The Daily Sign-Out

Procalcitonin in Critically Ill Patients: ProGUARD study results

We recently implemented a procalcitonin assay in my lab in the evaluation of patients with clinically suspected sepsis with undifferentiated infections.  How timely then that lead author Yahya Shehabi and members of the ProGUARD study group of the Australian and New Zealand Intensive Care Society (ANZICS) published quite interesting findings from a randomized prospective single-blind study of the use of procalcitonin to guide antibiotic decisions in ICU patients.  This article was published in the November 15, 2014 issue of the American Journal of Respiratory and Critical Care Medicine.

One of the challenges in bringing this test online is determining an appropriate cut-off value for "rule-out." The authors report their results using an algorithm with a low cut-off but show that it did not achieve the desired endpoint of reducing antibiotic duration.  The study did show, however, that the decline rate in log(PCT) over the first 72 hours independently predicted hospital and 90-day mortality.

In a personal communication with the lead author, Dr. Shehabi confirmed that this lower cut-off was used across different commercially available test methods (including the one we are using) that were used at the different participating centers.

If you are using or plan to implement procalcitonin in your facility, I highly suggest you review this paper.

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.

Implications of clonality in multifocal non small cell lung cancer

About 5% to 8% of NSCLC patients present with 2 or more anatomically separate lung tumors at diagnosis. The distinction between synchronous primary tumors and intrapulmonary metastases has important implications for staging and, thus, treatment strategies.

Arne Warth and colleagues from University Hospital Heidelberg published a single institution study in the June 1, 2012 European Respiratory Journal (abstract) analyzing the clonal relationship between multifocal NSCLC with indistinguishable morphology in a series of 78 patients.  Their analysis included LOH analysis of 14 polymorphic microsatellite markers and EGFR and KRAS mutation screening using single-strand conformation polymorphism, followed by direct sequencing of abnormally migrating bands. 

This study included 58 adenocarcinomas and 20 squamous cell carcinomas; 59 pT3, 18 pT4, and 1 pM1a. 97.4% of all specimens could be classified as clonal, likely clonal, or non-clonal; only 2 cases were non-informative.

Some results--

1. Tumor nodules of 22 patients (28%) showed divergent LOH status--indicating non-clonal origin. This is a surprising finding--remember this study only included multifocal tumors with indistinguishable morphology.
2. Activating EGFR mutations were found in both synchronous tumors in 4/58 ADC but none of the SQC.
3. KRAS mutations were found in 20 patients (17 ADC, 3 SQC) but in 6 patients the mutation was identified in only 1 of the tumors and in 1 patient there were divergent EGFR and KRAS mutations.
4. With combined allelotyping of LOH and mutational status of EGFR and KRAS, about 36% of cases (28/78 cases) showed evidence that they were not clonally related, including:
5.  14/18 ADC and 6/10 SQC located in the same lobe.
6. Kaplan-Meier curves illustrating the impact of clonality of multifocal NSCLC on overall survival did not identify a statistically significant difference but did show a tantalizing trend that patients with 2 clonally unrelated tumors have a better OS; notably, this difference did reach statistical significance by univariate analysis.

Practical "take-home" points.

There is no specific anatomical or morphological criteria that reliably indicate a clonal or nonclonal origin of multifocal NSCLC tumors. The authors reasonably recommend performing predictive molecular testing (EGFR and KRAS mutational analysis) or allelotyping separately in all cases with synchronous tumors to identify clonally related tumors. This study presents some intriguing data regarding the prognostic value of identifying nonclonalty, but the prognostic impact of clonality needs to be further analyzed in larger cohorts of NSCLC patients with multifocal synchronous tumors.

Exosomes as Possible Biomarker for Tuberculosis

I have previously posted on exosomes in the context of cancer.  Here is a very interesting and brief video from Dr. Jeffrey Schorey regarding exosomes in the pathogenesis of tuberculosis and their possible use as a biomarker for infection.  It's only 5 minutes--go ahead and enjoy!

Biomarkers in COPD

Chronic obstructive lung disease (COPD) is defined functionally as airflow limitation that is not fully reversible.  It is a MAJOR cause of morbidity and mortality in the U.S. and worldwide.  COPD has two distinct major, but often coexisting, forms that represent different manifestations of COPD: emphysema and chronic bronchitis.  Emphysema can be defined morphologically, either by radiography or pathology, while chronic bronchitis is defined clinically based upon the duration of productive cough and exclusion of other causes.  Treatment is focused on preventing progression of disease and the development of acute exacerbations, which are a major cause of hospitalizations, morbidity and mortality.  Common to both major forms is small airways inflammation and an abnormal inflammatory response either in large airways (chronic bronchitis) or in alveoli (emphysema).

COPD is also associated with low-grade systemic inflammation and biomarkers that could predict increased risk for mortality from progressive disease or acute exacerbations might be greatly beneficial in providing more intesive surveillance and treatment of this group.  A team of researchers led by Tufts University School of Medicine screened blood samples from people in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) to see if inflammatory biomarkers could predict disease outcome (abstract).  The study included 1843 patients who were followed for 3 years.  168 of the 1843 patients (9.1%) died.  Serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reative protein, Clara cell secretory protein-16, interleukin-6, IL-8, and tumor necrosis factor-alpha were measured at recruitment and at subsequent visits.

The addtion of a panel of biomarkers significantly improved predictive power and was able to better predict outcomes compared with current clinical variables, including age, BODE index, and hospitalization history. The addition of IL-6 provided the most improvement of discriminatory power, but this was improved further with the addition of all biomarkers measured.