Introduction
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or help clinicians to prognosticate patient risk. In daily bedside practice, for the diagnosis and management of sepsis as well as for antibiotic stewardship, clinicians combine data from different sources. Biomarkers could provide additional information in the vector systemic manifestations (host-response biomarkers e.g., C-reactive protein–CRP, and procalcitonin– PCT), organ dysfunction (e.g., kidney injury biomarkers) and microbiological documentation. Biomarkers have been studied in the context of prediction of sepsis, diagnosis of sepsis, assessment of sepsis response to therapy and biomarker-guided antibiotic therapy [9] (for examples of clinical scenarios of sepsis with biomarker use see—ESM). In addition, biomarkers of sepsis can be divided into prognostic, predictive and theranostic, i.e., to guide choice, dose, and duration of therapy. The aim of this review is to inform clinicians about biomarkers of infection or sepsis and guidance as to their use, namely pathogen-specific biomarkers, and two host-response biomarkers, PCT and CRP. Serial determinations are more informative than a single value. Biomarkers should never be used as a stand-alone test, but always in conjunction with a thorough clinical evaluation and comprehensive knowledge of the biomarkers’ biology, interferences, strengths, and limitations.
Pathogen-specific biomarkers
Most rapid antigen-based tests are based on immunochromatographic assays and have the potential for bedside use. Influenza and SARS-CoV-2 respiratory antigen tests, and Streptococcus pneumoniae and Legionella spp. urinary antigen tests are used in community-acquired pneumonia. Clostridioides difficile infection (CDI) can be diagnosed using a two-step algorithm with rapid enzyme immunoassays to test stool samples for both glutamate dehydrogenase (GDH) and free toxins A and B. Fungal antigen assays target structural polysaccharides derived from fungal cell walls. (1,3)-β-D-glucan (BDG) is a panfungal serum biomarker commonly used to detect invasive candidiasis. BDG has a high negative predictive value for the diagnosis of Pneumocystis jirovecii pneumonia in non-HIV patients. Galactomannan (GM) can be measured in serum and broncho-alveolar lavage samples for diagnosis of invasive pulmonary aspergillosis (IPA).
Host-response biomarkers
In the following section, we discuss two host-response biomarkers, PCT and CRP.
Procalcitonin
Procalcitonin is a prohormone that is the precursor of calcitonin; PCT is produced by almost all organs and macrophages, and its levels start to increase at 3–4 h after an inflammatory stimulus, peaking at about 24 h, and with a half-life of 22–35 h. However, PCT levels are influenced by glomerular filtration rate as well as renal replacement therapy.
Prediction of sepsis
PCT is the most studied biomarker in the setting of ventilator-associated pneumonia (VAP). The lack of utility of PCT measurements, either singly or serial, in VAP prediction and diagnosis has been shown. PCT kinetics in critically ill patients showed poor diagnostic accuracy and a low impact regarding guidance for the initiation of therapy.
Diagnosis of sepsis
There is no agreed PCT cutoff value for sepsis diagnosis; published studies have either not reported the cutoff value, or used values ranging from 0.5 to 2 μg/L. While PCT may be superior to CRP in patients with suspicion of septicism, PCT should not be used to guide antimicrobial prescription. In addition, a recent meta-analysis showed that PCT lacks sensitivity early during CAP and cannot reliably distinguish viral from bacterial infections at that point.
Assessment of sepsis response to therapy
In VAP patients, PCT measured at onset and on D4 of treatment could predict survival. Persistent high levels of PCT at D4 were indicative of a failure of infection control. A clinical approach algorithm based on the concept of “alert PCT” (PCT ≥ 1 ng/mL and not decreasing > 10%/day) was evaluated in an RCT showing no mortality benefit at the expense of higher large-spectrum antibiotic consumption, more days on antibiotics, prolonged length of mechanical ventilation and ICU stay.
PCT-guided antibiotic therapy
An increasingly popular approach is to use biomarkers to personalize antibiotic treatment duration. This approach matches the antibiotic discontinuation to the patient’s actual clinical course. Increasing evidence confirms a reduction in overall antibiotic use with PCT. Overall, PCT-guided strategy decreased antibiotic duration by 1 day and improved survival.
C-reactive protein
Serum CRP is an acute-phase protein exclusively synthesized in the liver in response to cytokines, in particular interleukin. Its levels start to increase 4–6 h after an inflammatory stimulus, doubling every 8 h, peaking at 36–50 h, and with a half-life of 19 h. Its level is not influenced by immunosuppression (steroids or neutropenia) nor influenced by renal failure or renal replacement therapy, and does not significantly differ between individuals with or without cirrhosis.
Prediction of sepsis
An increasingly popular approach is to use biomarkers to personalize antibiotic treatment duration. C-reactive protein kinetics in the days before ICU-acquired sepsis accurately predicted its diagnosis with a maximum daily CRP increase > 4.1 mg/dL. A similar finding was observed in a large study of BSI, where CRP concentration start to increase over the three days before a definitive diagnosis.
Diagnosis of sepsis
The variable accuracy of CRP in clinical studies is also impacted by the use of different cutoff points typically ranging between 2 and 10 mg/dL. No biomarker or combination performed better than CRP alone, and better than PCT.
Assessment of sepsis response to therapy
C-reactive protein (CRP) has been extensively studied in the assessment of response to therapy for several severe infections. Relative CRP variations were more informative than absolute CRP changes. A sharp decrease in CRP-ratio is a surrogate marker of sepsis resolution. In severe CAP, VAP and BSI patients with fast and slow response patterns had significantly lower mortality.
CRP-guided antibiotic therapy
CRP-guided strategy presented no substantial differences in the ability to reflect improvement (or worsening) in the clinical course of sepsis and septic shock as well as in reducing antibiotic exposure. Early trials investigating biomarker-guided strategies to guide antibiotic duration had control group patients treated according to standard practices. To overcome these limitations, more recent trials have used shorter, fixed control durations. After some days of therapy, antibiotics could be stopped according to the clinical course and either decreases in biomarker levels (CRP or PCT), according to a predefined algorithm, or the completion of 5–7 days of full days of antibiotic therapy, whichever came first (Fig. 1).
Conclusion
In conclusion, it will take a big shift to move from where we are with sepsis biomarkers now to a position where we have clinically meaningful markers guiding patient treatment pathways to enhance outcomes. Studies with a single core or only one dimension are unlikely to make significant progress. Large multi-center cohort studies using cutting-edge omics, bioinformatics, and machine learning techniques are required to find the biomarkers that indicate how distinct clinical endotypes will respond to therapies. The most efficient strategy to find new biomarkers that may be used in clinical practise to improve patient care is to combine existing technologies in multicenter and multidisciplinary collaborations.
Source: Póvoa, P., Coelho, L., Dal-Pizzol, F. et al. How to use biomarkers of infection or sepsis at the bedside: 9 guide to clinicians. Intensive Care Med (2023). https://doi.org/10.1007/s00134-022-06956-y.
