November 1st, 2022
On September 21st during the Clinical Chemistry congress on Jönköping, Sweden, Dr. Francois Ventura, Intensive Care Physician and Chief Medical Officer gave an academic lecture addressing the disease burden of sepsis and antimicrobial resistance (AMR), and the place of biomarkers in the management of sepsis and how they could help improve the management of sepsis and overcome the challenges related to the management of nosocomial infection, sepsis and AMR.
Sepsis affects nearly 50 million patients and is responsible for 11 million deaths every year worldwide. It is the 2nd leading cause of death worldwide and the 1st cause of hospital deaths in children.
An editorial published this year in the Lancet reported nearly 5 million deaths associated with drug-resistant bacterial infections and 1.27 million attributable to AMR. Causes of antimicrobial resistances are mostly due to unnecessary use of antibiotics and broad-spectrum antibiotics.
The solution to reduce the current 11 million deaths due to sepsis is “to give timely and adequate antibiotics, but the way to reduce the projected future 10 million deaths due to AMR is to not give unnecessary antibiotics”. Thus, this raises an important question: “To give or not to give antibiotics?”.
What do the guidelines say? The latest Surviving Sepsis Campaign recommend against using biomarkers and clinical evaluation to start antibiotics in cases of clinical suspicion of sepsis, compared to clinical evaluation only. But what about a biomarker for the pre-symptomatic diagnosis of nosocomial sepsis, meaning it would be able to give the alert before there is a clinical suspicion?
Pancreatic Stone Protein (PSP) has been shown to be the best biomarker for the detection of early sepsis. PSP is 16 kDa C-type lectin protein mostly secreted by the pancreas. Numerous clinical studies on PSP have been published already, including a recently published systematic-review and meta-analysis (Prazak et al., 2021) and literature review of 23 prospective studies (Fidalgo et al., 2022). PSP has shown promising results in the detection of early sepsis in high-risk ICU patients. In particular, conclusions of the European multicentric study (Pugin et al., 2021) mentioned that “Serial measurements of biomarker revealed that PSP blood levels increased incrementally 3 days before the clinical diagnosis of nosocomial sepsis before the appearance of signs and symptoms and positioning the concept of serial measurements of PSP as a promising approach to help physicians identifying sepsis earlier”. Based on an estimate, daily PSP testing to each patient every day in Switzerland for pre-symptomatic diagnosis of sepsis could help save around CHF 350-500 million on the Swiss public healthcare system per year.
Currently there are no clear criteria or guidelines to NOT start antibiotics. As a result, antibiotic therapy is often prescribed, as there are fewer risks on morbidity and mortality (e.g. drug adverse events, allergies…) on an individual level compared to those of an untreated sepsis.
Dr. Ventura highlighted “before the rise of AMR, it was easier and safer to give antibiotics than not to give them. Now, we need a tool to rule-out infection sepsis in less than an hour!”. To fulfill this need, we need to find a biomarker (or combination of biomarkers) with a high negative predictive value (NPV) and thus presents the lowest risk of giving a false-negative. Throughout the cited studies in the presentation, PSP has shown a very good NPV of around 90%, making it a good candidate as biomarker to help in the decision to not start antibiotics. A recent health economic study (Schneider et al., 2022) found that routine measurement of PSP in ICU and ED patients with suspected sepsis could help save 7 billion USD/year in the USA.
What about the criteria to STOP antibiotics? The SSC recommend discontinuing antibiotics as soon as possible based on clinical evaluation and the use of biomarkers (such as procalcitonin). A study assessing whether PSP could be a good biomarker for the discontinuation of antibiotic therapy in the management of sepsis in the ICU is currently on-going.
In summary, pre-sepsis daily assessment with routine PSP testing for the pre-symptomatic diagnosis of sepsis could not only prevent the unnecessary administration of prophylactic antibiotics in hospitalized patients, but also significantly reduce healthcare costs. The combination of PSP/CRP could also help in the decision of not starting antibiotics in suspected sepsis. Finally clinical evaluation and the use of biomarkers could help de-escalate antibiotherapy, as part of the post-sepsis daily assessment.
Caroline Cateau, Medical Affairs Manager, Abionic SA
- Fidalgo, P., Nora, D., Coelho, L., & Povoa, P. (2022). Pancreatic Stone Protein: Review of a New Biomarker in Sepsis. Journal of Clinical Medicine, 11(4), Article 4. https://doi.org/10.3390/jcm11041085
- Prazak, J., Irincheeva, I., Llewelyn, M. J., Stolz, D., García de Guadiana Romualdo, L., Graf, R., Reding, T., Klein, H. J., Eggimann, P., & Que, Y.-A. (2021). Accuracy of pancreatic stone protein for the diagnosis of infection in hospitalized adults: A systematic review and individual patient level meta-analysis. Critical Care, 25(1), 182. https://doi.org/10.1186/s13054-021-03609-2
- Pugin, J., Daix, T., Pagani, J.-L., Morri, D., Giacomucci, A., Dequin, P.-F., Guitton, C., Que, Y.-A., Zani, G., Brealey, D., Lepape, A., Creagh-Brown, B., Wyncoll, D., Silengo, D., Irincheeva, I., Girard, L., Rebeaud, F., Maerki, I., Eggimann, P., & François, B. (2021). Serial measurement of pancreatic stone protein for the early detection of sepsis in intensive care unit patients: A prospective multicentric study. Critical Care, 25(1), 151. https://doi.org/10.1186/s13054-021-03576-8
- Schneider, J. E., Dick, K., Cooper, J. T., & Chami, N. (2022). Pancreatic stone protein point-of-care testing can reduce healthcare expenditure in sepsis. Health Economics Review, 12(1), 39. https://doi.org/10.1186/s13561-022-00381-z