Proadrenomedullin in prognosis of community-acquired pneumonia

Community-acquired pneumonia is still a major healthcare problem and is under intense scrutiny as an "opportunity" to measure hospital performance (and thus determine reimbursement). With the advent of the modern antibiotic era, there has been an ongoing search for a way to assess which patients with CAP need more intensive therapy because of a greater likelihood to experience complications or death. The Pneumonia Severity Index (PSI) and CRB-65 score are established clinical scoring systems to determine mortality risk from CAP. Unfortunately, the biomarker ash heap of history is filled with biomarkers for prognosis in CAP.

I came across a fascinating article by BELLO et al. of the Hospital Universitario Miguel Servet from the May 2012 European Respiratory Journal (abstract) that adds to several previous studies on the prognostic value of proadrenomedullin (pro-ADM) in CAP.  There are now 5 studies showing that proADM improves the prognostic value of established risk scores in CAP. This follows an intriguing line of investigation moving away from the pursuit of inflammatory markers that focus on microbiological etiology toward markers that are associated with the severity of CAP and complications regardless of etiology.

 Adrenomedullin (ADM) is a member of the calcitonin peptide family. ADM is synthesized and secreted by a wide variety of cell types and synthesis is accelerated during severe infections. It exerts multiple effects including, antimicrobial activity, immune modulation by potentiating the effects of TNF-alpha, and hypotensive and vasodilatory effects. Pro-ADM is the precursor of ADM and gives rise to several biologically active products. Midregional-pro-ADM is more stable than full-length pro-ADM (and thus easier to measure) and directly reflects plasma levels of ADM.

This is a prospective cohort study of 228 immunocompetent patients with CAP. The authors measured PSI and CRB-65 scores, blood C-reactive protein, procalcitonin, and midregional (MR)-pro-ADM and performed microbiological cultures on all patients. Patients were grouped into bacterial, viral/atypical, and mixed CAP subtypes. The patients were followed at 30, 60, and 180 days and at 1 year.

RESULTS

1. Admission levels of MR-pro-ADM increased significantly with increasing severity of CAP according to both PSI and CRB-65 scores. Moreover, MR-pro-ADM was the only biomarker able to distinguish amongst all different PSI scores and was also the best biomarker for distinguishing between low-risk CAP (PSI risk classes I-III) and high-risk CAP (PSI IV-V).
2. Using an optimized cut-off of 0.646 ng/L, the sensitivity was 92%, specificity was 55%, positive predictive value was 76% and negative predictive value was 80%.
3. Multivariate analysis identified only CURB-65 and MR-proADM as predictors of complications.
4. MR-proADM was the only biomarker able to discriminate between patients who died at 30, 90 and 180 days, and 1 yr (p,0.0001).
5. No association between MR-pro-ADM and etiology was found.

There are two important conclusions from this study:

1. MR-pro-ADM is the best biomarker to predict short-term outcome in hospitalised CAP, regardless of its etiology.
2. MR-pro-ADM can also be used to monitor the long-term follow-up of CAP patients discharged from hospital. 

One caveat to this study (acknowledged by the authors) is that it is a single institution study. But this study and the four others previously reported justify serious consideration of a large multicenter prospective study to validate the prognostic value of pro-ADM in CAP.