Intensive Care Med (2021) 47:97–100

https://doi.org/10.1007/s00134-020-06271-4

LESS IS MORE IN INTENSIVE CARE

Biomarkers in the ICU: less is more? No

Antoni Torres1,2*  , Antoni Artigas3 and Ricard Ferrer4,5*

© 2020 Springer-Verlag GmbH Germany, part of Springer Nature

In recent years, the use of biomarkers in the ICU has membranes can remove PCT, which can lead to falsely
increased exponentially. Only a few of them are used low measurements (Figure 1). Taking into account all the
in clinical practice. However, as any measurement that considerations mentioned above, both PCT measure-
helps to make clinical decisions, these biomarkers have ments and clinical judgment have to be included in the
detractors and defenders. Due to space constrictions, initial management of CAP, including severe CAP [2].
we decided to give arguments in favor of using biomark- The second indication of PCT is the duration of antibi-
ers only in two frequent medical conditions with high otic treatment. In the ProCAP study, serial measure-
morbidity and mortality in ICU, such as pneumonia and ments of PCT were used to guide treatment duration,
sepsis. which was 55% shorter with PCT guidance than in the
control group, although the duration in the control group
Pneumonia was longer than current standards (12 days vs. 5 days for
Most of the information about biomarkers in pneumo- the PCT group). A study of 1359 Emergency Department
nia comes from procalcitonin (PCT), which is the most patients (68% with CAP) from six hospitals showed that
frequent biomarker currently used in clinical practice. PCT guidance reduced antibiotic treatment duration,
PCT is an acute-phase reactant primarily produced by use, and side effects compared to standard care [3]. Fur-
the liver in response to bacterial infections. Cytokines thermore, a patient-level meta-analysis of 2910 patients
associated with viral infections attenuate PCT induction, showed that PCT guidance reduced antibiotic treatment
but some elevation in its expression can occur in atypical duration to 5.7 days from 6.2 days in controls (p < 0.0001)
pathogen pneumonia. Thus, patients with lower respira- [4]. In another randomized study of 1546 ICU patients,
tory tract infections, including those with lung infiltrates, PCT guidance reduced the duration of antibiotic treat-
can often have antibiotics safely withheld when PCT lev- ment and increased the number of antibiotic-free days
els are low, provided that clinical judgment supplements compared to control, although the number of CAP
biomarker measurements. patients was not specified [5].
PCT levels may vary during illness, with higher lev- Blood C reactive protein (CRP) is another acute-phase
els in patients presenting within 3  days from symptoms reactant produced by the liver that shows a good corre-
onset [1]. In documented influenza cases, PCT levels do lation with interleukin [6]. It is more influenced by anti-
not have a sufficient positive predictive value to indicate a biotic treatment and corticosteroids than PCT. Although
bacterial coinfection; however, they have a high negative it is very inexpensive, its lack of specificity precludes its
predictive value and could help rule out bacterial coin- use for withholding antibiotics or shorten the antibiotic
fections. PCT measurements may be inaccurate in renal duration. However, it has been successfully used to strat-
failure, which can falsely elevate PCT levels by inter- ify patients in randomized clinical trials to search for an
fering with their elimination. Moreover, some dialysis inflammatory phenotype [6].
The diagnosis of ventilator-associated pneumonia
(VAP) and the duration of antibiotic treatment are two
*Correspondence: [email protected]; [email protected]
1
Department of Pulmonology, Respiratory Institute, Hospital Clinic
important clinical challenges in which biomarkers can
of Barcelona, Barcelona, Spain be useful. As in CAP, PCT is the best-studied biomarker
4
Intensive Care Department, Vall D’Hebron University Hospital, Barcelona, in VAP. The lack of utility of PCT measurements in VAP
Spain
Full author information is available at the end of the article
diagnosis has been well proven in several observational
studies. The main reason for explaining these findings is
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Fig. 1  Utility of biomarkers in community-acquired, ventilator-associated pneumonia and sepsis

that other non-infectious diseases or infections outside were elevated three days before VAP, but its predictive
the lung can increase PCT values in patients on mechani- level was moderate [10].
cal ventilation. The recent ERS/ESICM/ESCMID/ALAT In summary, biomarkers are not useful for diagnosis in
[7] guidelines do not recommend the use of biomarkers VAP, and they cannot replace clinical and microbiological
for the diagnosis of VAP. However, they do suggest that evaluation. However, PCT measurements using predeter-
PCT can be useful to guide treatment duration or pro- mined algorithms are helpful in guiding the duration of
long it in several circumstances, such as inappropriate antibiotic treatment, decreasing or prolonging treatment
antibiotic treatments, infections caused by multidrug- in particular circumstances.
resistant/extensively drug-resistant microorganisms, or
when using second-line antibiotics such as colistin and Sepsis
tigecycline. CRP is not used to diagnose or guide anti- Procalcitonin (PCT) is the most studied biomarker in
biotic treatments in VAP due to its low specificity. Some sepsis, with a cut-off value of 1.1 ng/ml [sensitivity of 77%
groups have found an excellent prediction of evolution and specificity of 79%; area under the receiver operating
when measuring the delta variations of CRP over time characteristic curve of 0.85 (95% CI 0·81–0·88)] used for
[8]. The BioVAP is a multicenter study that investigated diagnosis of sepsis, depending on pre-test probability
the kinetics of biomarkers to predict VAP, and found that [11]. A single measurement of PCT for early diagnosis is
CRP and CRP slopes over time were good indicators of clinically useful when sepsis-3 criteria are used [12, 13].
VAP occurrence. This finding was not shown with PCT The combination of using sepsis biomarkers and clinical
and Pro adrenomedullin (Pro-ADM) [9]. Finally, the sol- variables, known as ‘bioscores’, improves early detection
uble urokinase plasminogen receptor (SUPAR) was also [14].
investigated in the same cohort. Plasma SUPAR levels
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An initial measurement of PCT should be obtained Compliance with ethical standards

at the time of diagnosis, as well as serial measurements Conflicts of interest
to aid antimicrobial stewardship algorithms. This can RF has received personal fees from MSD, Pfizer, Gilead, Toray, Jafron and
lead to improved diagnostic interventions, therapeutic Thermofisher.
approaches, and patient outcomes. PCT-guided therapy
should be implemented with caution in patients with Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
immunosuppression, cystic fibrosis, pancreatitis, trauma, lished maps and institutional affiliations.
pregnancy, high volume transfusion, renal dysfunction,
and malaria [15]. Accepted: 30 September 2020
Published online: 15 October 2020
A drop to levels < 0.5 ng/ml or by at least 80–90% of the
peak in combination with clinical improvement can be
used to support the clinical decision to reduce antimicro-
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