The Daily Sign-Out

Video discussing red cell storage lesion

As a follow-up to my post on the red cell storage lesion from a couple days ago, Transfusion News has posted a video interview with Dr. Zimring, the author of the recent article in Blood that I referenced.

Reassessment of the red cell storage lesion

James C. Zimring has published a wonderful perspectives article in the April 2, 2015 issue of Blood (abstract) that nicely summarizes what is known about the red cell storage lesion from clinical and experimental studies.  However, recent RCTs (ARIPI abstract, RECESS abstract, and ABLE presentation) have failed to show in clinically significant difference between groups receiving fresher versus older blood.  So why should we bother about the red cell storage lesion when there doesn't appear to be any clinically relevant differences in outcome whether a patient is transfused with "older" blood?

 Dr. Zimring's article answers this by framing the question in terms of precisely what is known about the storage lesion, but more importantly, what is not known.  There is myriad studies describing various aspects of the storage lesion but there hasn't been that "unified theory" that really condenses all that has been described about the storage lesion into a discrete "lesion." Perhaps there isn't one.  But the author concisely outlines the limitations of clinical studies, biological studies of RBCs, and animal models of the storage lesion to build the argument that the broad question, "Is older blood bad for you?," seeks an answer that would be an oversimplification and is neither testable nor applicable.  What is needed, Dr. Zimring concludes, are more focused questions.

There are many important insights and informed in this article and I highly recommend it!

New International Society of Blood Transfusion Website

The International Society of Blood Transfusion (ISBT) recently highlighted its new website, which is more user-friendly and has links to other useful content, including their LinkedIn page and recent presentations.  You can also register for their "My ISBT" that provides additional content.

RBC Transfusion Associated with Increased Susceptibility to Lung Inflammation

Another recent article that I finally had a chance to read and ruminate on: Danielle Qing and colleagues from have published an intriguing article in the December 1, 2014 issue of the American Journal of Critical Care and Respiratory Medicine, "Red Blood Cells Induce Necroptosis of Lung Endothelial Cells and Increase Susceptibility to Lung Inflammation."  The article merits a read if you're interested in either transfusion medicine or lung pathology.

In both in vitro and murine models, RBC transfusion seems to prime lung inflammation through necroptosis (link to recent review article) of lung endothelial cells, followed by danger signal release of disease-associated molecular patterns, or DAMPs.  A novel finding in this study is that necroptosis may be an important mechanism that for cellular damage and organ dysfunction that is clinically observed associated with RBC transfusion. The methodology of using human lung microvascular endothelial cells and human RBCs stored under clinical conditions makes this model of injury more potentially relevant at the clinical level since it likely is a better approximation of what is occurring in vivo.

However, these findings quite jibe with the results of the TRISS trial published in NEJM last October.  One might expect that patients with sepsis who receive more RBC transfusions would have worse clinical outcomes than those who receive none or fewer transfusions.  But in this study similar clinical outcomes (mortality at 90 days and rates of ischemic events and use of life support) were observed in ICU patients with severe sepsis between those who received RBC transfusion at liberal transfusion threshold versus a restrictive threshold, even though the latter group received more transfusions.  It would be great to have a RCT that compared no to any RBC transfusions in this study population, measure necroptosis and DAMPs, and observe clinical outcomes.

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.

Effectiveness of crossmatched or HLA-platelets vs. random platelets for refractory patients

Rioux-Massé et al from University of Minnesota Medical Center report in the December 2014 issue of Transfusion (abstract) a retrospective study of 32 patients who had laboratory confirmation of immune-mediated PLT refractoriness, and received platelet transfusion with crossmatched or HLA-matched PLTs.  

Immune-mediated refractoriness was called "positive" when a PLT crossmatch was incompatible with at least 1 unit or an HLA antibody screen detected HLA Class I antibody against any number of antigens in a single-well test system.  The HLA antibody avoidance technique was not used by the blood supplier, ARC Mid-America Blood Services Division.  Finally, PLTs were either ABO-identical or -compatible.

Out of 354 total PLT transfusions, 45% were random-donor apheresis PLTs, 42% were crossmatched PLTs, and 13% were HLA-matched.  Using a CCI of 5.0 X 109/L as defining a satisfactory response to PLT transfusion, the rates of satisfactory responses for random-donor units was 13%, for crossmatched PLTs 25%, and HLA-matched PLTs 29%.  There was no statistically significant differences in the frequency of satisfactory transfusion between the different PLT products, although this study was probably not adequately powered to detect any true differences.  One of the interesting, albeit frustrating, things about this study is how miserably crossmatched PLT and HLA-matched platelets performed overall.

The authors did not correlate the panel-reactive antigen (PRA) with the crossmatch assay, since they only used a screening test for HLA antibodies.  This is somewhat odd to me, since we use at Rush University Medical Center a Luminex screening assay for PRA and reflex to a more comprehensive test if the PRA is over 40%; I and the heme/onc clinicians are looking for the PRA to determine whether or not to pursue HLA-matching.  

Another interesting thing is that patients in this study were tested for platelet-specific antibodies but this was not used to define immune-mediated PLT refractoriness nor administer HPA-negative PLT units, and, further, did not correlate with refractoriness.  (Why were the patients tested for HPA antibodies anyway, then?)

The limitations of this study are that it is a small study and was not a randomized trial between random, crossmatched, and HLA-matched PLTs.  However, this study adds to literature suggesting that clinicians should not expect any dramatic PLT increments from either crossmatched or HLA-matched PLT transfusions once refractoriness has been established.  We really need a randomized controlled trial to definitely determine the best approach to PLT transfusion in this difficult to manage group of patients.  Currently, much time and many resources are consumed chasing after HLA-matched PLTs, which generally do not appear to provide any more clinical benefit than random apheresis PLTs.  

 

DNA Methylation and Gene Expression in Idiopathic Pulmonary Fibrosis

In case you may have missed this one, Ivana Yang and colleagues from the University of Colorado have published a fascinating article in the December 1, 2014 issue of American Journal of Respiratory and Critical Care Medicine, "Relationship of DNA Methylation and Gene Expression in Idiopathic Pulmonary Fibrosis," that explores possible epigenetic mechanisms through DNA methylation that may be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF).

Many of these studies are being done in various cancers, but this one suggests one or more programs that unfold with IPF.

 

Lung Cancer Screening--from the International Association for the Study of Lung Cancer

November is Lung Cancer Awarenesss Month and IASLC has issued some valuable talking points that could be useful for lung cancer screening with patients, colleagues, and the general public.

 

1. Lung Cancer is the #1 cancer killer in the world, killing more people than breast, colorectal and prostate cancers combined. 
2. Recent advances in Lung Cancer Screening and Early Detection are providing hope for patients and their families that has never before existed in the field of lung cancer. 
3. The potential for saving lives through lung cancer low-dose computed tomography (LDCT) screening will dramatically change the disease statistics in the coming years. 
4. Most patients (~60%) are diagnosed after the disease has spread. The 5-year survival rate for patients with advanced disease is only around 4%. However, if detected early, the 5-year survival rate is much higher (55%-75%) with many of these being cured.
5. The National Lung Cancer Screening Trial (NLST) showed that a baseline LDCT screen followed by two annual screens, in contrast to standard lung x-rays, reduced lung cancer mortality by 20% and overall mortality by 7% over a 6 year follow-up period in individuals at high-risk for developing lung cancer.
6. Based on the NLST trial, the US Preventive Services Task Force (USPSTF) and many professional societies have recommended annual LDCT screening for individuals at high risk. 
7. There are a number of ongoing trials evaluating value of LDCT screening for reducing lung cancer mortality in high risk subjects. These include the Dutch Belgian randomized lung cancer screening trial (NELSON) and the United Kingdom Lung Cancer Screening (UKLS) trial. 
8. The IASLC acknowledges that for implementation of LDCT screening worldwide each national health service has the opportunity to decide its own course of action regarding the usefulness of CT screening based on their interpretation of the existing data from lung cancer screening trials. The implementation of any screening program should incorporate a multidisciplinary group of experts and the best practice for excellence in screening care. 
9. In the US many private health insurance companies cover screening now and starting in January 2015 all will, under provisions of the Affordable Care Act. A decision was be made November 10th, by CMS in a draft proposal to cover low-dose CT screenings for high risk individuals. 
10.  Currently, advances are being made in identifying high risk individuals with computer models using patient characteristics. Furthermore computer models are evaluating the nodule characteristics on the CT images to better define cancer potential. Likewise a range of biomarkers are being evaluated in conjunction with or independent of LDCT screening in order to detect cancer early.

Please re-post and share!

Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies

http://clincancerres.aacrjournals.org/content/20/20/5322.abstract?etoc

Sent from my iPad

Novel cutaneous and pulmonary syndrome associated with mutations in STING

Fascinating article describing a vasculopathic cutaneous and pulmonary syndrome associated with autosomal dominant mutations in TMEM173, the gene encoding stimulator of interferon genes (STING).  An incredible body of work presented with numerous clinical pictures and photomicrographs in the supplementary appendix that nicely illustrate the pathologic changes.  This work sheds light on an important inflammatory pathway through the description of this "experiment of nature."

Liu Y, Jesus AA, Marrero B, et al. Activated STING in a Vascular and Pulmonary Syndrome. New England Journal of Medicine published online July 16, 2014.

Abstract

Studies involving children with monogenic autoinflammatory disease have provided insights into the regulation of key proinflammatory cytokine pathways and their role in causing systemic and organ-specific inflammation.1,2 We studied six patients who presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks, and ears that progressed to acral necrosis in most of the patients and did not respond to therapy. A mixed histologic pattern was observed, consisting of a prominent dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels. Three of the patients had severe interstitial lung disease.

Although many of the genetically defined autoinflammatory diseases are associated with increased interleukin-1 signaling and have a clinical response to interleukin-1 inhibition,2 interleukin-1–inhibiting therapy was ineffective in one of the patients. A prominent interferon-response-gene signature in the peripheral blood of this participant suggested interferon dysregulation similar to that seen in other genetically defined inflammatory syndromes, including the Aicardi–Goutières syndrome,3,4 an early-onset inflammatory encephalopathy, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE),5,6 a proteasome-associated autoinflammatory syndrome with proposed interferon-mediated pathologic features.7,8 We detected autosomal dominant mutations in TMEM173, the gene encoding the stimulator of interferon genes (STING), in the six children we assessed, who presented with a clinical syndrome we have called STING-associated vasculopathy with onset in infancy (SAVI).