chemistry examined inflammatory biomarkers in the emergency diagnosis of urgent abdominal pain. Dr. Tobias Breidthardt is a senior consultant and clinical researcher at the Division of Internal Medicine at the University Hospital Basel in Switzerland and was the lead author of that paper. He is our guest in this podcast.
So, Dr. Breidthardt, why did your research focus on patients with acute abdominal pain? That’s not really a very common research topic.
Actually, over the last two years, emergency physicians worldwide have recognized acute abdominal pain as a growing problem. In the U.S., for example, the Center for Disease Control points out that about 7 million emergency department visits per year are due to acute abdominal pain, and this makes it the most common reason for Americans to visit the emergency department. This number is still increasing and between 2006 and 2011, for example, visits for acute abdominal pain increased by 20%.
So, acute abdominal pain is very common. And on top of this, it can be caused by urgent acutely life-threatening conditions such as, for example, a perforated viscus, but this is also because of harmless but painful conditions such as intestinal cramps or menstrual pain. Differentiating these urgent from non-urgent causes of abdominal pain is very difficult and it is time consuming and is therefore very expensive to our healthcare systems.
In our study, for example, we found patients with acute abdominal pain to be treated in emergency departments for about, on average, five and a half hours. And then, 50% of these patients were subsequently admitted to hospital, but only a third of all patients in our study eventually suffered from an urgent cause of abdominal pain.
So, we believe that a tool to quickly and adequately differentiate those potentially life threatening and urgent causes of abdominal pain from non-urgent causes of abdominal pain would be very helpful for clinicians in the emergency departments. It would help initiate effective therapy in those patients who need it. It would allow an efficient patient flow through the emergency department and it would allow to increase patient satisfaction.
So, we believe that the provision of care for patients with acute abdominal pain can still be improved and that’s why we focused on this special case of patients.
Your study shows that interleukin-6 significantly improves the early diagnosis of urgent causes of acute abdominal pain in the emergency department. Can you tell us just a bit about interleukin-6, and why did you specifically study this biomarker?
The two reasons for us to investigate interleukin-6, the first reason is simple biochemistry. So, the release mechanism of interleukin-6. Interleukin-6 is a small protein and it is released from various immune and non-immune cells in response to tissue injury, to inflammation, to infections. That primary mode of action is the mediation of the acute phase response, which is the body’s first line of untargeted defense, as characterized by fever, leukocytosis, but also the release of acute-phase proteins, such as, for example, C-reactive protein or CRP.
CRP is the most commonly used parameter in clinical practice to judge the severity, but also the presence, of inflammation and infection, and clinicians often base treatment decisions on CRP concentrations. However, the release of CRP depends on an interleukin-6 stimulus and therefore, there’s a time delay of about 12 to 24 hours between the initial interleukin-6 response and the increase in CRP. And this delayed response led us to specifically investigate interleukin-6.In our study, the interleukin-6 was significantly superior in detecting urgent causes of abdominal pain compared to CRP, which was an open-label blood parameter in our study.
The second reason to investigate interleukin-6 is a series of
small pilot study observations, which suggested that
interleukin-6 could be a disease severity parameter with
higher levels being associated with the need for surgery in
patients with suspected appendicitis, but also with higher
levels being associated with the degree of tissue injury and
even mortality in trauma patients.
So, the release mechanism of interleukin-6 and the earlier
release compared to C-reactive protein, and previous pilot
study of results, are the reasons why we specifically
Doctor, your study was, of course, was a blinded diagnostic
study, meaning, physicians treating the patients in your
study were not aware of the interleukin-6 values. How do
you suggest that physicians use interleukin-6 values in
patients with acute abdominal pain?
I think this is a very important question. And one, our key
finding was that interleukin-6 was not a standalone test, but
provided incremental diagnostic value on top of all other
clinical information. Meaning, low interleukin-6 levels
helped clinicians on top of all the other information they had
already gathered for that patient to adequately and quickly
rule out urgent abdominal pain, to identify patients without
urgent abdominal pain.On the other side, very high levels helped to identify
patients with urgent abdominal pain, again, on top of all
other clinical information. So, interleukin-6 can be an
important additional tool on top of our clinical knowledge.
To best integrate this into clinical practice, we derived a
treatment algorithm putting patients either in a rule out
category, which has a very low risk of urgent abdominal
pain and sensitivity of 97% to rule out urgent abdominal
pain. This was 20% of all patients in our study.
And on the other side, a rule in category with very high-risk
patients, again, a specificity of 93% of patients having
actually urgent abdominal pain. So, the clinical
consequences of these two strategies would be patients
ruled out to have a very low probability of urgent abdominal
pain and these patients you could consider early discharge
from the emergency department and early outpatient
On the other side, due to very high specificity of the
combined algorithm for urgent abdominal pain, patients in
the high-risk group should probably have a quick abdominal
CT scan performed and also quickly be seen by a surgeon.
These will be the consequences in how we would advocate
to use interleukin-6 on top of our clinical knowledge.
What do you see as the benefit of using the combined triage
algorithm in clinical practice?
To best answer this, we probably need to look at the two
other major symptoms that lead to emergency department
presentations worldwide. This is acute dyspnea and acute
chest pain. In both of these settings biomarkers, namely
nitrite and peptides for acute dyspnea and high-sensitive
troponin for acute chest pain, have significantly increased
the diagnostic accuracy over the clinical judgment alone. So
very similar to the setting we are currently describing for
interleukin-6 and acute abdominal pain.
And in both of these situations, acute chest pain and acute
dyspnea, biomarkers have shown to adequately decrease
the time to therapy, to decrease the need for further
diagnostic work up, to decrease the time in the emergency
department, and to decrease treatment cost.
So, these biomarkers in chest pain and dyspnea are quietly
used in clinical practice, and are supported by Class I
recommendations throughout the world and clinical practice
Our study, as you said, was not an intervention-designed
study, but a diagnostic study. So, we cannot comment on
the economic impact of our management strategy, but we
find it highly likely that interleukin-6 will also reduce the
time to discharge and reduce treatment costs in the
Well, finally, Dr. Breidthardt, let’s look ahead. What are the
next steps of your investigation?
Going back to what I just said, we cannot comment on the
economic impact of interleukin-6 yet. So, I think there are
two next steps. The first one clearly has to be the clinical
implementation of our combined triage algorithm into
clinical practice. But at the same time, we need to prove
this economic impact of the strategy on our patient
treatment. We’re currently looking at two possible study
So, the first will be a patient-level randomized trial,
comparing patients treated either according to this
combined treatment algorithm using interleukin-6 and
clinical judgment, versus patients treated just according to
clinical judgment. They are randomized patient by patient
into one of these two treatment algorithms.
And the second possible trial will be a cluster-randomized
trial, basically before and after trial, in which you compare
all patients before a certain date that were treated
according to clinical standards compared to all patients
treated afterwards, after you have initiated this clinical
standard into practice. So, you compare before and
We are looking at both of these possibilities and we will use
one of the mechanisms to show the economic impact of
interleukin-6 on our patients.
That was Dr. Tobias Breidthardt from the Division of Internal
Medicine at the University Hospital Basel in Switzerland. He
has been our guest in this podcast about inflammatory
biomarkers in the diagnosis of abdominal pain. That article
appears in the February 2019 issue of Clinical Chemistry.
I’m Bob Barrett, thanks for listening!