B·R·A·H·M·S MR-proADM KRYPTOR: Clinical Benefits

Target patient population

Early risk stratification in patients with (suspected) infection or sepsis is essential to provide the best level of care for the patient and improve outcomes. However, assessing early risk and the potential for progression to a more severe disease state can be challenging, especially in patients with atypical symptoms, such as children, geriatric patients, or high-risk patients with co-morbidities as cardiac or oncological conditions.

 

Different clinical scores have been developed to assess disease severity and risk of adverse outcome – typically mortality, including qSOFA, NEWS, NEWS2 CURB-65 in the ED and APACHE, SOFA, SAPS in the ICU. However, the ED risk scores often lack specificity, leading to unnecessary hospitalization and increased hospital workload. ICU scores require laboratory testing and thus may not promptly capture individual organ system dysfunction1, and incorporation into daily routine is hampered by their relative complexity. Furthermore, ICU scores measure the status of all the different organs but not the risk for organ failure progression.

 

An increase in MR-proADM concentration indicates a (pathophysiological) disturbance in the microcirculation and elevation of endothelial permeability independent of infection etiology and may recognize (pending) organ dysfunction early2-3, before the appearance of clinical signs and symptoms, thereby identifying the risk for disease progression and providing an opportunity for early intervention.

Clinical indications of B·R·A·H·M·S MR-proADM Assay

MR-proADM is a diagnostic parameter which can more accurately, compared to standard of care (e.g. risk scores), determine outcome and risk in patients with conditions such as lower respiratory tract infections4-7, urinary tract infections and kidney disease8-10, as well as in patients suffering from sepsis, severe sepsis and septic shock.3,11,12-14 Furthermore, it has been proven that MR-proADM is a very good predictor of outcome in patients with acute15 and chronic heart failure16-17, as well as in patients after myocardial infarction.15,18

 

MR-proADM is especially effective in patients with low to moderate SOFA scores, serving as a strong predictor of outcomes2, identifying the risk of disease progression early, and providing an opportunity for early intervention.

 

MR-proADM results can aid, in conjunction with clinical evaluation and other laboratory findings, in making decisions on level of care3,9,19-20, monitoring treatment response and making prognostic assessments for patients3,21-23 independent of the etiology of infection.24 Serial measurements can be used to monitor and track progression of the disease.3,19,25

Clinical performance characteristics

MR-proADM concentration is low in a healthy population, with a median concentration of 0.38 nmol/L and a 97.5th percentile at 0.55 nmol/L. In patients suspected of having an infection, an elevated MR-proADM concentration, in conjunction with clinical evaluation and other laboratory findings, can assist clinicians in making decisions on hospital discharge (≤0.87 nmol/L), hospital admission (>0.87 nmol/L) or potential need for a higher level of care (>1.50 nmol/L).

 

MR-proADM allows for easier and more accurate risk assessment in patients with sepsis or septic shock compared to standard of care methods (e.g. SOFA). Serial measurements and detection of increasing values of MR-proADM can be used to monitor disease progression and treatment response.3,21-23 At the same time, a decrease in MR-proADM concentration aids in the decision for out-patient management.26

 

For patients with cardiovascular disease, MR-proADM concentrations above 1.5 nmol/L can aid, along with clinical evaluation and other laboratory findings, such as NT-proBNP, troponin, and other routine biomarkers of cardiovascular disease, to assess the risk of early progression to a more severe disease state and to determine the necessity of hospital admission and level of care.27-28

B·R·A·H·M·S MR-proADM Assay use in the ED

Identify low disease severity

An observational study with 1000+ patients across 9 EDs in Europe identified and validated the 0.87 nmol/L MR-proADM cut-off in patients presenting to the ED with signs of infection. Values equal to or below 0.87 nmol/L can accurately identify patients eligible for outpatient treatment and can potentially reduce hospital admission by 15% in this population.20

Remeasure after 24 hours if clinical evaluation and MR-proADM value do not agree.

 

In a subsequent interventional trial in 5 EDs in Spain with 200 patients, the investigators could show that implementation of the algorithm led to a 50% increase in patients discharged (42% in SoC vs. 63% in the interventional group).26

Identify high risk for disease progression and potential need for ICU admission

MR-proADM values higher than 0.87 nmol/L have demonstrated a strong predictive capability in determining the necessity of hospitalization for patients with (suspected) infection. Moreover, patients with concentrations exceeding 1.5 nmol/L are associated with an elevated 28-day mortality rate (LR+ 3.47). In light of these results, a higher level of care should be considered.20

 

Furthermore, when used in addition to NEWS, qSOFA, and CRB-65, MR-proADM can identify patients who are at risk for disease progression, i.e. a complicated infection, which are missed by scores. An observational study was able to show that 89% of patients with a low clinical score, i.e. NEWS below 4, underwent an uncomplicated infection and 11% progressed to a more severe disease state of which 23% died within 28 days. Addition of MR-proADM to the risk assessment would have identified all of these patients at hospital admission.20

Covid-19 - accurate prediction of disease progression from ED presentation

The assessment of disease severity and progression became a critical focus during the COVID-19 pandemic given the scarcity of hospital resources. Numerous observational studies conducted in both ED and ICU have highlighted the benefits of MR-proADM in assessing the risk of early progression to a more severe disease state and in supporting decisions regarding the appropriate level of care.29-31 Of the biomarkers independently associated with outcome, MR-proADM had the highest hazard ratio for disease progression (6.8) and 28-day mortality (10.5), compared to D-dimer, IL-6 and Ferritin.32 When applying the low disease severity cut-off at hospital admission, the negative predictive value of MR-proADM was more than 97% for predicting in-hospital mortality.32

 

These studies demonstrate the value of MR-proADM in viral infections, a benefit that has been previously described in cases of community-acquired pneumonia.24,33

B·R·A·H·M·S MR-proADM Assay use in the ICU

Sepsis has a reported hospital mortality in the ICU of 26% according to the Sepsis-3 guidelines.34 Prompt assessment of infectious load and disease severity in the early stages of sepsis is crucial for improving outcomes. Furthermore, rapid treatment with antibiotics is central, as a delay progressively increases mortality.35 Assessment of organ failure, integral to the Sepsis-3 definition, provides a measure for disease severity. Clinical scores such as SOFA, APACHE II, and SAPS II have been developed for this purpose36; however, their incorporation into daily routine is often hindered by their relative complexity. Although lactate measurement for poor perfusion is readily available, it is often too unspecific and late to be effective.

 

MR-proADM utility in assessing ICU patients with sepsis and septic shock was shown by Elke et al. in 2018.3 MR-proADM had the strongest association with 28-day mortality across the patient population and could facilitate a more accurate classification of low and high disease severity. Especially in patients with low to moderate SOFA scores, MR-proADM is a good predictor of outcomes2, identifying the risk for disease progression early and providing the opportunity for early intervention, for example for renal replacement therapy, to prevent adverse outcomes. Failure to decrease the concentration of MR-proADM in the bloodstream despite appropriate antimicrobial therapy may indicate a risk of treatment failure and may require alternative diagnosis and possible therapeutic interventions, whereas decreasing concentrations may support decisions to decrease the level of care.3 

Economical benefits of B·R·A·H·M·S MR-proADM Assay

Healthcare professionals face numerous challenges in the current healthcare system, including overcrowded EDs, staff shortages, and limited hospital bed availability.37-39 These challenges necessitate an efficient decision-making process to effectively manage patient care and mitigate the risk of adverse outcomes.

 

One reason for ED overcrowding is the influx of patients with minor complaints that could be treated as outpatients, further straining ED resources.40-41

 

Notably, infections of the respiratory tract, urinary tract, intra-abdominal region, as well as skin and soft tissue infections are among the leading causes of ED admissions.42-45 For these patients, it is crucial to assess the severity of their condition and the likelihood of disease progression. This assessment is essential in determining the appropriate therapy measures to prevent the disease from advancing to more severe stages. If these infections are poorly managed, they can potentially lead to life-threatening conditions, with sepsis being the most common.20

 

Given these circumstances, there is a clear public need for improving the diagnostic and prognostic approach to infections in the ED. This improvement would aid in making safe discharge decisions and enable the early detection of potentially at-risk patients.

 

In 2023, a health economic analysis was conducted using primary data from a single hospital in Spain. The study incorporated data from 473 patients to develop a model simulating 10,000 patients. These results demonstrated that MR-proADM-aided triage resulted in an admission of 41%, compared to 63.5% with standard care, leading to an approximate 30% cost reduction.46 

Dual B·R·A·H·M·S marker: MR-proADM and PCT

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) specified Sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection.1,47

 

While B·R·A·H·M·S PCT measurements can identify and confirm a clinically suspected bacterial infection thereby guiding the initiation and duration of antibiotic treatment, B·R·A·H·M·S MR-proADM measurements provide early identification of disease severity and progression by monitoring the development of organ dysfunction. Consequently, these measurements can support informed decisions regarding early organ support, appropriate level of care, and the determination of safe and reliable in-patient and out-patient treatment options. 

The combined used of PCT and MR-proADM was part of the LIFE-POC study including more than 1,400 patients presenting with suspected organ dysfunction based on a qSOFA score greater than or equal to 1 to three large tertiary care EDs in Germany. Among those patients, 29% developed sepsis. While PCT outperformed other markers for the prediction of sepsis within 96 hours, MR-proADM showed prognostic value for in-hospital mortality. The combined use of PCT and MR-proADM predicted septic shock within 96 hours best.48
Using PCT to aid in diagnosis and MR-proADM for prognosis has also been described previously for sepsis and septic shock.49-50

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  2. Elke G, Bloos F, Wilson DC, Meybohm P, SepNet Critical Care Trials G. Identification of developing multiple organ failure in sepsis patients with low or moderate SOFA scores. Crit Care. 2018;22(1):147.
  3. Elke G, Bloos F, Wilson DC, Brunkhorst FM, Briegel J, Reinhart K, et al. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial. Crit Care. 2018;22(1):79.
  4. Kruger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T, et al. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: Results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med. 2010;182(11):1426-34.
  5. Renaud B, Schuetz P, Claessens YE, Labarere J, Albrich W, Mueller B. Proadrenomedullin improves Risk of Early Admission to ICU score for predicting early severe community-acquired pneumonia. Chest. 2012;142(6):1447-54.
  6. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care. 2010;14(3):R106.
  7. Gordo-Remartinez S, Calderon-Moreno M, Fernandez-Herranz J, Castuera-Gil A, Gallego-Alonso-Colmenares M, Puertas-Lopez C, et al. Usefulness of midregional proadrenomedullin to predict poor outcome in patients with community acquired pneumonia. PloS one. 2015;10(6):e0125212.
  8. Gouya G, Sturm G, Lamina C, Zitt E, Freistatter O, Struck J, et al. The association of mid-regional pro-adrenomedullin and mid-regional pro-atrial natriuretic peptide with mortality in an incident dialysis cohort. PloS one. 2011;6(3):e17803.
  9. Litke A, Bossart R, Regez K, Schild U, Guglielmetti M, Conca A, et al. The potential impact of biomarker-guided triage decisions for patients with urinary tract infections. Infection. 2013;41(4):799-809.
  10. Stalenhoef JE, van Nieuwkoop C, Wilson DC, van der Starre WE, Delfos NM, Leyten EMS, et al. Biomarker guided triage can reduce hospitalization rate in community acquired febrile urinary tract infection. J Infect. 2018;77(1):18-24.
  11. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2005;9(6):R816-24.
  12. Guignant C, Voirin N, Venet F, Poitevin F, Malcus C, Bohe J, et al. Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients. Intensive care medicine. 2009;35(11):1859-67.
  13. Hagag AA, Elmahdy HS, Ezzat AA. Prognostic value of plasma pro-adrenomedullin and antithrombin levels in neonatal sepsis. Indian pediatrics. 2011;48(6):471-3.
  14. Li Q, Wang BS, Yang L, Peng C, Ma LB, Chai C. Assessment of adrenomedullin and proadrenomedullin as predictors of mortality in septic patients: A systematic review and meta-analysis. Med Intensiva. 2018;42(7):416-24.
  15. Klip IT, Voors AA, Anker SD, Hillege HL, Struck J, Squire I, et al. Prognostic value of mid-regional pro-adrenomedullin in patients with heart failure after an acute myocardial infarction. Heart (British Cardiac Society). 2011;97(11):892-8.
  16. Adlbrecht C, Hulsmann M, Strunk G, Berger R, Mortl D, Struck J, et al. Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients. Eur J Heart Fail. 2009;11(4):361-6.
  17. Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, et al. The predictive value of stable precursor fragments of vasoactive peptides in patients with chronic heart failure: data from the GISSI-heart failure (GISSI-HF) trial. Eur J Heart Fail. 2010;12(4):338-47.
  18. O'Donoghue ML, Morrow DA, Cannon CP, Jarolim P, Desai NR, Sherwood MW, et al. Multimarker Risk Stratification in Patients With Acute Myocardial Infarction. Journal of the American Heart Association. 2016;5(5).
  19. Mockel M, Koehler K, Anker SD, Vollert J, Moeller V, Koehler M, et al. Biomarker Guidance allows a more personalized allocation of patients for Remote Patient Management in Heart Failure Results from the TIM-HF2 Trial. Eur J Heart Fail. 2019.
  20. Saeed K, Wilson DC, Bloos F, Schuetz P, van der Does Y, Melander O, et al. The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study. Crit Care. 2019;23(1):40.
  21. Valenzuela-Sanchez F, Valenzuela-Mendez B, Rodriguez-Gutierrez JF, Estella-Garcia A, Gonzalez-Garcia MA. New role of biomarkers: mid-regional pro-adrenomedullin, the biomarker of organ failure. Annals of translational medicine. 2016;4(17):329.
  22. Pereira JM, Azevedo A, Basilio C, Sousa-Dias C, Mergulhao P, Paiva JA. Mid-regional proadrenomedullin: An early marker of response in critically ill patients with severe community-acquired pneumonia? Rev Port Pneumol (2006). 2016;22(6):308-14.
  23. Gregoriano C, Koch D, Kutz A, Haubitz S, Conen A, Bernasconi L, et al. The vasoactive peptide MR-pro-adrenomedullin in COVID-19 patients: an observational study. Clin Chem Lab Med. 2021.
  24. Bello S, Lasierra AB, Minchole E, Fandos S, Ruiz MA, Vera E, et al. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J. 2012;39(5):1144-55.
  25. Maisel A, Mueller C, Nowak R, Peacock WF, Landsberg JW, Ponikowski P, et al. Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. Journal of the American College of Cardiology. 2010;55(19):2062-76.
  26. Gonzalez Del Castillo J, Clemente-Callejo C, Llopis F, Irimia A, Oltra-Hostalet F, Rechner C, et al. Midregional proadrenomedullin safely reduces hospitalization in a low severity cohort with infections in the ED: a randomized controlled multi-centre interventional pilot study. European journal of internal medicine. 2021;88:104-13.
  27. Nishikimi T, Nakagawa Y. Adrenomedullin as a Biomarker of Heart Failure. Heart Failure Clinics. 2018;14(1):49-55.
  28. Spoto S, Argemi J, Di Costanzo R, Gavira Gomez JJ, Salterain Gonzales N, Basili S, et al. Mid-Regional Pro-Adrenomedullin and N-Terminal Pro-B-Type Natriuretic Peptide Measurement: A Multimarker Approach to Diagnosis and Prognosis in Acute Heart Failure. Journal of personalized medicine. 2023;13(7).
  29. Montrucchio G, Balzani E, Lombardo D, Giaccone A, Vaninetti A, D'Antonio G, et al. Proadrenomedullin in the Management of COVID-19 Critically Ill Patients in Intensive Care Unit: A Systematic Review and Meta-Analysis of Evidence and Uncertainties in Existing Literature. J Clin Med. 2022;11(15).
  30. Fialek B, De Roquetaillade C, Pruc M, Navolokina A, Chirico F, Ladny JR, et al. Systematic review with meta-analysis of mid-regional pro-adrenomedullin (MR-proadm) as a prognostic marker in Covid-19-hospitalized patients. Annals of medicine. 2023;55(1):379-87.
  31. Wang N, Liu L, He W, Shang N, Li J, Qin Z, et al. Circulating mid-regional proadrenomedullin is a predictor of mortality in patients with COVID-19: a systematic review and meta-analysis. BMC infectious diseases. 2023;23(1):305.
  32. Garcia de Guadiana-Romualdo L, Calvo Nieves MD, Rodriguez Mulero MD, Calcerrada Alises I, Hernandez Olivo M, Trapiello Fernandez W, et al. MR-proADM as marker of endotheliitis predicts COVID-19 severity. European journal of clinical investigation. 2021:e13511.
  33. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care. 2006;10(3):R96.
  34. Fleischmann C, Thomas-Rueddel DO, Hartmann M, Hartog CS, Welte T, Heublein S, et al. Hospital Incidence and Mortality Rates of Sepsis. Dtsch Arztebl Int. 2016;113(10):159-66.
  35. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine. 2006;34(6):1589-96.
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  37. Pines JM, Hilton JA, Weber EJ, Alkemade AJ, Al Shabanah H, Anderson PD, et al. International perspectives on emergency department crowding. Acad Emerg Med. 2011;18(12):1358-70.
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  45. Kamath RS, Sudhakar D, Gardner JG, Hemmige V, Safar H, Musher DM. Guidelines vs Actual Management of Skin and Soft Tissue Infections in the Emergency Department. Open Forum Infect Dis. 2018;5(1):ofx188.
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